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Bhardwaj JK, Siwach A, Sachdeva SN. Nicotine as a female reproductive toxicant-A review. J Appl Toxicol 2025; 45:534-550. [PMID: 39323358 DOI: 10.1002/jat.4702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 08/28/2024] [Accepted: 09/11/2024] [Indexed: 09/27/2024]
Abstract
The preceding decades have seen an extensive emergence of the harmful effects of tobacco smoke on systemic health. Among the various compounds of tobacco, nicotine is one of the principal, potentially hazardous, and toxic components which is an oxidant agent that can affect both men's and women's fertility. Nicotine exerts its effect by modulating the expression of transmembrane ligand-gated ion channels called nicotinic acetylcholine receptors. The activities of female reproduction might be disrupted by exposure to nicotine at various sites, such as the ovary or reproductive tract. It's been demonstrated that nicotine might cause oxidative stress, apoptosis, hormonal imbalance, abnormalities in chromosomal segregation, impact oocyte development, and disruption in ovarian morphology and functions. This review paper summarizes the findings and provides an updated overview of the evidence on the harmful effects of nicotine use on women's reproductive health and the resulting detrimental impacts on the body. Additionally, it provides the detailed possible mechanisms involved in impairing reproductive processes like folliculogenesis, oocyte maturation, steroidogenesis, and pregnancy in different animal species.
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Affiliation(s)
- Jitender Kumar Bhardwaj
- Reproductive Physiology Laboratory, Department of Zoology, Kurukshetra University, Kurukshetra, Haryana, India
| | - Anshu Siwach
- Reproductive Physiology Laboratory, Department of Zoology, Kurukshetra University, Kurukshetra, Haryana, India
| | - Som Nath Sachdeva
- Department of Civil Engineering, National Institute of Technology, Kurukshetra and Kurukshetra University, Kurukshetra, Haryana, India
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Shafiullah S, Dhaneshwar S. Current Perspectives on Attention-deficit Hyperactivity Disorder. Curr Mol Med 2025; 25:289-304. [PMID: 37221690 DOI: 10.2174/1566524023666230522145950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 02/19/2023] [Accepted: 02/28/2023] [Indexed: 05/25/2023]
Abstract
Attention-deficit hyperactivity disorder (ADHD) is a neurobiological and neurodevelopmental disorder with an idiosyncratic genetic base. ADHD presents various characteristics, such as inattention, hyperactivity, and impulsivity. Over the period, ADHD leads to noticeable functional disability. A five- to ten-fold progressed risk of disorder development is observed in the populations with familial history of ADHD. The abnormal structure of the brain in ADHD results in altered neural mechanisms, such as cognition, attention, and memorial function. The mesolimbic, nigrostriatal, and mesocortical pathways in the brain get affected by the deterioration of the levels of dopamine. The hypothesis of dopamine in ADHD and its etiopathology suggests that detained attention and impaired arousal functions are due to reduced levels of dopamine. The quickest way to improve strategical treatment is by clarifying the etiological aspects of ADHD and identifying the underlying mechanisms of pathophysiology, which will assist in exploring the biomarkers for better diagnosis. The implementation of life course theory is a very important research principle announced by Grand Challenges in Global Health Initiative (GCMHI). Long-term research is needed to define the progression of ADHD. Interdisciplinary collaborations promise a great future for research innovations in ADHD.
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Affiliation(s)
- Shaik Shafiullah
- Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, Sector 125, Noida, U.P., India
| | - Suneela Dhaneshwar
- Department of Pharmaceutical Chemistry, Amity Institute of Pharmacy, Amity University Maharashtra, Mumbai, Maharashtra, India
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Gonzalez-Padilla D, Eagles NJ, Cano M, Pertea G, Jaffe AE, Maynard KR, Hancock DB, Handa JT, Martinowich K, Collado-Torres L. Molecular impact of nicotine and smoking exposure on the developing and adult mouse brain. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.05.622149. [PMID: 39574597 PMCID: PMC11580964 DOI: 10.1101/2024.11.05.622149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/01/2024]
Abstract
Maternal smoking during pregnancy (MSDP) is associated with significant cognitive and behavioral effects on offspring. While neurodevelopmental outcomes have been studied for prenatal exposure to nicotine, the main psychoactive component of cigarette smoke, its contribution to MSDP effects has never been explored. Comparing the effects of these substances on molecular signaling in the prenatal and adult brain may provide insights into nicotinic and broader tobacco consequences that are developmental-stage specific or age-independent. Pregnant mice were administered nicotine or exposed to chronic cigarette smoke, and RNA-sequencing was performed on frontal cortices of postnatal day 0 pups born to these mice, as well as on frontal cortices and blood of the adult dams. We identified 1,010 and 4,165 differentially expressed genes (DEGs) in nicotine and smoking-exposed pup brains, respectively (FDR<0.05, Ns = 19 nicotine-exposed vs 23 vehicle-exposed; 46 smoking-exposed vs 49 controls). Prenatal nicotine exposure (PNE) alone was related to dopaminergic synapses and long-term synaptic depression, whereas MSDP was associated with the SNARE complex and vesicle transport. Both substances affected SMN-Sm protein complexes and postsynaptic endosomes. Analyses at the transcript, exon, and exon-exon junction levels supported gene level results and revealed additional smoking-affected processes. No DEGs at FDR<0.05 were found in adult mouse brain for any substance (12 nicotine-administered vs 11 vehicle-administered; 12 smoking-exposed vs 12 controls), nor in adult blood (12 smoking-exposed vs 12 controls), and only 3% and 6.41% of the DEGs in smoking-exposed pup brain replicated in smoking-exposed blood and human prenatal brain, respectively. Together, these results demonstrate variable but overlapping molecular effects of PNE and MSDP on the developing brain, and attenuated effects of both smoking and nicotine on adult versus fetal brain.
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Karatayev O, Collier AD, Targoff SR, Leibowitz SF. Neurological Disorders Induced by Drug Use: Effects of Adolescent and Embryonic Drug Exposure on Behavioral Neurodevelopment. Int J Mol Sci 2024; 25:8341. [PMID: 39125913 PMCID: PMC11313660 DOI: 10.3390/ijms25158341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/10/2024] [Accepted: 07/17/2024] [Indexed: 08/12/2024] Open
Abstract
Clinical studies demonstrate that the risk of developing neurological disorders is increased by overconsumption of the commonly used drugs, alcohol, nicotine and cannabis. These drug-induced neurological disorders, which include substance use disorder (SUD) and its co-occurring emotional conditions such as anxiety and depression, are observed not only in adults but also with drug use during adolescence and after prenatal exposure to these drugs, and they are accompanied by long-lasting disturbances in brain development. This report provides overviews of clinical and preclinical studies, which confirm these adverse effects in adolescents and the offspring prenatally exposed to the drugs and include a more in-depth description of specific neuronal systems, their neurocircuitry and molecular mechanisms, affected by drug exposure and of specific techniques used to determine if these effects in the brain are causally related to the behavioral disturbances. With analysis of further studies, this review then addresses four specific questions that are important for fully understanding the impact that drug use in young individuals can have on future pregnancies and their offspring. Evidence demonstrates that the adverse effects on their brain and behavior can occur: (1) at low doses with short periods of drug exposure during pregnancy; (2) after pre-conception drug use by both females and males; (3) in subsequent generations following the initial drug exposure; and (4) in a sex-dependent manner, with drug use producing a greater risk in females than males of developing SUDs with emotional conditions and female offspring after prenatal drug exposure responding more adversely than male offspring. With the recent rise in drug use by adolescents and pregnant women that has occurred in association with the legalization of cannabis and increased availability of vaping tools, these conclusions from the clinical and preclinical literature are particularly alarming and underscore the urgent need to educate young women and men about the possible harmful effects of early drug use and to seek novel therapeutic strategies that might help to limit drug use in young individuals.
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Affiliation(s)
| | | | | | - Sarah F. Leibowitz
- Laboratory of Behavioral Neurobiology, The Rockefeller University, New York, NY 10065, USA; (O.K.); (S.R.T.)
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Riyahi J, Taslimi Z, Gelfo F, Petrosini L, Haghparast A. Trans-generational effects of parental exposure to drugs of abuse on offspring memory functions. Neurosci Biobehav Rev 2024; 160:105644. [PMID: 38548003 DOI: 10.1016/j.neubiorev.2024.105644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 03/10/2024] [Accepted: 03/22/2024] [Indexed: 04/01/2024]
Abstract
Recent evidence reported that parental-derived phenotypes can be passed on to the next generations. Within the inheritance of epigenetic characteristics allowing the transmission of information related to the ancestral environment to the offspring, the specific case of the trans-generational effects of parental drug addiction has been extensively studied. Drug addiction is a chronic disorder resulting from complex interactions among environmental, genetic, and drug-related factors. Repeated exposures to drugs induce epigenetic changes in the reward circuitry that in turn mediate enduring changes in brain function. Addictive drugs can exert their effects trans-generally and influence the offspring of addicted parents. Although there is growing evidence that shows a wide range of behavioral, physiological, and molecular phenotypes in inter-, multi-, and trans-generational studies, transmitted phenotypes often vary widely even within similar protocols. Given the breadth of literature findings, in the present review, we restricted our investigation to learning and memory performances, as examples of the offspring's complex behavioral outcomes following parental exposure to drugs of abuse, including morphine, cocaine, cannabinoids, nicotine, heroin, and alcohol.
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Affiliation(s)
- Javad Riyahi
- Department of Cognitive and Behavioral Science and Technology in Sport, Faculty of Sport Sciences and Health, Shahid Beheshti University, Tehran, Iran
| | - Zahra Taslimi
- Behavioral Disorders and Substance Abuse Research Center, Hamadan University of Medical Sciences, Hamadan, Iran; Fertility and Infertility Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Francesca Gelfo
- IRCCS Santa Lucia Foundation, Rome, Italy; Department of Human Sciences, Guglielmo Marconi University, Rome, Italy
| | | | - Abbas Haghparast
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; School of Cognitive Sciences, Institute for Research in Fundamental Sciences, Tehran, Iran; Department of Basic Sciences, Iranian Academy of Medical Sciences, Tehran, Iran.
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Xie T, Mao Y. The causal impact of maternal smoking around birth on offspring ADHD: A two-sample Mendelian randomization study. J Affect Disord 2024; 351:24-30. [PMID: 38266926 DOI: 10.1016/j.jad.2024.01.196] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 01/06/2024] [Accepted: 01/19/2024] [Indexed: 01/26/2024]
Abstract
BACKGROUND The previous literature highlights a relationship between maternal smoking around birth (MSAB) and offspring attention-deficit/hyperactivity disorder (ADHD). These studies have focused on the causal effects of MSAB on offspring ADHD. METHOD A Mendelian randomization analysis was conducted using summary statistics. Data on MSAB were obtained from a recent study including 391,992 participants. ADHD data were obtained from six sources for 246,888 participants. The present study used five methods to examine the causal impact from outcomes on exposures. The inverse variance weighted (IVW) was the main method of analysis, while the other four methods were supplementary methods. RESULT The IVW revealed that MSAB was a risk factor for offspring ADHD (OR: 2.54; 95 % confidence interval [CI]: 1.61-4.00, p = 6.04 × 10-5). Concerning ADHD in both sexes, MSAB was associated with females (OR = 3.96, 95 % CI: 1.99-7.90, p = 8.98 × 10-5) and males (OR = 3.74, 95 % CI: 1.74-5.72, p = 1.48 × 10-4). In different diagnosis periods for ADHD, MSAB increased the risk of childhood (OR = 3.63, 95 % CI: 2.25-5.87, p = 1.31 × 10-7), late-diagnosed (OR = 2.99, 95 % CI: 1.74-5.14, p = 7.33 × 10-5), and persistent (OR = 4.77, 95 % CI: 1.88-12.14, p = 1.03 × 10-3) ADHD. The final analysis did not reveal heterogeneity. CONCLUSIONS A causal impact of MSAB on offspring ADHD was observed. These findings highlight the need for careful consideration of prenatal exposure (MSAB) during the assessment of offspring ADHD. Additionally, it can provide targeted guidance for prenatal interventions. Future studies should analyze the effects of different doses of maternal smoking on ADHD.
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Affiliation(s)
- Tao Xie
- School of Public Policy and Administration, Xi'an Jiaotong University, Xi'an 710049, China
| | - Ying Mao
- School of Public Policy and Administration, Xi'an Jiaotong University, Xi'an 710049, China.
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McCarthy DM, Spencer TJ, Bhide PG. Preclinical Models of Attention Deficit Hyperactivity Disorder: Neurobiology, Drug Discovery, and Beyond. J Atten Disord 2024; 28:880-894. [PMID: 38084074 DOI: 10.1177/10870547231215286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
OBJECTIVE We offer an overview of ADHD research using mouse models of nicotine exposure. METHOD Nicotine exposure of C57BL/6 or Swiss Webster mice occurred during prenatal period only or during the prenatal and the pre-weaning periods. Behavioral, neuroanatomical and neurotransmitter assays were used to investigate neurobiological mechanisms of ADHD and discover candidate ADHD medications. RESULTS Our studies show that norbinaltorphimine, a selective kappa opioid receptor antagonist is a candidate novel non-stimulant ADHD treatment and that a combination of methylphenidate and naltrexone has abuse deterrent potential with therapeutic benefits for ADHD. Other studies showed transgenerational transmission of ADHD-associated behavioral traits and demonstrated that interactions between untreated ADHD and repeated mild traumatic brain injury produced behavioral traits not associated with either condition alone. CONCLUSION Preclinical models contribute to novel insights into ADHD neurobiology and are valuable tools for drug discovery and translation to benefit humans with ADHD.
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Affiliation(s)
| | - Thomas J Spencer
- Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Pradeep G Bhide
- Florida State University College of Medicine, Tallahassee, FL, USA
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Collier AD, Abdulai AR, Leibowitz SF. Utility of the Zebrafish Model for Studying Neuronal and Behavioral Disturbances Induced by Embryonic Exposure to Alcohol, Nicotine, and Cannabis. Cells 2023; 12:2505. [PMID: 37887349 PMCID: PMC10605371 DOI: 10.3390/cells12202505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/28/2023] [Accepted: 09/28/2023] [Indexed: 10/28/2023] Open
Abstract
It is estimated that 5% of pregnant women consume drugs of abuse during pregnancy. Clinical research suggests that intake of drugs during pregnancy, such as alcohol, nicotine and cannabis, disturbs the development of neuronal systems in the offspring, in association with behavioral disturbances early in life and an increased risk of developing drug use disorders. After briefly summarizing evidence in rodents, this review focuses on the zebrafish model and its inherent advantages for studying the effects of embryonic exposure to drugs of abuse on behavioral and neuronal development, with an emphasis on neuropeptides known to promote drug-related behaviors. In addition to stimulating the expression and density of peptide neurons, as in rodents, zebrafish studies demonstrate that embryonic drug exposure has marked effects on the migration, morphology, projections, anatomical location, and peptide co-expression of these neurons. We also describe studies using advanced methodologies that can be applied in vivo in zebrafish: first, to demonstrate a causal relationship between the drug-induced neuronal and behavioral disturbances and second, to discover underlying molecular mechanisms that mediate these effects. The zebrafish model has great potential for providing important information regarding the development of novel and efficacious therapies for ameliorating the effects of early drug exposure.
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Affiliation(s)
| | | | - Sarah F. Leibowitz
- Laboratory of Behavioral Neurobiology, The Rockefeller University, New York, NY 10065, USA
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Gelner H, Karska J, Gawęda Ł, Samochowiec J, Misiak B. Effects of the interaction between PTSD and ADHD symptoms on the level of reporting psychotic-like experiences: findings from a non-clinical population. Front Psychiatry 2023; 14:1232606. [PMID: 37867761 PMCID: PMC10587572 DOI: 10.3389/fpsyt.2023.1232606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 09/21/2023] [Indexed: 10/24/2023] Open
Abstract
Objective Psychotic-like experiences (PLEs) are increasingly being recognized as subclinical phenomena that might predict the development of various mental disorders that are not limited to the psychosis spectrum. Accumulating evidence suggests that attention-deficit/hyperactivity disorder (ADHD) and post-traumatic stress disorder (PTSD) are highly comorbid mental disorders. However, their interactive effect on the occurrence of PLEs has not been investigated so far. Therefore, in the present study we aimed to investigate the effect of interaction between ADHD and PTSD symptoms on the level of psychotic-like experiences (PLEs) in the non-clinical sample. Methods The study included 3,000 individuals aged 18-35 years with a negative history of psychiatric treatment. The symptoms of ADHD and PTSD were assessed using self-reports. Results There was a significant association of the interaction between ADHD and PTSD with the level of reporting PLEs. This association remained significant after adjustment for age, gender, the level of education, the current vocational situation, lifetime history of problematic substance use, and depressive symptoms. Post-hoc tests demonstrated significantly higher levels of reporting PLEs in participants with positive screening for both ADHD and PTSD compared to other subgroups of participants. Also, individuals with positive screening for one vulnerability (either ADHD or PTSD) reported significantly higher levels of reporting PLEs compared to those with a negative screening for ADHD and PTSD. In turn, no significant differences between individuals reporting one vulnerability, i.e., between those with positive screening for ADHD and those with positive screening for PTSD, were observed. Conclusion Findings from the present study imply that both PTSD and ADHD symptoms the interaction effect on the level of reporting PLEs that might be of importance for early intervention strategies. However, observed associations require replication in clinical samples.
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Affiliation(s)
- Hanna Gelner
- Experimental Psychopathology Lab, Institute of Psychology, Polish Academy of Sciences, Warsaw, Poland
| | - Julia Karska
- Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland
| | - Łukasz Gawęda
- Experimental Psychopathology Lab, Institute of Psychology, Polish Academy of Sciences, Warsaw, Poland
| | - Jerzy Samochowiec
- Department of Psychiatry, Pomeranian Medical University, Szczecin, Poland
| | - Błażej Misiak
- Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland
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Ugarte G, Piña R, Contreras D, Godoy F, Rubio D, Rozas C, Zeise M, Vidal R, Escobar J, Morales B. Attention Deficit-Hyperactivity Disorder (ADHD): From Abnormal Behavior to Impairment in Synaptic Plasticity. BIOLOGY 2023; 12:1241. [PMID: 37759640 PMCID: PMC10525904 DOI: 10.3390/biology12091241] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 09/08/2023] [Accepted: 09/10/2023] [Indexed: 09/29/2023]
Abstract
Attention deficit-hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high incidence in children and adolescents characterized by motor hyperactivity, impulsivity, and inattention. Magnetic resonance imaging (MRI) has revealed that neuroanatomical abnormalities such as the volume reduction in the neocortex and hippocampus are shared by several neuropsychiatric diseases such as schizophrenia, autism spectrum disorder and ADHD. Furthermore, the abnormal development and postnatal pruning of dendritic spines of neocortical neurons in schizophrenia, autism spectrum disorder and intellectual disability are well documented. Dendritic spines are dynamic structures exhibiting Hebbian and homeostatic plasticity that triggers intracellular cascades involving glutamate receptors, calcium influx and remodeling of the F-actin network. The long-term potentiation (LTP)-induced insertion of postsynaptic glutamate receptors is associated with the enlargement of spine heads and long-term depression (LTD) with spine shrinkage. Using a murine model of ADHD, a delay in dendritic spines' maturation in CA1 hippocampal neurons correlated with impaired working memory and hippocampal LTP has recently reported. The aim of this review is to summarize recent evidence that has emerged from studies focused on the neuroanatomical and genetic features found in ADHD patients as well as reports from animal models describing the molecular structure and remodeling of dendritic spines.
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Affiliation(s)
- Gonzalo Ugarte
- Laboratory of Neuroscience, Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile, Santiago 9170022, Chile; (G.U.); (D.C.); (F.G.); (D.R.); (C.R.)
| | - Ricardo Piña
- Department of Biology, Faculty of Sciences, Metropolitan University of Education Sciences, Santiago 7760197, Chile;
- Department of Human Sciences, Faculty of Human Science, Bernardo O’Higgins University, Santiago 8370854, Chile
| | - Darwin Contreras
- Laboratory of Neuroscience, Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile, Santiago 9170022, Chile; (G.U.); (D.C.); (F.G.); (D.R.); (C.R.)
| | - Felipe Godoy
- Laboratory of Neuroscience, Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile, Santiago 9170022, Chile; (G.U.); (D.C.); (F.G.); (D.R.); (C.R.)
| | - David Rubio
- Laboratory of Neuroscience, Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile, Santiago 9170022, Chile; (G.U.); (D.C.); (F.G.); (D.R.); (C.R.)
| | - Carlos Rozas
- Laboratory of Neuroscience, Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile, Santiago 9170022, Chile; (G.U.); (D.C.); (F.G.); (D.R.); (C.R.)
| | - Marc Zeise
- School of Psychology, Faculty of Humanities, University of Santiago of Chile, Santiago 9170022, Chile;
| | - Rodrigo Vidal
- Laboratory of Genomics, Molecular Ecology and Evolutionary Studies, Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile, Santiago 9170022, Chile;
| | - Jorge Escobar
- Institute of Chemistry, Pontifical Catholic University of Valparaíso, Valparaíso 2340000, Chile
| | - Bernardo Morales
- Laboratory of Neuroscience, Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile, Santiago 9170022, Chile; (G.U.); (D.C.); (F.G.); (D.R.); (C.R.)
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Kuś J, Saramowicz K, Czerniawska M, Wiese W, Siwecka N, Rozpędek-Kamińska W, Kucharska-Lusina A, Strzelecki D, Majsterek I. Molecular Mechanisms Underlying NMDARs Dysfunction and Their Role in ADHD Pathogenesis. Int J Mol Sci 2023; 24:12983. [PMID: 37629164 PMCID: PMC10454781 DOI: 10.3390/ijms241612983] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/17/2023] [Accepted: 08/18/2023] [Indexed: 08/27/2023] Open
Abstract
Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, although the aetiology of ADHD is not yet understood. One proposed theory for developing ADHD is N-methyl-D-aspartate receptors (NMDARs) dysfunction. NMDARs are involved in regulating synaptic plasticity and memory function in the brain. Abnormal expression or polymorphism of some genes associated with ADHD results in NMDAR dysfunction. Correspondingly, NMDAR malfunction in animal models results in ADHD-like symptoms, such as impulsivity and hyperactivity. Currently, there are no drugs for ADHD that specifically target NMDARs. However, NMDAR-stabilizing drugs have shown promise in improving ADHD symptoms with fewer side effects than the currently most widely used psychostimulant in ADHD treatment, methylphenidate. In this review, we outline the molecular and genetic basis of NMDAR malfunction and how it affects the course of ADHD. We also present new therapeutic options related to treating ADHD by targeting NMDAR.
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Affiliation(s)
- Justyna Kuś
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Mazowiecka 5, 92-215 Lodz, Poland; (J.K.); (K.S.); (M.C.); (W.W.); (N.S.); (W.R.-K.); (A.K.-L.)
| | - Kamil Saramowicz
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Mazowiecka 5, 92-215 Lodz, Poland; (J.K.); (K.S.); (M.C.); (W.W.); (N.S.); (W.R.-K.); (A.K.-L.)
| | - Maria Czerniawska
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Mazowiecka 5, 92-215 Lodz, Poland; (J.K.); (K.S.); (M.C.); (W.W.); (N.S.); (W.R.-K.); (A.K.-L.)
| | - Wojciech Wiese
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Mazowiecka 5, 92-215 Lodz, Poland; (J.K.); (K.S.); (M.C.); (W.W.); (N.S.); (W.R.-K.); (A.K.-L.)
| | - Natalia Siwecka
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Mazowiecka 5, 92-215 Lodz, Poland; (J.K.); (K.S.); (M.C.); (W.W.); (N.S.); (W.R.-K.); (A.K.-L.)
| | - Wioletta Rozpędek-Kamińska
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Mazowiecka 5, 92-215 Lodz, Poland; (J.K.); (K.S.); (M.C.); (W.W.); (N.S.); (W.R.-K.); (A.K.-L.)
| | - Aleksandra Kucharska-Lusina
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Mazowiecka 5, 92-215 Lodz, Poland; (J.K.); (K.S.); (M.C.); (W.W.); (N.S.); (W.R.-K.); (A.K.-L.)
| | - Dominik Strzelecki
- Department of Affective and Psychotic Disorders, Medical University of Lodz, Czechoslowacka 8/10, 92-216 Lodz, Poland;
| | - Ireneusz Majsterek
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Mazowiecka 5, 92-215 Lodz, Poland; (J.K.); (K.S.); (M.C.); (W.W.); (N.S.); (W.R.-K.); (A.K.-L.)
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Saito H, Furukawa Y, Sasaki T, Kitajima S, Kanno J, Tanemura K. Behavioral effects of adult male mice induced by low-level acetamiprid, imidacloprid, and nicotine exposure in early-life. Front Neurosci 2023; 17:1239808. [PMID: 37662107 PMCID: PMC10469492 DOI: 10.3389/fnins.2023.1239808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 07/28/2023] [Indexed: 09/05/2023] Open
Abstract
Introduction Acetamiprid (ACE) and imidacloprid (IMI), the neonicotinoid chemicals, are widely used as pesticides because of their rapid insecticidal activity. Although these neonicotinoids exert very low toxicity in mammals, the effects of early, low-level, chronic exposure on the adult central nervous system are largely unclear. This study investigated the effects of low-level, chronic neonicotinoids exposure in early life on the brain functions of adult mice, using environmentally relevant concentrations. Methods We exposed mice to an acceptable daily intake level of neonicotinoids in drinking water during the prenatal and postnatal periods. Additionally, we also exposed mice to nicotine (NIC) as a positive control. We then examined the effects on the central nervous system in adult male offspring. Results In the IMI and NIC exposure groups, we detected behavior that displayed impairment in learning and memory. Furthermore, immunohistochemical analysis revealed a decrease in SOX2 (as a neural stem cell marker) and GFAP (as an astrocyte marker) positive cells of the hippocampal dentate gyrus in the IMI and NIC exposure groups compared to the control group. Discussion These results suggest that exposure to neonicotinoids at low levels in early life affects neural circuit base formation and post-maturation behavior. Therefore, in the central nervous system of male mice, the effects of low-level, chronic neonicotinoids exposure during the perinatal period were different from the expected effects of neonicotinoids exposure in mature animals.
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Affiliation(s)
- Hirokatsu Saito
- Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki, Japan
| | - Yusuke Furukawa
- Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki, Japan
| | - Takahiro Sasaki
- Laboratory of Animal Reproduction and Development, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Satoshi Kitajima
- Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki, Japan
| | - Jun Kanno
- Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki, Japan
| | - Kentaro Tanemura
- Laboratory of Animal Reproduction and Development, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
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Wells AC, Lotfipour S. Prenatal nicotine exposure during pregnancy results in adverse neurodevelopmental alterations and neurobehavioral deficits. ADVANCES IN DRUG AND ALCOHOL RESEARCH 2023; 3:11628. [PMID: 38389806 PMCID: PMC10880762 DOI: 10.3389/adar.2023.11628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 07/28/2023] [Indexed: 02/24/2024]
Abstract
Maternal tobacco use and nicotine exposure during pregnancy have been associated with adverse birth outcomes in infants and can lead to preventable pregnancy complications. Exposure to nicotine and other compounds in tobacco and electronic cigarettes (e-cigarettes) has been shown to increases the risk of miscarriage, prematurity, stillbirth, low birth weight, perinatal morbidity, and sudden infant death syndrome (SIDS). Additionally, recent data provided by clinical and pre-clinical research demonstrates that nicotine exposure during pregnancy may heighten the risk for adverse neurodevelopmental disorders such as Attention-Deficit Hyperactivity (ADHD), anxiety, and depression along with altering the infants underlying brain circuitry, response to neurotransmitters, and brain volume. In the United States, one in 14 women (7.2%) reported to have smoked cigarettes during their pregnancy with the global prevalence of smoking during pregnancy estimated to be 1.7%. Approximately 1.1% of women in the United States also reported to have used e-cigarettes during the last 3 months of pregnancy. Due to the large percentage of women utilizing nicotine products during pregnancy in the United States and globally, this review seeks to centralize pre-clinical and clinical studies focused on the neurobehavioral and neurodevelopmental complications associated with prenatal nicotine exposure (PNE) such as alterations to the hypothalamic-pituitary-adrenal (HPA) axis and brain regions such as the prefrontal cortex (PFC), ventral tegmental area (VTA), nucleus accumbens (NA), hippocampus, and caudate as well as changes to nAChR and cholinergic receptor signaling, long-term drug seeking behavior following PNE, and other related developmental disorders. Current literature analyzing the association between PNE and the risk for offspring developing schizophrenia, attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), anxiety, and obesity will also be discussed.
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Affiliation(s)
- Alicia C Wells
- School of Medicine, University of California, Irvine, Irvine, CA, United States
| | - Shahrdad Lotfipour
- School of Medicine, University of California, Irvine, Irvine, CA, United States
- Department of Emergency Medicine, Pharmaceutical Sciences, Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, United States
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Lee WS, Yoon BE. Necessity of an Integrative Animal Model for a Comprehensive Study of Attention-Deficit/Hyperactivity Disorder. Biomedicines 2023; 11:biomedicines11051260. [PMID: 37238931 DOI: 10.3390/biomedicines11051260] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 04/13/2023] [Accepted: 04/20/2023] [Indexed: 05/28/2023] Open
Abstract
Animal models of attention-deficit/hyperactivity disorder (ADHD) have been used to study and understand the behavioral, neural, and physiological mechanisms underlying ADHD. These models allow researchers to conduct controlled experiments and manipulate specific brain regions or neurotransmitter systems to investigate the underlying causes of ADHD and test potential drug targets or treatments. However, it is essential to note that while these models can provide valuable insights, they do not ideally mimic the complex and heterogeneous nature of ADHD and should be interpreted cautiously. Additionally, since ADHD is a multifactorial disorder, environmental and epigenetic factors should be considered simultaneously. In this review, the animal models of ADHD reported thus far are classified into genetic, pharmacological, and environmental models, and the limitations of the representative models are discussed. Furthermore, we provide insights into a more reliable alternative model for the comprehensive study of ADHD.
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Affiliation(s)
- Won-Seok Lee
- Department of Molecular Biology, Dankook University, Cheonan 31116, Chungcheongnam-do, Republic of Korea
| | - Bo-Eun Yoon
- Department of Molecular Biology, Dankook University, Cheonan 31116, Chungcheongnam-do, Republic of Korea
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Mize TJ, Funkhouser SA, Buck JM, Stitzel JA, Ehringer MA, Evans LM. Testing Association of Previously Implicated Gene Sets and Gene-Networks in Nicotine Exposed Mouse Models with Human Smoking Phenotypes. Nicotine Tob Res 2023; 25:1030-1038. [PMID: 36444815 PMCID: PMC10077928 DOI: 10.1093/ntr/ntac269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 08/15/2022] [Accepted: 11/23/2022] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Smoking behaviors are partly heritable, yet the genetic and environmental mechanisms underlying smoking phenotypes are not fully understood. Developmental nicotine exposure (DNE) is a significant risk factor for smoking and leads to gene expression changes in mouse models; however, it is unknown whether the same genes whose expression is impacted by DNE are also those underlying smoking genetic liability. We examined whether genes whose expression in D1-type striatal medium spiny neurons due to DNE in the mouse are also associated with human smoking behaviors. METHODS Specifically, we assessed whether human orthologs of mouse-identified genes, either individually or as a set, were genetically associated with five human smoking traits using MAGMA and S-LDSC while implementing a novel expression-based gene-SNP annotation methodology. RESULTS We found no strong evidence that these genes sets were more strongly associated with smoking behaviors than the rest of the genome, but ten of these individual genes were significantly associated with three of the five human smoking traits examined (p < 2.5e-6). Three of these genes have not been reported previously and were discovered only when implementing the expression-based annotation. CONCLUSIONS These results suggest the genes whose expression is impacted by DNE in mice are largely distinct from those contributing to smoking genetic liability in humans. However, examining a single mouse neuronal cell type may be too fine a resolution for comparison, suggesting that experimental manipulation of nicotine consumption, reward, or withdrawal in mice may better capture genes related to the complex genetics of human tobacco use. IMPLICATIONS Genes whose expression is impacted by DNE in mouse D1-type striatal medium spiny neurons were not found to be, as a whole, more strongly associated with human smoking behaviors than the rest of the genome, though ten individual mouse-identified genes were associated with human smoking traits. This suggests little overlap between the genetic mechanisms impacted by DNE and those influencing heritable liability to smoking phenotypes in humans. Further research is warranted to characterize how developmental nicotine exposure paradigms in mice can be translated to understand nicotine use in humans and their heritable effects on smoking.
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Affiliation(s)
- Travis J Mize
- Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA
- Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, CO, USA
| | - Scott A Funkhouser
- Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA
| | - Jordan M Buck
- Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA
- Department of Integrative Physiology, University of Colorado, Boulder, CO, USA
| | - Jerry A Stitzel
- Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA
- Department of Integrative Physiology, University of Colorado, Boulder, CO, USA
| | - Marissa A Ehringer
- Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA
- Department of Integrative Physiology, University of Colorado, Boulder, CO, USA
| | - Luke M Evans
- Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA
- Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, CO, USA
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Wendt FR, Garcia-Argibay M, Cabrera-Mendoza B, Valdimarsdóttir UA, Gelernter J, Stein MB, Nivard MG, Maihofer AX, Nievergelt CM, Larsson H, Mattheisen M, Polimanti R, Meier SM. The Relationship of Attention-Deficit/Hyperactivity Disorder With Posttraumatic Stress Disorder: A Two-Sample Mendelian Randomization and Population-Based Sibling Comparison Study. Biol Psychiatry 2023; 93:362-369. [PMID: 36335070 PMCID: PMC10496427 DOI: 10.1016/j.biopsych.2022.08.012] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 08/11/2022] [Accepted: 08/17/2022] [Indexed: 01/21/2023]
Abstract
BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. METHODS Linkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (rg) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons). RESULTS ADHD and PTSD had consistent rg (rg range, 0.43-0.52; p < .001). ADHD genetic liability was causally linked with increased risk for PTSD (β = 0.367; 95% CI, 0.186-0.552; p = 7.68 × 10-5). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10-4, p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98-3.53). CONCLUSIONS Our findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.
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Affiliation(s)
- Frank R Wendt
- Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut; Department of Anthropology, University of Toronto, Toronto, Ontario, Canada
| | | | - Brenda Cabrera-Mendoza
- Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut
| | - Unnur A Valdimarsdóttir
- Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
| | - Joel Gelernter
- Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut
| | - Murray B Stein
- Department of Psychiatry, UC San Diego School of Medicine, University of California, San Diego, La Jolla, California; Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California
| | - Michel G Nivard
- Department of Biological Psychology, Faculty of Behaviour and Movement Sciences, VU University, Amsterdam, The Netherlands
| | - Adam X Maihofer
- Department of Psychiatry, UC San Diego School of Medicine, University of California, San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California; Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, California
| | - Caroline M Nievergelt
- Department of Psychiatry, UC San Diego School of Medicine, University of California, San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California; Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, California
| | - Henrik Larsson
- School of Medical Sciences, Örebro University, Örebro, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Manuel Mattheisen
- Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada; Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich, Munich, Germany; Faculty of Computer Science, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Renato Polimanti
- Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut.
| | - Sandra M Meier
- Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada; Faculty of Computer Science, Dalhousie University, Halifax, Nova Scotia, Canada.
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Pavlock S, McCarthy DM, Kesarwani A, Jean-Pierre P, Bhide PG. Hippocampal neuroinflammation following combined exposure to cyclophosphamide and naproxen in ovariectomized mice. Int J Neurosci 2023; 133:159-168. [PMID: 33635748 DOI: 10.1080/00207454.2021.1896508] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Aim: Cancer patients undergoing chemotherapy report cognitive changes collectively termed "chemo brain." Neuroinflammation is among the factors believed to contribute to "chemo brain" suggesting a potential beneficial role for anti-inflammatory drugs in cancer patients undergoing chemotherapy. We investigated whether the non-steroidal anti-inflammatory drug naproxen influenced hippocampal inflammation in non-tumor bearing female mice receiving the chemotherapy drug cyclophosphamide (CP).Materials and methods: Intact and ovariectomized C57BL/6 mice were used to examine potential role of ovarian hormones on neuroinflammation. The mice were placed on naproxen (375 ppm) or control diet, and a week later CP (100 mg/kg; i.p.) was administered every 3 days for 2 weeks. We analyzed hippocampal inflammatory biomarkers, anxiety-like behavior, spatial working memory, exploratory behavior, spontaneous locomotor activity and depression-like behavior.Results: CP produced significant effects on anti-inflammatory but not pro-inflammatory biomarkers. However, CP and naproxen in combination produced significant effects on both pro- and anti- inflammatory biomarkers. Naproxen and ovariectomy individually produced significant effects on pro- and anti-inflammatory biomarkers as well. Working memory and depression-like behavior were not significantly influenced by CP, naproxen or ovariectomy individually although CP and ovariectomy produced significant interaction effects on depression-like behavior. Exploratory behavior and locomotor activity showed significant effects of CP, and interaction between CP and naproxen was significant for locomotor activity.Conclusions: Ovariectomy, naproxen and a combination of CP and naproxen upregulate hippocampal pro- and anti- inflammatory biomarkers. None of the factors individually produce significant behavioral changes that could be consistent with chemo brain, although CP and ovariectomy in combination produced significant effects on depression-like behavior, a co-morbidity of chemo brain.
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Affiliation(s)
- Samantha Pavlock
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, USA
| | - Deirdre M McCarthy
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, USA
| | - Anisha Kesarwani
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, USA
| | - Pascal Jean-Pierre
- Department of Behavioral Sciences and Social Medicine, Florida State University College of Medicine, Tallahassee, FL, USA
| | - Pradeep G Bhide
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, USA
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Vázquez-González D, Carreón-Trujillo S, Alvarez-Arellano L, Abarca-Merlin DM, Domínguez-López P, Salazar-García M, Corona JC. A Potential Role for Neuroinflammation in ADHD. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1411:327-356. [PMID: 36949317 DOI: 10.1007/978-981-19-7376-5_15] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
Attention deficit hyperactivity disorder (ADHD) is a neurobehavioural disorder in children and adolescents. Although increases in oxidative stress and disturbances of neurotransmitter system such as the dopaminergic and abnormalities in several brain regions have been demonstrated, the pathophysiology of ADHD is not fully understood. Nevertheless, ADHD involves several factors that have been associated with an increase in neuroinflammation. This chapter presents an overview of factors that may increase neuroinflammation and play a potential role in the development and pathophysiology of ADHD. The altered immune response, polymorphisms in inflammatory-related genes, ADHD comorbidity with autoimmune and inflammatory disorders and prenatal exposure to inflammation are associated with alterations in offspring brain development and are a risk factor; genetic and environmental risk factors that may increase the risk for ADHD and medications can increase neuroinflammation. Evidence of an association between these factors has been an invaluable tool for research on inflammation in ADHD. Therefore, evidence studies have made it possible to generate alternative therapeutic interventions using natural products as anti-inflammatories that could have great potential against neuroinflammation in ADHD.
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Affiliation(s)
| | - Sonia Carreón-Trujillo
- Laboratory of Neurosciences, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
| | | | | | - Pablo Domínguez-López
- Unidad de Investigación Médica en Medicina Reproductiva, Hospital Gineco-Obstetricia, IMSS, Mexico City, Mexico
| | - Marcela Salazar-García
- Laboratorio de Investigación en Biología del Desarrollo y Teratogénesis Experimental, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
| | - Juan Carlos Corona
- Laboratory of Neurosciences, Hospital Infantil de México Federico Gómez, Mexico City, Mexico.
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Ireland D, Zhang S, Bochenek V, Hsieh JH, Rabeler C, Meyer Z, Collins EMS. Differences in neurotoxic outcomes of organophosphorus pesticides revealed via multi-dimensional screening in adult and regenerating planarians. FRONTIERS IN TOXICOLOGY 2022; 4:948455. [PMID: 36267428 PMCID: PMC9578561 DOI: 10.3389/ftox.2022.948455] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 08/25/2022] [Indexed: 11/07/2022] Open
Abstract
Organophosphorus pesticides (OPs) are a chemically diverse class of commonly used insecticides. Epidemiological studies suggest that low dose chronic prenatal and infant exposures can lead to life-long neurological damage and behavioral disorders. While inhibition of acetylcholinesterase (AChE) is the shared mechanism of acute OP neurotoxicity, OP-induced developmental neurotoxicity (DNT) can occur independently and/or in the absence of significant AChE inhibition, implying that OPs affect alternative targets. Moreover, different OPs can cause different adverse outcomes, suggesting that different OPs act through different mechanisms. These findings emphasize the importance of comparative studies of OP toxicity. Freshwater planarians are an invertebrate system that uniquely allows for automated, rapid and inexpensive testing of adult and developing organisms in parallel to differentiate neurotoxicity from DNT. Effects found only in regenerating planarians would be indicative of DNT, whereas shared effects may represent neurotoxicity. We leverage this unique feature of planarians to investigate potential differential effects of OPs on the adult and developing brain by performing a comparative screen to test 7 OPs (acephate, chlorpyrifos, dichlorvos, diazinon, malathion, parathion and profenofos) across 10 concentrations in quarter-log steps. Neurotoxicity was evaluated using a wide range of quantitative morphological and behavioral readouts. AChE activity was measured using an Ellman assay. The toxicological profiles of the 7 OPs differed across the OPs and between adult and regenerating planarians. Toxicological profiles were not correlated with levels of AChE inhibition. Twenty-two "mechanistic control compounds" known to target pathways suggested in the literature to be affected by OPs (cholinergic neurotransmission, serotonin neurotransmission, endocannabinoid system, cytoskeleton, adenyl cyclase and oxidative stress) and 2 negative controls were also screened. When compared with the mechanistic control compounds, the phenotypic profiles of the different OPs separated into distinct clusters. The phenotypic profiles of adult vs. regenerating planarians exposed to the OPs clustered differently, suggesting some developmental-specific mechanisms. These results further support findings in other systems that OPs cause different adverse outcomes in the (developing) brain and build the foundation for future comparative studies focused on delineating the mechanisms of OP neurotoxicity in planarians.
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Affiliation(s)
- Danielle Ireland
- Department of Biology, Swarthmore College, Swarthmore, PA, United States
| | - Siqi Zhang
- Department of Bioengineering, University of California San Diego, La Jolla, CA, United States
| | - Veronica Bochenek
- Department of Biology, Swarthmore College, Swarthmore, PA, United States
| | - Jui-Hua Hsieh
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Durham, NC, United States
| | - Christina Rabeler
- Department of Biology, Swarthmore College, Swarthmore, PA, United States
| | - Zane Meyer
- Department of Engineering, Swarthmore College, Swarthmore, PA, United States
- Department of Computer Science, Swarthmore College, Swarthmore, PA, United States
| | - Eva-Maria S. Collins
- Department of Biology, Swarthmore College, Swarthmore, PA, United States
- Department of Physics and Astronomy, Swarthmore College, Swarthmore, PA, United States
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Center of Excellence in Environmental Toxicology, University of Pennsylvania, Philadelphia, PA, United States
- Department of Physics, University of California San Diego, La Jolla, CA, United States
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Fasakin OW, Oboh G, Ademosun AO. The prevalence, mechanism of action, and toxicity of Nigerian psychoactive plants. COMPARATIVE CLINICAL PATHOLOGY 2022; 31:853-873. [PMID: 35789743 PMCID: PMC9243860 DOI: 10.1007/s00580-022-03374-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 06/19/2022] [Indexed: 06/15/2023]
Abstract
Cannabis sativa, Datura stramonium, Nicotiana tabacum, and Carica papaya are plants that naturally grow in Nigeria. They are reportedly rich in neuroactive compounds that are capable of reacting with the nervous system to elicit psychoactive and/or toxic effects that deter predators. However, despite the toxicological potential of these plants, their recreational use is on the rise due to the psychoactivity they proffer and prevalence in Nigeria. The aim of the present study is to evaluate the plants' recreational use, mechanism of actions and toxicities. Relevant published documents on psychoactive plants in Nigeria were obtained from Web of Science between 2002 and 2020. Non-English documents, documents not in Science Citation Index Expanded and Google Scholar were removed while 1186 documents were reviewed. Results showed that the plants are recreationally used in Nigeria with a higher prevalence than the global frequency. They are very addictive and lead to dependence. The plants were also observed to elicit different mechanism of action, though the activation of monoaminergic neurotransmission system was common to all. Regrettably, the plants could be toxic when ingested under non-medical conditions. Conclusively, these plants are addictive with potential toxic effects. Therefore, control of the recreational use of these plants should be revamped and overhauled.
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Affiliation(s)
- Olamide Wilson Fasakin
- Functional Foods, Nutraceuticals and Phytomedicine Unit, Department of Biochemistry, Federal University of Technology, P.M.B. 704, Akure, 340001 Nigeria
| | - Ganiyu Oboh
- Functional Foods, Nutraceuticals and Phytomedicine Unit, Department of Biochemistry, Federal University of Technology, P.M.B. 704, Akure, 340001 Nigeria
| | - Ayokunle Olubode Ademosun
- Functional Foods, Nutraceuticals and Phytomedicine Unit, Department of Biochemistry, Federal University of Technology, P.M.B. 704, Akure, 340001 Nigeria
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Contreras D, Piña R, Carvallo C, Godoy F, Ugarte G, Zeise M, Rozas C, Morales B. Methylphenidate Restores Behavioral and Neuroplasticity Impairments in the Prenatal Nicotine Exposure Mouse Model of ADHD: Evidence for Involvement of AMPA Receptor Subunit Composition and Synaptic Spine Morphology in the Hippocampus. Int J Mol Sci 2022; 23:ijms23137099. [PMID: 35806103 PMCID: PMC9266648 DOI: 10.3390/ijms23137099] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/22/2022] [Accepted: 06/22/2022] [Indexed: 02/04/2023] Open
Abstract
In ADHD treatment, methylphenidate (MPH) is the most frequently used medication. The present work provides evidence that MPH restored behavioral impairments and neuroplasticity due to changes in AMPAR subunit composition and distribution, as well as maturation of dendritic spines, in a prenatal nicotine exposure (PNE) ADHD mouse model. PNE animals and controls were given a single oral dose of MPH (1 mg/kg), and their behavior was tested for attention, hyperactivity, and working memory. Long-term potentiation (LTP) was induced and analyzed at the CA3/CA1 synapse in hippocampal slices taken from the same animals tested behaviorally, measuring fEPSPs and whole-cell patch-clamp EPSCs. By applying crosslinking and Western blots, we estimated the LTP effects on AMPAR subunit composition and distribution. The density and types of dendritic spines were quantified by using the Golgi staining method. MPH completely restored the behavioral impairments of PNE mice. Reduced LTP and AMPA-receptor-mediated EPSCs were also restored. EPSC amplitudes were tightly correlated with numbers of GluA1/GluA1 AMPA receptors at the cell surface. Finally, we found a lower density of dendritic spines in hippocampal pyramidal neurons in PNE mice, with a higher fraction of thin-type immature spines and a lower fraction of mushroom mature spines; the latter effect was also reversed by MPH.
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Affiliation(s)
- Darwin Contreras
- Laboratory of Neuroscience, Faculty of Chemistry and Biology, University of Santiago de Chile, Alameda 3363, Santiago 9170022, Chile; (D.C.); (F.G.); (G.U.)
| | - Ricardo Piña
- Departamento de Biología, Facultad de Ciencias Básicas, Universidad Metropolitana de Ciencias de la Educación, Santiago 7760197, Chile;
- Departamento de Ciencias Pedagógicas, Facultad de Educación, Universidad Bernardo O’Higgins, Santiago 8370993, Chile
| | - Claudia Carvallo
- Centro de investigación e innovación en Gerontología Aplicada (CIGAP), Facultad de Salud, Universidad Santo Tomás, Santiago 8370003, Chile;
| | - Felipe Godoy
- Laboratory of Neuroscience, Faculty of Chemistry and Biology, University of Santiago de Chile, Alameda 3363, Santiago 9170022, Chile; (D.C.); (F.G.); (G.U.)
| | - Gonzalo Ugarte
- Laboratory of Neuroscience, Faculty of Chemistry and Biology, University of Santiago de Chile, Alameda 3363, Santiago 9170022, Chile; (D.C.); (F.G.); (G.U.)
| | - Marc Zeise
- School of Psychology, Faculty of Humanities, University of Santiago de Chile, Santiago 9170022, Chile;
| | - Carlos Rozas
- Laboratory of Neuroscience, Faculty of Chemistry and Biology, University of Santiago de Chile, Alameda 3363, Santiago 9170022, Chile; (D.C.); (F.G.); (G.U.)
- Correspondence: (C.R.); (B.M.)
| | - Bernardo Morales
- Laboratory of Neuroscience, Faculty of Chemistry and Biology, University of Santiago de Chile, Alameda 3363, Santiago 9170022, Chile; (D.C.); (F.G.); (G.U.)
- Correspondence: (C.R.); (B.M.)
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22
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Yim G, Roberts A, Ascherio A, Wypij D, Kioumourtzoglou MA, Weisskopf AMG. Smoking During Pregnancy and Risk of Attention-deficit/Hyperactivity Disorder in the Third Generation. Epidemiology 2022; 33:431-440. [PMID: 35213510 PMCID: PMC9010055 DOI: 10.1097/ede.0000000000001467] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND Animal experiments indicate that environmental factors, such as cigarette smoke, can have multigenerational effects through the germline. However, there are little data on multigenerational effects of smoking in humans. We examined the associations between grandmothers' smoking while pregnant and risk of attention-deficit/hyperactivity disorder (ADHD) in her grandchildren. METHODS Our study population included 53,653 Nurses' Health Study II (NHS-II) participants (generation 1 [G1]), their mothers (generation 0 [G0]), and their 120,467 live-born children (generation 2 [G2]). In secondary analyses, we used data from 23,844 mothers of the nurses who were participants in the Nurses' Mothers' Cohort Study (NMCS), a substudy of NHS-II. RESULTS The prevalence of G0 smoking during the pregnancy with the G1 nurse was 25%. ADHD was diagnosed in 9,049 (7.5%) of the grandchildren (G2). Grand-maternal smoking during pregnancy was associated with increased odds of ADHD among the grandchildren (adjusted odds ratio [aOR] = 1.2; 95% confidence interval [CI] = 1.1, 1.2), independent of G1 smoking during pregnancy. In the Nurses' Mothers' Cohort Study, odds of ADHD increased with increasing cigarettes smoked per day by the grandmother (1-14 cigarettes: aOR = 1.1; 95% CI = 1.0, 1.2; 15+: aOR = 1.2; 95% CI = 1.0, 1.3), compared with nonsmoking grandmothers. CONCLUSIONS Grandmother smoking during pregnancy is associated with an increased risk of ADHD among the grandchildren.
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Affiliation(s)
- Gyeyoon Yim
- From the Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Andrea Roberts
- From the Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Alberto Ascherio
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA
| | - David Wypij
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
- Department of Pediatrics, Harvard Medical School, Boston, MA
- Department of Cardiology, Children's Hospital Boston, Boston, MA
| | | | - And Marc G Weisskopf
- From the Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
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23
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Stankovic IN, Colak D. Prenatal Drugs and Their Effects on the Developing Brain: Insights From Three-Dimensional Human Organoids. Front Neurosci 2022; 16:848648. [PMID: 35401083 PMCID: PMC8990163 DOI: 10.3389/fnins.2022.848648] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 02/01/2022] [Indexed: 11/13/2022] Open
Abstract
Decades of research have unequivocally demonstrated that fetal exposure to both recreational and prescription drugs in utero negatively impacts the developing brain. More recently, the application of cutting-edge techniques in neurodevelopmental research has attempted to identify how the fetal brain responds to specific environmental stimuli. Meanwhile, human fetal brain studies still encounter ethical considerations and technical limitations in tissue collection. Human-induced pluripotent stem cell (iPSC)-derived brain organoid technology has emerged as a powerful alternative to examine fetal neurobiology. In fact, human 3D organoid tissues recapitulate cerebral development during the first trimester of pregnancy. In this review, we aim to provide a comprehensive summary of fetal brain metabolic studies related to drug abuse in animal and human models. Additionally, we will discuss the current challenges and prospects of using brain organoids for large-scale metabolomics. Incorporating cutting-edge techniques in human brain organoids may lead to uncovering novel molecular and cellular mechanisms of neurodevelopment, direct novel therapeutic approaches, and raise new exciting questions.
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Affiliation(s)
- Isidora N. Stankovic
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, Cornell University, New York, NY, United States
- *Correspondence: Isidora N. Stankovic,
| | - Dilek Colak
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, Cornell University, New York, NY, United States
- Gale & Ira Drukier Institute for Children’s Health, Weill Cornell Medicine, Cornell University, New York, NY, United States
- Dilek Colak,
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24
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McCarthy DM, Zhang L, Wilkes BJ, Vaillancourt DE, Biederman J, Bhide PG. Nicotine and the developing brain: Insights from preclinical models. Pharmacol Biochem Behav 2022; 214:173355. [PMID: 35176350 PMCID: PMC9063417 DOI: 10.1016/j.pbb.2022.173355] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 02/08/2022] [Accepted: 02/09/2022] [Indexed: 11/26/2022]
Abstract
Use of tobacco products during pregnancy is associated with increased risk for neurodevelopmental disorders in the offspring. Preclinical models of developmental nicotine exposure have offered valuable insights into the neurobiology of nicotine's effects on the developing brain and demonstrated lasting effects of developmental nicotine exposure on brain structure, neurotransmitter signaling and behavior. These models have facilitated discovery of novel compounds as candidate treatments for attention deficit hyperactivity disorder, a neurodevelopmental disorder associated with prenatal nicotine exposure. Using these models the significance of heritability of behavioral phenotypes from the nicotine-exposed pregnant female or adult male to multiple generations of descendants has been demonstrated. Finally, research using the preclinical models has demonstrated synergistic interactions between developmental nicotine exposure and repetitive mild traumatic brain injury that contribute to "worse" outcomes from the injury in individuals with attention deficit hyperactivity disorder associated with developmental nicotine exposure.
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Affiliation(s)
- Deirdre M McCarthy
- Biomedical Sciences, Florida State University, College of Medicine, Tallahassee, FL 32306, United States of America
| | - Lin Zhang
- Biomedical Sciences, Florida State University, College of Medicine, Tallahassee, FL 32306, United States of America
| | - Bradley J Wilkes
- Laboratory for Rehabilitation Neuroscience, Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL 32611, United States of America
| | - David E Vaillancourt
- Laboratory for Rehabilitation Neuroscience, Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL 32611, United States of America
| | - Joseph Biederman
- Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States of America
| | - Pradeep G Bhide
- Biomedical Sciences, Florida State University, College of Medicine, Tallahassee, FL 32306, United States of America.
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25
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Toxic effects of smokeless tobacco on female reproductive health: A review. Curr Res Toxicol 2022; 3:100066. [PMID: 35310558 PMCID: PMC8927787 DOI: 10.1016/j.crtox.2022.100066] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/11/2022] [Accepted: 03/03/2022] [Indexed: 12/04/2022] Open
Abstract
Smokeless tobacco use can lead to impairments of ovarian function, morphology, oocyte quality and hormonal regulation. Use of smokeless tobacco during pregnancy has adverse health effects on both the mother and fetus. Exposure to smokeless tobacco in utero has long term health consequences on offspring. The habitual consumption of tobacco in its various form is widespread and a serious public health issue globally. In particular, the use of smokeless tobacco has increased substantially due to its easy availability and misconception that it is relatively harmless compared to smoking. Tobacco use has been well established from numerous studies as a causative agent of devastating illnesses such as cancer, insulin resistance, hypertension, acute respiratory disease, osteoporosis, etc. Limited but growing evidence have also suggested its role in adversely affecting reproductive capabilities and outcomes in women of reproductive age and during pregnancy. This paper provides an updated review on available literature regarding the negative effects of smokeless tobacco use on female reproductive health, during pregnancy and its adverse consequences on the offspring. Existing data suggests the association between chronic smokeless tobacco use and impairment of ovarian morphology and function, oocyte quality, hormonal perturbations, fetal development and long-term health effects on the fetus. Improved understanding of these issues can contribute to better awareness of the dangers of smokeless tobacco products.
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26
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Kantak KM. Rodent models of attention-deficit hyperactivity disorder: An updated framework for model validation and therapeutic drug discovery. Pharmacol Biochem Behav 2022; 216:173378. [DOI: 10.1016/j.pbb.2022.173378] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 03/22/2022] [Accepted: 03/28/2022] [Indexed: 01/21/2023]
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27
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Polli FS, Kohlmeier KA. Prenatal nicotine alters development of the laterodorsal tegmentum: Possible role for attention-deficit/hyperactivity disorder and drug dependence. World J Psychiatry 2022; 12:212-235. [PMID: 35317337 PMCID: PMC8900586 DOI: 10.5498/wjp.v12.i2.212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 08/07/2021] [Accepted: 01/14/2022] [Indexed: 02/06/2023] Open
Abstract
As we cycle between the states of wakefulness and sleep, a bilateral cholinergic nucleus in the pontine brain stem, the laterodorsal tegmentum (LDT), plays a critical role in controlling salience processing, attention, behavioral arousal, and electrophysiological signatures of the sub- and microstates of sleep. Disorders involving abnormal alterations in behavioral and motivated states, such as drug dependence, likely involve dysfunctions in LDT signaling. In addition, as the LDT exhibits connectivity with the thalamus and mesocortical circuits, as well as receives direct, excitatory input from the prefrontal cortex, a role for the LDT in cognitive symptoms characterizing attention-deficit/hyperactivity disorder (ADHD) including impulsivity, inflexibility, and dysfunctions of attention is suggested. Prenatal nicotine exposure (PNE) is associated with a higher risk for later life development of drug dependence and ADHD, suggesting alteration in development of brain regions involved in these behaviors. PNE has been shown to alter glutamate and cholinergic signaling within the LDT. As glutamate and acetylcholine are major excitatory mediators, these alterations would likely alter excitatory output to target regions in limbic motivational circuits and to thalamic and cortical networks mediating executive control. Further, PNE alters neuronal development and transmission within prefrontal cortex and limbic areas that send input to the LDT, which would compound effects of differential processing within the PNE LDT. When taken together, alterations in signaling in the LDT are likely to play a role in negative behavioral outcomes seen in PNE individuals, including a heightened risk of drug dependence and ADHD behaviors.
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Affiliation(s)
- Filip S Polli
- Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
| | - Kristi A Kohlmeier
- Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
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28
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Jenkins S, Harker A, Gibb R. Distinct sex-dependent effects of maternal preconception nicotine and enrichment on the early development of rat offspring brain and behavior. Neurotoxicol Teratol 2022; 91:107062. [PMID: 34998861 DOI: 10.1016/j.ntt.2021.107062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 12/14/2021] [Accepted: 12/30/2021] [Indexed: 10/19/2022]
Abstract
Developmental nicotine exposure is harmful to offspring. Whereas much is known about the consequences of prenatal nicotine exposure, relatively little is understood about how maternal preconception nicotine impacts the next generation. Positive experiences, such as environmental enrichment/complexity, have considerable potential to improve developmental outcomes and even treat and prevent drug addiction. Therefore, the current study sought to identify how maternal exposure to moderate levels of nicotine prior to conception impacts offspring development, and if the presumably negative consequence of nicotine could be reversed by concurrent exposure to an enriched environment. We treated female Long Evans rats with nicotine in their drinking water (15 mg nicotine salt/L) for seven weeks while residing in either standard or enriched conditions. Both experiences occurred exclusively prior to mating. Nicotine exposure reduced dam fertility by ~20% (p = .06). Females reared their own litters, and offspring were tested in two assessments of early development: negative geotaxis and open field. Offspring were euthanized at weaning (P21), and their brains were processed with Golgi-Cox solution to allow quantification of dendritic spine density. Results indicate that neither maternal nicotine or enrichment had an impact on maternal care, but male offspring were impaired at negative geotaxis due to maternal nicotine, female offspring showed altered open field exploration due to maternal enrichment, and offspring of both sexes had increased spine density in OFC due to maternal enrichment. Therefore, this experiment provides novel insights into the unique, sex-dependent consequences of maternal preconception nicotine and enrichment on the early development of rat behavior and brain.
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Affiliation(s)
- Serena Jenkins
- Canadian Centre for Behavioural Neuroscience, University of Lethbridge, 4401 University Dr W, Lethbridge, AB T1K 3M4, Canada.
| | - Allonna Harker
- Canadian Centre for Behavioural Neuroscience, University of Lethbridge, 4401 University Dr W, Lethbridge, AB T1K 3M4, Canada.
| | - Robbin Gibb
- Canadian Centre for Behavioural Neuroscience, University of Lethbridge, 4401 University Dr W, Lethbridge, AB T1K 3M4, Canada.
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29
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Zhang L, Levenson CW, Salazar VC, Biederman J, Zafonte R, Bhide PG. Repetitive Mild Traumatic Brain Injury in an Awake, Unanesthetized Mouse Model of Perinatal Nicotine Exposure Produces Transient Novelty-Seeking and Depression-Like Behaviors. J Neurotrauma 2022; 39:954-963. [PMID: 34913733 DOI: 10.1089/neu.2021.0268] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Attention deficit hyperactivity disorder (ADHD) can be a risk factor for repetitive mild traumatic brain injury (mTBI) or concussions such as those that can occur in contact sports. Individuals with ADHD also appear to have a higher risk of poor neurocognitive outcomes after repetitive mTBI. Findings from clinical studies examining the interactions between ADHD and repetitive mTBI vary, likely because of variabilities in experimental design and outcome measures. We used a mouse model of perinatal nicotine exposure (PNE), which displays behavioral, neuroanatomical, and neurotransmitter features consistent with ADHD and subjected the mice to repetitive mTBI. We used a closed head model of mTBI in awake, unanesthetized mice to mimic concussions in humans. The mTBI was repeated three times daily for seven days. The mice in the PNE-mTBI group took longer to regain consciousness after the mTBI and showed transient novelty-seeking and depression-like behaviors. Before the repetitive mTBI, the mice in the PNE group showed attention deficit, which persisted after the mTBI. The mice in the control (non-PNE) group showed a transient attention deficit after the repetitive mTBI but not any of the other behavioral changes seen in the PNE-mTBI group. These findings from an unanesthetized mouse model with a pre-existing condition show that ADHD and repetitive mTBI together contribute to transient novelty-seeking and depression-like behavior supporting the notion that untreated ADHD may be a risk factor for poor neurocognitive outcomes after concussions.
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Affiliation(s)
- Lin Zhang
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Cathy W Levenson
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Valentina Cea Salazar
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Joseph Biederman
- Pediatric Psychopharmacology, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ross Zafonte
- Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Massachusetts General Hospital, Brigham and Women's Hospital, and Harvard Medical School, Charlestown, Massachusetts, USA
| | - Pradeep G Bhide
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
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30
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Buck JM, Yu L, Knopik VS, Stitzel JA. DNA methylome perturbations: an epigenetic basis for the emergingly heritable neurodevelopmental abnormalities associated with maternal smoking and maternal nicotine exposure†. Biol Reprod 2021; 105:644-666. [PMID: 34270696 PMCID: PMC8444709 DOI: 10.1093/biolre/ioab138] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 06/29/2021] [Accepted: 07/14/2021] [Indexed: 11/13/2022] Open
Abstract
Maternal smoking during pregnancy is associated with an ensemble of neurodevelopmental consequences in children and therefore constitutes a pressing public health concern. Adding to this burden, contemporary epidemiological and especially animal model research suggests that grandmaternal smoking is similarly associated with neurodevelopmental abnormalities in grandchildren, indicative of intergenerational transmission of the neurodevelopmental impacts of maternal smoking. Probing the mechanistic bases of neurodevelopmental anomalies in the children of maternal smokers and the intergenerational transmission thereof, emerging research intimates that epigenetic changes, namely DNA methylome perturbations, are key factors. Altogether, these findings warrant future research to fully elucidate the etiology of neurodevelopmental impairments in the children and grandchildren of maternal smokers and underscore the clear potential thereof to benefit public health by informing the development and implementation of preventative measures, prophylactics, and treatments. To this end, the present review aims to encapsulate the burgeoning evidence linking maternal smoking to intergenerational epigenetic inheritance of neurodevelopmental abnormalities, to identify the strengths and weaknesses thereof, and to highlight areas of emphasis for future human and animal model research therein.
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Affiliation(s)
- Jordan M Buck
- Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA
- Department of Integrative Physiology, University of Colorado, Boulder, Boulder, CO, USA
| | - Li Yu
- Department of Human Development and Family Studies, Purdue University, West Lafayette, IN, USA
| | - Valerie S Knopik
- Department of Human Development and Family Studies, Purdue University, West Lafayette, IN, USA
| | - Jerry A Stitzel
- Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA
- Department of Integrative Physiology, University of Colorado, Boulder, Boulder, CO, USA
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31
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McCarthy DM, Bhide PG. Heritable consequences of paternal nicotine exposure: from phenomena to mechanisms†. Biol Reprod 2021; 105:632-643. [PMID: 34126634 PMCID: PMC8444703 DOI: 10.1093/biolre/ioab116] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/14/2021] [Accepted: 06/07/2021] [Indexed: 12/25/2022] Open
Abstract
Our understanding of the interactions between genetic and environmental factors in shaping behavioral phenotypes has expanded to include environment-induced epigenetic modifications and the intriguing possibility of their association with heritable behavioral phenotypes. The molecular basis of heritability of phenotypes arising from environment-induced epigenetic modifications is not well defined yet. However, phenomenological evidence in favor of it is accumulating rapidly. The resurgence of interest has led to focus on epigenetic modification of germ cells as a plausible mechanism of heritability. Perhaps partly because of practical reasons such as ease of access to male germ cells compared to female germ cells, attention has turned toward heritable effects of environmental influences on male founders. Public health implications of heritable effects of paternal exposures to addictive substances or to psycho-social factors may be enormous. Considering nicotine alone, over a billion people worldwide use nicotine-containing products, and the majority are men. Historically, the adverse effects of nicotine use by pregnant women received much attention by scientists and public policy experts alike. The implications of nicotine use by men for the physical and mental well-being of their children were not at the forefront of research until recently. Here, we review progress in the emerging field of heritable effects of paternal nicotine exposure and its implications for behavioral health of individuals in multiple generations.
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Affiliation(s)
- Deirdre M McCarthy
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, 32306, USA
| | - Pradeep G Bhide
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, 32306, USA
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32
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Developmental nicotine exposure impairs memory and reduces acetylcholine levels in the hippocampus of mice. Brain Res Bull 2021; 176:1-7. [PMID: 34358612 DOI: 10.1016/j.brainresbull.2021.07.030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 06/15/2021] [Accepted: 07/30/2021] [Indexed: 12/22/2022]
Abstract
Nicotine is a strong psychoactive and addictive compound found in tobacco. Use of nicotine in the form of smoking, vaping or other less common methods during pregnancy has been shown to be related to poor health conditions, including cognitive problems, in babies and children. However, mechanisms of such cognitive deficits are not fully understood. In this study we analyzed hippocampus dependent cognitive deficits using a mouse model of developmental nicotine exposure. Pregnant dams were exposed to nicotine and experiments were performed in one month old offspring. Our results show that nicotine exposure did not affect locomotor behavior in mice. Hippocampus dependent working memory and object location memory were diminished in nicotine exposed mice. Furthermore, acetylcholine levels in the hippocampus of nicotine exposed mice were reduced along with reduced activity of acetylcholinesterase enzyme. Analysis of transcripts for proteins that are known to regulate acetylcholine levels revealed a decline in mRNA levels of high affinity choline transporters in the hippocampus of nicotine exposed mice but those of vesicular acetylcholine transporter, choline acetyltransferase, and α7-nicotinic acetylcholine receptors were not altered. These results suggest that developmental nicotine exposure impairs hippocampus dependent memory forms and this effect is likely mediated by altered cholinergic function.
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33
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Buck JM, O'Neill HC, Stitzel JA. The Intergenerational Transmission of Developmental Nicotine Exposure-Induced Neurodevelopmental Disorder-Like Phenotypes is Modulated by the Chrna5 D397N Polymorphism in Adolescent Mice. Behav Genet 2021; 51:665-684. [PMID: 34159514 DOI: 10.1007/s10519-021-10071-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 06/07/2021] [Indexed: 12/01/2022]
Abstract
Maternal tobacco smoking during pregnancy constitutes developmental nicotine exposure (DNE) and is associated with nicotine dependence and neurodevelopmental disorders in both children and grandchildren as well as animal models thereof. Genetic variants such as the CHRNA5 single nucleotide polymorphism (SNP) rs16969968, which leads to an aspartic acid to asparagine substitution at amino acid position 398 (D398N) in the alpha-5 nicotinic acetylcholine receptor subunit, can also confer risk for nicotine dependence and neurodevelopmental disorders in the absence of DNE. However, the degrees to which, the consequences of maternal smoking on offspring outcomes are influenced by genetic variants and interactions therewith are not well understood. Addressing this void in the literature, the present study utilizes a DNE mouse model engineered to possess the equivalent of the human D398N SNP in CHRNA5 (D397N SNP in mice) to assess how the N397 risk allele impacts the induction and intergenerational transmission of a range of neurodevelopmental disorder-related behavioral phenotypes in first- and second-generation DNE offspring. Results reveal that offspring possessing the N397 variant in the absence of DNE as well as DNE offspring and grand offspring possessing theD397 variant exhibit analogous neurodevelopmental disorder-like phenotypes including hyperactivity, risk-taking behaviors, aberrant rhythmicity of activity, and enhanced nicotine consumption. DNE amplified these behavioral anomalies in first-generation N397 progeny, but the severity of DNE-evoked behavioral perturbations did not significantly differ between first-generation D397 and N397 DNE mice for any measure. Remarkably, the behavioral profiles of second-generation N397 DNE progeny closely resembled DNE-naive D397 mice, suggesting that the N397 variant may protect against the intergenerational transmission of DNE-induced neurodevelopmental disorder-like behaviors.
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Affiliation(s)
- Jordan M Buck
- Institute for Behavioral Genetics, University of Colorado Boulder, 1480 30th Street, Boulder, CO, 80309-0447, USA
- Department of Integrative Physiology, University of Colorado, Boulder, USA
| | - Heidi C O'Neill
- Institute for Behavioral Genetics, University of Colorado Boulder, 1480 30th Street, Boulder, CO, 80309-0447, USA
| | - Jerry A Stitzel
- Institute for Behavioral Genetics, University of Colorado Boulder, 1480 30th Street, Boulder, CO, 80309-0447, USA.
- Department of Integrative Physiology, University of Colorado, Boulder, USA.
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34
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Martin MM, McCarthy DM, Schatschneider C, Trupiano MX, Jones SK, Kalluri A, Bhide PG. Effects of Developmental Nicotine Exposure on Frontal Cortical GABA-to-Non-GABA Neuron Ratio and Novelty-Seeking Behavior. Cereb Cortex 2021; 30:1830-1842. [PMID: 31599922 DOI: 10.1093/cercor/bhz207] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Cigarette smoking during pregnancy is a major public health concern, resulting in detrimental health effects in the mother and her offspring. The adverse behavioral consequences for children include increased risk for attention deficit hyperactivity disorder, working memory deficits, epilepsy, novelty-seeking, and risk-taking behaviors. Some of these behavioral conditions are consistent with an imbalance in frontal cortical excitatory (glutamate) and inhibitory (GABA) neurotransmitter signaling. We used a GAD67-GFP knock-in mouse model to examine if developmental nicotine exposure alters frontal cortical GABA neuron numbers, GABA-to-non-GABA neuron ratio and behavioral phenotypes. Female mice were exposed to nicotine (100 or 200 μg/mL) in drinking water beginning 3 weeks prior to breeding and until 3 weeks postpartum. Male and female offspring were examined beginning at 60 days of age. The nicotine exposure produced dose-dependent decreases in GABA-to-non-GABA neuron ratios in the prefrontal and medial prefrontal cortices without perturbing the intrinsic differences in cortical thickness and laminar distribution of GABA or non-GABA neurons between these regions. A significant increase in exploratory behavior and a shift toward "approach" in the approach-avoidance paradigm were also observed. Thus, developmental nicotine exposure shifts the cortical excitation-inhibition balance toward excitation and produces behavioral changes consistent with novelty-seeking behavior.
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Affiliation(s)
- Melissa M Martin
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306-4300, USA
| | - Deirdre M McCarthy
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306-4300, USA
| | - Chris Schatschneider
- Department of Psychology, Florida State University, Tallahassee, FL 32306-4300, USA
| | - Mia X Trupiano
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306-4300, USA
| | - Sara K Jones
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306-4300, USA
| | - Aishani Kalluri
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306-4300, USA
| | - Pradeep G Bhide
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306-4300, USA
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35
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Zhang L, Levenson CW, Salazar VC, McCarthy DM, Biederman J, Zafonte R, Bhide PG. Repetitive Mild Traumatic Brain Injury in a Perinatal Nicotine Exposure Mouse Model of Attention Deficit Hyperactivity Disorder. Dev Neurosci 2021; 43:63-72. [PMID: 33849015 DOI: 10.1159/000515198] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 02/11/2021] [Indexed: 11/19/2022] Open
Abstract
Attention deficit hyperactivity disorder (ADHD) increases the risk for concussion or mild traumatic brain injury (mTBI). At the same time, recommendations for the management of ADHD include participation in sports and other organized physical activities, including those that carry an increased risk of mTBI. Very little work has been done to determine the extent to which untreated ADHD adversely impacts behavioral outcomes of repeated mild concussions. Here, we used a perinatal nicotine exposure (PNE) mouse model of ADHD combined with a closed-head, repetitive mTBI model. The PNE mouse model carries significant construct, face, and predictive validity as a preclinical model of ADHD. Two-month-old PNE and control mice were subjected to closed-head repetitive mTBI or sham procedure once daily for 5 days. Object-based attention, novel object recognition memory, spatial working memory, and depression-like behavior were analyzed 1 day and 2 weeks following repeated mTBI. Consistent with our previous reports, mice in the PNE group showed significant deficits in object-based attention and working memory prior to mTBI. These deficits persisted following the repeated mTBI. Repeated mTBI produced a transient attention deficit in the control group but did not exacerbate the attention deficit that is characteristic of the PNE group. Although neither PNE nor repetitive mTBI alone influenced immobility in the tail suspension test, when PNE mice were subjected to mTBI, there was a transient increase in this measurement suggesting a synergistic effect of ADHD and mTBI on depression-like behavior. Thus, our data using the PNE mouse model suggest that ADHD may be a risk factor for transient depression following repeated mTBI and that repeated mTBI may be a risk factor for transient attention deficit.
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Affiliation(s)
- Lin Zhang
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Cathy W Levenson
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Valentina Cea Salazar
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Deirdre M McCarthy
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Joseph Biederman
- Pediatric Psychopharmacology, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ross Zafonte
- Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Massachusetts General hospital, Brigham and Women's Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
| | - Pradeep G Bhide
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
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Zhang L, McCarthy DM, Eskow Jaunarajs KL, Biederman J, Spencer TJ, Bhide PG. Frontal Cortical Monoamine Release, Attention, and Working Memory in a Perinatal Nicotine Exposure Mouse Model Following Kappa Opioid Receptor Antagonism. Cereb Cortex 2021; 31:483-496. [PMID: 32869057 DOI: 10.1093/cercor/bhaa238] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 08/01/2020] [Accepted: 08/03/2020] [Indexed: 02/27/2024] Open
Abstract
Perinatal nicotine exposure (PNE) produces frontal cortical hypo-dopaminergic state and attention and working memory deficits consistent with neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD). Methylphenidate alleviates ADHD symptoms by increasing extracellular dopamine and noradrenaline. Kappa opioid receptor (KOR) antagonism may be another mechanism to achieve the same results because KOR activation inhibits frontal cortical dopamine release. We administered the selective KOR antagonist norbinaltorphimine (norBNI) (20 mg/kg; intraperitoneal) or methylphenidate (0.75 mg/kg; intraperitoneal) to PNE mouse model and examined frontal cortical monoamine release, attention, and working memory. Both compounds increased dopamine and noradrenaline release but neither influenced serotonin release. Both compounds improved object-based attention and working memory in the PNE group, with norBNI's effects evident at 2.5 h and 5.5 h but absent at 24 h. Methylphenidate's effects were evident at 0.5 h but not at 2.5 h. norBNI's effects temporally coincided with frontal cortical c-Jun N-terminal kinase phosphorylation. norBNI did not alter tissue dopamine content in the nucleus accumbens, offering preliminary support for lack of reinforcement.
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Affiliation(s)
- Lin Zhang
- Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA
| | - Deirdre M McCarthy
- Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA
| | | | - Joseph Biederman
- Pediatric Psychopharmacology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Thomas J Spencer
- Pediatric Psychopharmacology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Pradeep G Bhide
- Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA
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Jamshed L, Perono GA, Jamshed S, Holloway AC. Early Life Exposure to Nicotine: Postnatal Metabolic, Neurobehavioral and Respiratory Outcomes and the Development of Childhood Cancers. Toxicol Sci 2020; 178:3-15. [PMID: 32766841 PMCID: PMC7850035 DOI: 10.1093/toxsci/kfaa127] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Cigarette smoking during pregnancy is associated with numerous obstetrical, fetal, and developmental complications, as well as an increased risk of adverse health consequences in the adult offspring. Nicotine replacement therapy and electronic nicotine delivery systems (e-cigarettes) have been developed as a pharmacotherapy for smoking cessation and are considered safer alternatives for women to smoke during pregnancy. The safety of nicotine replacement therapy use during pregnancy has been evaluated in a limited number of short-term human trials, but there is currently no information on the long-term effects of developmental nicotine exposure in humans. However, animal studies suggest that nicotine alone may be a key chemical responsible for many of the long-term effects associated with maternal cigarette smoking on the offspring and increases the risk of adverse neurobehavioral outcomes, dysmetabolism, respiratory illness, and cancer. This review will examine the long-term effects of fetal and neonatal nicotine exposure on postnatal health.
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Affiliation(s)
- Laiba Jamshed
- Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario L8N 3Z5, Canada
| | - Genevieve A Perono
- Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario L8N 3Z5, Canada
| | - Shanza Jamshed
- Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario L8N 3Z5, Canada
| | - Alison C Holloway
- Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario L8N 3Z5, Canada
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Schmidt S. E-Cigarette Aerosols and the Brain: Behavioral and Neuroinflammatory Changes in Prenatally Exposed Adult Mice. ENVIRONMENTAL HEALTH PERSPECTIVES 2020; 128:104005. [PMID: 33104447 PMCID: PMC7587668 DOI: 10.1289/ehp7315] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 04/29/2020] [Indexed: 06/11/2023]
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McCarthy DM, Lowe SE, Morgan TJ, Cannon EN, Biederman J, Spencer TJ, Bhide PG. Transgenerational transmission of behavioral phenotypes produced by exposure of male mice to saccharin and nicotine. Sci Rep 2020; 10:11974. [PMID: 32686722 PMCID: PMC7371742 DOI: 10.1038/s41598-020-68883-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Accepted: 06/30/2020] [Indexed: 12/12/2022] Open
Abstract
The use of non-nutritive sweeteners such as saccharin is widely prevalent. Although saccharin is considered safe for human consumption, it produces behavioral changes in experimental animals. We report that saccharin’s behavioral effects are much more pervasive than currently recognized. In a mouse model, saccharin exposure produced motor impulsivity not only in the saccharin-exposed males but also in their offspring. In addition, the offspring showed locomotor hyperactivity and working memory deficit not observed in fathers. Spermatazoal DNA was hypermethylated in the saccharin-exposed fathers, especially at dopamine receptor promoter regions, suggesting that epigenetic modification of germ cell DNA may mediate transgenerational transmission of behavioral phenotypes. Dopamine’s role in hyperactivity was further highlighted by the finding that the stimulant drug methylphenidate mitigated the hyperactivity. Nicotine is another substance that is widely used. Its use via smokeless tobacco products, some of which contain saccharin, is on the rise contributing to concerns about adverse outcomes of co-exposure to saccharin and nicotine. We found that co-exposure of male mice to saccharin and nicotine produced significant behavioral impairment in their offspring. Thus, our data point to potential adverse neurobehavioral consequences of exposure to saccharin alone or saccharin and nicotine for the exposed individuals and their descendants.
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Affiliation(s)
- Deirdre M McCarthy
- Biomedical Sciences and Center for Brain Repair, College of Medicine, Florida State University, 1115, West Call Street, Tallahassee, FL, 32306, USA
| | - Sarah E Lowe
- Biomedical Sciences and Center for Brain Repair, College of Medicine, Florida State University, 1115, West Call Street, Tallahassee, FL, 32306, USA
| | - Thomas J Morgan
- Biomedical Sciences and Center for Brain Repair, College of Medicine, Florida State University, 1115, West Call Street, Tallahassee, FL, 32306, USA.,School of Physician Assistant Practice, College of Medicine, Florida State University, 1115, West Call Street, Tallahassee, FL, 32306, USA
| | - Elisa N Cannon
- Biomedical Sciences and Center for Brain Repair, College of Medicine, Florida State University, 1115, West Call Street, Tallahassee, FL, 32306, USA
| | - Joseph Biederman
- Pediatric Psychopharmacology, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Thomas J Spencer
- Pediatric Psychopharmacology, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Pradeep G Bhide
- Biomedical Sciences and Center for Brain Repair, College of Medicine, Florida State University, 1115, West Call Street, Tallahassee, FL, 32306, USA.
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Mamiya T, Tanase S, Takeuchi S, Kato S, Ito A, Hiramatsu M, Nabeshima T. Galantamine improves enhanced impulsivity, impairments of attention and long-term potentiation induced by prenatal nicotine exposure to mice. Biochem Pharmacol 2020; 180:114139. [PMID: 32652142 DOI: 10.1016/j.bcp.2020.114139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/02/2020] [Accepted: 07/06/2020] [Indexed: 12/21/2022]
Abstract
Prenatal nicotine exposure (PNE) causes behavioral abnormalities in offspring, such as an enhancement of impulsivity and decrease in attention at adolescence. Here we examined the effects of galantamine (GAL) on the behavioral and electrophysiological changes induced by PNE in mice. Pregnant C57BL/6J mice were exposed to nicotine (0.2 mg/mL) dissolved in sweetened (2% saccharin) drinking water during gestational day 14 and perinatal day 0 (P0). At the ages of postnatal days 42-49 (P42-P49), female offspring displayed impulsivity in the cliff avoidance test and impairment of visual attention in the object-based attention test. Decrease of long-term potentiation (LTP) and extracellular glutamate levels were observed in the prefrontal cortex of PNE mice. Systemic treatment with GAL (1 mg/kg, s.c.), an allosteric potentiating ligand for the nicotinic acetylcholine receptor (nAChR) and a weak cholinesterase inhibitor, attenuated the enhancement of impulsivity and impairment of attention induced by PNE in mice. Further, GAL reversed the impairment of LTP induced by PNE in the prefrontal cortex of mice, although it failed to attenuate the decrease of extracellular glutamate levels. The effects of GAL were blocked by an α 7 nAChR antagonist, methyllycaconitine (1 mg/kg, i.p.). These results suggest that PNE during cortex development affects nicotinic cholinergic-dependent plasticity and formation of impulsivity and attention. Furthermore, GAL could be a useful drug for cognitive impairments-related to attention deficit hyperactivity disorder.
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Affiliation(s)
- Takayoshi Mamiya
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan; Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan.
| | - Shota Tanase
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Shino Takeuchi
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Shunsuke Kato
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Ai Ito
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Masayuki Hiramatsu
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan; Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan
| | - Toshitaka Nabeshima
- Advanced Diagnostic System Research Laboratory, Graduate School of Health Sciences, Fujita Health University, Toyoake, Japan; Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan
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Piña R, Rozas C, Contreras D, Hardy P, Ugarte G, Zeise ML, Rojas P, Morales B. Atomoxetine Reestablishes Long Term Potentiation in a Mouse Model of Attention Deficit/Hyperactivity Disorder. Neuroscience 2020; 439:268-274. [DOI: 10.1016/j.neuroscience.2019.10.040] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 06/21/2019] [Accepted: 10/23/2019] [Indexed: 10/25/2022]
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Polli FS, Scharff MB, Ipsen TH, Aznar S, Kohlmeier KA, Andreasen JT. Prenatal nicotine exposure in mice induces sex-dependent anxiety-like behavior, cognitive deficits, hyperactivity, and changes in the expression of glutamate receptor associated-genes in the prefrontal cortex. Pharmacol Biochem Behav 2020; 195:172951. [PMID: 32439454 DOI: 10.1016/j.pbb.2020.172951] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 12/29/2022]
Abstract
In rodents, prenatal nicotine exposure (PNE) has been associated with increased risk for development of cognitive and emotional disturbances, but the findings are somewhat conflicting. Lack of behavioral alterations following PNE could be due to the variety of methods available for nicotine delivery, exposure time and species used, with inbred strains being mostly employed. Such differences suggest the need to investigate the behavioral phenotype in each PNE model available if we are to find models with enhanced translational value. In this study, we assessed sex-dependent effects of PNE on ADHD-related behaviors and on the levels of mRNA coding for glutamate receptor subunits within the prefrontal cortex in the outbred NMRI mice exposed to nicotine via maternal drinking water during gestation. Cotinine levels were assessed in newborn pups. Behaviors related to anxiety, compulsivity, working memory, and locomotion were evaluated in both sexes of young adult offspring using the elevated zero maze, marble burying, spontaneous alternation behavior, and locomotor activity tests. Expression of mRNA coding for different glutamate receptors subunits within the prefrontal cortex (PFC) was measured using RT-qPCR. Cotinine levels in the serum of newborns confirmed fetal nicotine exposure. Both male and female offspring showed ADHD-like behaviors, such as deficit in the SAB test and hyperactivity. In addition, PNE male mice displayed anxiety- and compulsive-like behaviors, effects that were absent in female offspring. Finally, PNE reduced the mRNA expression of GluN1-, GluN2B-, and mGluR2-related genes within the PFC of male offspring, whereas it reduced the expression of mRNA coding for GluA2 subunit in female mice. PNE in NMRI mice induced sex-dependent behavioral changes, which parallels clinical findings following maternal cigarette smoke exposure. Alterations detected in PFC mRNA glutamate receptor proteins could contribute to the abnormal behavioral responses observed, but other signaling pathways or brain regions are likely involved in the behavioral susceptibility of PNE individuals.
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Affiliation(s)
- Filip S Polli
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark
| | - Malthe B Scharff
- Research Laboratory for Stereology and Neuroscience, Bispebjerg Hospital, Copenhagen 2400, Denmark
| | - Theis H Ipsen
- Research Laboratory for Stereology and Neuroscience, Bispebjerg Hospital, Copenhagen 2400, Denmark
| | - Susana Aznar
- Research Laboratory for Stereology and Neuroscience, Bispebjerg Hospital, Copenhagen 2400, Denmark
| | - Kristi A Kohlmeier
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark
| | - Jesper T Andreasen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark.
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Church JS, Chace-Donahue F, Blum JL, Ratner JR, Zelikoff JT, Schwartzer JJ. Neuroinflammatory and Behavioral Outcomes Measured in Adult Offspring of Mice Exposed Prenatally to E-Cigarette Aerosols. ENVIRONMENTAL HEALTH PERSPECTIVES 2020; 128:47006. [PMID: 32293200 PMCID: PMC7228099 DOI: 10.1289/ehp6067] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
BACKGROUND In an effort to decrease the rates of smoking conventional tobacco cigarettes, electronic cigarettes (e-cigarettes) have been proposed as an effective smoking cessation tool. However, little is known about their toxicological impacts. This is concerning given that e-cigarette use is perceived as less harmful than conventional tobacco cigarettes during pregnancy for both the mother and fetus. OBJECTIVE The goal of this study was to test the neurodevelopmental consequences of maternal e-cigarette use on adult offspring behavior and neuroimmune outcomes. METHODS Pregnant female CD-1 mice were randomly assigned to one of three treatment groups (n=8-10 per group) and exposed daily to either filtered air, propylene glycol and vegetable glycerol (50:50 PG/VG vehicle), or to PG/VG with 16mg/mL nicotine (+Nic). Whole-body exposures were carried out for 3 h/d, 7 d/week, from gestational day (GD)0.5 until GD17.5. Adult male and female offspring (8 weeks old) were assessed across a battery of behavioral assessments followed by region-specific quantification of brain cytokines using multiplex immunoassays. RESULTS Adult offspring of both sexes exposed to +Nic exhibited elevated locomotor activity in the elevated plus maze and altered stress-coping strategies in the forced swim task. Moreover, male and female offspring exposed to PG/VG with and without nicotine had a 5.2% lower object discrimination score in the novel object recognition task. In addition to differences in offspring behavior, maternal e-cigarette exposure with nicotine led to a reduction in interleukin (IL)-4 and interferon-gamma (IFNγ) in the diencephalon, as well as lower levels of hippocampal IFNγ (females only). E-cigarette exposure without nicotine resulted in a 2-fold increase of IL-6 in the cerebellum. DISCUSSION These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.
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Affiliation(s)
- Jamie S. Church
- Program in Neuroscience and Behavior, Department of Psychology and Education, Mount Holyoke College, South Hadley, Massachusetts, USA
| | - Fiona Chace-Donahue
- Program in Neuroscience and Behavior, Department of Psychology and Education, Mount Holyoke College, South Hadley, Massachusetts, USA
| | - Jason L. Blum
- Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA
| | - Jill R. Ratner
- Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA
| | - Judith T. Zelikoff
- Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA
| | - Jared J. Schwartzer
- Program in Neuroscience and Behavior, Department of Psychology and Education, Mount Holyoke College, South Hadley, Massachusetts, USA
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Buck JM, O'Neill HC, Stitzel JA. Developmental nicotine exposure engenders intergenerational downregulation and aberrant posttranslational modification of cardinal epigenetic factors in the frontal cortices, striata, and hippocampi of adolescent mice. Epigenetics Chromatin 2020; 13:13. [PMID: 32138755 PMCID: PMC7059320 DOI: 10.1186/s13072-020-00332-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 02/19/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Maternal smoking of traditional or electronic cigarettes during pregnancy, which constitutes developmental nicotine exposure (DNE), heightens the risk of neurodevelopmental disorders including ADHD, autism, and schizophrenia in children. Modeling the intergenerationally transmissible impacts of smoking during pregnancy, we previously demonstrated that both the first- and second-generation adolescent offspring of nicotine-exposed female mice exhibit enhanced nicotine preference, hyperactivity and risk-taking behaviors, aberrant rhythmicity of home cage activity, nicotinic acetylcholine receptor and dopamine transporter dysfunction, impaired furin-mediated proBDNF proteolysis, hypocorticosteronemia-related glucocorticoid receptor hypoactivity, and global DNA hypomethylation in the frontal cortices and striata. This ensemble of multigenerational DNE-induced behavioral, neuropharmacological, neurotrophic, neuroendocrine, and DNA methylomic anomalies recapitulates the pathosymptomatology of neurodevelopmental disorders such as ADHD, autism, and schizophrenia. Further probing the epigenetic bases of DNE-induced multigenerational phenotypic aberrations, the present study examined the expression and phosphorylation of key epigenetic factors via an array of immunoblot experiments. RESULTS Data indicate that DNE confers intergenerational deficits in corticostriatal DNA methyltransferase 3A (DNMT3A) expression accompanied by downregulation of methyl-CpG-binding protein 2 (MeCP2) and histone deacetylase 2 (HDAC2) in the frontal cortices and hippocampi, while the expression of ten-eleven translocase methylcytosine dioxygenase 2 (TET2) is unaltered. Moreover, DNE evokes multigenerational abnormalities in HDAC2 (Ser394) but not MeCP2 (Ser421) phosphorylation in the frontal cortices, striata, and hippocampi. CONCLUSIONS In light of the extensive gene regulatory roles of DNMT3A, MeCP2, and HDAC2, the findings of this study that DNE elicits downregulation and aberrant posttranslational modification of these factors in both first- and second-generation DNE mice suggest that epigenetic perturbations may constitute a mechanistic hub for the intergenerational transmission of DNE-induced neurodevelopmental disorder-like phenotypes.
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Affiliation(s)
- Jordan M Buck
- Institute for Behavioral Genetics, University of Colorado, 1480 30th Street, Boulder, CO, 80309-0447, USA.
- Department of Integrative Physiology, University of Colorado, Boulder, USA.
| | - Heidi C O'Neill
- Institute for Behavioral Genetics, University of Colorado, 1480 30th Street, Boulder, CO, 80309-0447, USA
| | - Jerry A Stitzel
- Institute for Behavioral Genetics, University of Colorado, 1480 30th Street, Boulder, CO, 80309-0447, USA
- Department of Integrative Physiology, University of Colorado, Boulder, USA
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Wu CS, Jew CP, Sun H, Ballester Rosado CJ, Lu HC. mGlu5 in GABAergic neurons modulates spontaneous and psychostimulant-induced locomotor activity. Psychopharmacology (Berl) 2020; 237:345-361. [PMID: 31646346 PMCID: PMC7024012 DOI: 10.1007/s00213-019-05367-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 09/22/2019] [Indexed: 12/17/2022]
Abstract
RATIONALE A role of group I metabotropic glutamate receptor 5 (mGlu5) in regulating spontaneous locomotion and psychostimulant-induced hyperactivity has been proposed. OBJECTIVES This study aims to determine if mGlu5 in GABAergic neurons regulates spontaneous or psychostimulant-induced locomotion. METHODS We generated mice specifically lacking mGlu5 in forebrain GABAergic neuron by crossing DLX-Cre mice with mGlu5flox/flox mice to generate DLX-mGlu5 KO mice. The locomotion of adult mice was examined in the open-field assay (OFA) and home cage setting. The effects of the mGlu5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP), cocaine, and methylphenidate on acute motor behaviors in DLX-mGlu5 KO and littermate control mice were assessed in OFA. Striatal synaptic plasticity of these mice was examined with field potential electrophysiological recordings. RESULTS Deleting mGlu5 from forebrain GABAergic neurons results in failure to induce long-term depression (LTD) in the dorsal striatum and absence of habituated locomotion in both novel and familiar settings. In a familiar environment (home cage), DLX-mGlu5 KO mice were hyperactive. In the OFA, DLX-mGlu5 KO mice exhibited initial hypo-activity, and then gradually increased their locomotion with time, resulting in no habituation response. DLX-mGlu5 KO mice exhibited almost no locomotor response to MPEP (40 mg/kg), while the same dose elicited hyperlocomotion in control mice. The DLX-mGlu5 KO mice also showed reduced hyperactivity response to cocaine, while they retained normal hyperactivity response to methylphenidate, albeit with delayed onset. CONCLUSION mGlu5 in forebrain GABAergic neurons is critical to trigger habituation upon the initiation of locomotion as well as to mediate MPEP-induced hyperlocomotion and modulate psychostimulant-induced hyperactivity.
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Affiliation(s)
- Chia-Shan Wu
- The Cain Foundation Laboratories, Baylor College of Medicine, Houston, 77030, TX, USA.
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, 77030, TX, USA.
- Department of Nutrition and Food Science, Texas A&M University, 123 Cater-Mattil, 2253 TAMU, College Station, TX, 77843, USA.
| | - Christopher P Jew
- The Cain Foundation Laboratories, Baylor College of Medicine, Houston, 77030, TX, USA
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, 77030, TX, USA
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Hao Sun
- The Cain Foundation Laboratories, Baylor College of Medicine, Houston, 77030, TX, USA
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, 77030, TX, USA
| | - Carlos J Ballester Rosado
- The Cain Foundation Laboratories, Baylor College of Medicine, Houston, 77030, TX, USA
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, 77030, TX, USA
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Hui-Chen Lu
- The Cain Foundation Laboratories, Baylor College of Medicine, Houston, 77030, TX, USA.
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, 77030, TX, USA.
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
- Linda and Jack Gill Center, Department of Psychological and Brain Sciences, Indiana University, 1101 E. 10th Street, Bloomington, IN, 47405, USA.
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Zhang M, Zhang D, Dai J, Cao Y, Xu W, He G, Wang Z, Wang L, Li R, Qiao Z. Paternal nicotine exposure induces hyperactivity in next-generation via down-regulating the expression of DAT. Toxicology 2020; 431:152367. [DOI: 10.1016/j.tox.2020.152367] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 12/29/2019] [Accepted: 01/12/2020] [Indexed: 11/29/2022]
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Cellular and Molecular Changes in Hippocampal Glutamate Signaling and Alterations in Learning, Attention, and Impulsivity Following Prenatal Nicotine Exposure. Mol Neurobiol 2020; 57:2002-2020. [PMID: 31916029 DOI: 10.1007/s12035-019-01854-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 12/11/2019] [Indexed: 12/18/2022]
Abstract
Over 70 million European pregnant women are smokers during their child-bearing years. Consumption of tobacco-containing products during pregnancy is associated with several negative behavioral outcomes for the offspring, including a higher susceptibility for the development of attention-deficit/hyperactive disorder (ADHD). In efforts to minimize fetal exposure to tobacco smoke, many women around the world switch to nicotine replacement therapies (NRTs) during the gestational period; however, prenatal nicotine exposure (PNE) in any form has been associated with alterations in cognitive processes, including learning, memory, and attention. These processes are controlled by glutamatergic signaling of hippocampal pyramidal neurons within the CA1 region, suggesting actions of nicotine on glutamatergic transmission in this region if present prenatally. Accordingly, we aimed to investigate hippocampal glutamatergic function following PNE treatment in NMRI mice employing molecular, cellular electrophysiology, and pharmacological approaches, as well as to evaluate cognition in the rodent continuous performance task (rCPT), a recently developed mouse task allowing assessment of learning, attention, and impulsivity. PNE induced increases in the expression levels of mRNA coding for different glutamate receptors and subunits within the hippocampus. Functional alterations in AMPA and NMDA receptors on CA1 pyramidal neurons of PNE mice were suggestive of higher GluA2-lacking and lower GluN2A-containing receptors, respectively. Finally, PNE was associated with reduced learning, attention, and enhanced impulsivity in the rCPT. Alterations in glutamatergic functioning in CA1 neurons parallel changes seen in the spontaneously hypertensive rat ADHD model and likely contribute to the lower cognitive performance in the rCPT.
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Lai IC, Dulcis D. Nicotine-induced dopamine plasticity: a gateway to neurotransmitter replacement? Neural Regen Res 2020; 15:73-74. [PMID: 31535653 PMCID: PMC6862394 DOI: 10.4103/1673-5374.264451] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- I-Chi Lai
- Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Davide Dulcis
- Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA
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Polli FS, Kohlmeier KA. Prenatal Nicotine Exposure in Rodents: Why Are There So Many Variations in Behavioral Outcomes? Nicotine Tob Res 2019; 22:1694-1710. [DOI: 10.1093/ntr/ntz196] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 10/05/2019] [Indexed: 01/01/2023]
Abstract
Abstract
Introduction
The World Health Organization (WHO) reported that smoking cessation rates among women have stagnated in the past decade and estimates that hundreds of millions of women will be smokers in the next decade. Social, environmental, and biological conditions render women more susceptible to nicotine addiction, imposing additional challenges to quit smoking during gestation, which is likely why more than 8% of pregnancies in Europe are associated with smoking. In epidemiological investigations, individuals born from gestational exposure to smoking exhibit a higher risk of development of attention-deficit/hyperactive disorder (ADHD) and liability to drug dependence. Among other teratogenic compounds present in tobacco smoke, nicotine actions during neuronal development could contribute to the observed outcomes as nicotine misleads signaling among progenitor cells during brain development. Several experimental approaches have been developed to address the consequences of prenatal nicotine exposure (PNE) to the brain and behavior but, after four decades of studies, inconsistent data have been reported and the lack of consensus in the field has compromised the hypothesis that gestational nicotine exposure participates in cognitive and emotional behavioral deficits.
Aims
In this review, we discuss the most commonly used PNE models with focus on their advantages and disadvantages, their relative validity, and how the different technical approaches could play a role in the disparate outcomes.
Results
We propose methodological considerations, which could improve the translational significance of the PNE models.
Conclusions
Such alterations might be helpful in reconciling experimental findings, as well as leading to development of treatment targets for maladaptive behaviors in those prenatally exposed.
Implications
In this article, we have reviewed the advantages and disadvantages of different variables of the commonly used experimental models of PNE. We discuss how variations in the nicotine administration methods, the timing of nicotine exposure, nicotine doses, and species employed could contribute to the disparate findings in outcomes for PNE offspring, both in behavior and neuronal changes. In addition, recent findings suggest consideration of epigenetic effects extending across generations. Finally, we have suggested improvements in the available PNE models that could contribute to the enhancement of their validity, which could assist in the reconciliation of experimental findings.
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Affiliation(s)
- Filip Souza Polli
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kristi Anne Kohlmeier
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Buck JM, O'Neill HC, Stitzel JA. Developmental nicotine exposure elicits multigenerational disequilibria in proBDNF proteolysis and glucocorticoid signaling in the frontal cortices, striata, and hippocampi of adolescent mice. Biochem Pharmacol 2019; 168:438-451. [PMID: 31404529 DOI: 10.1016/j.bcp.2019.08.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 08/07/2019] [Indexed: 01/03/2023]
Abstract
Maternal smoking of conventional or vapor cigarettes during pregnancy, a form of developmental nicotine exposure (DNE), enhances the risk of neurodevelopmental disorders such as ADHD, autism, and schizophrenia in children. Modeling the multigenerational effects of smoking during pregnancy and nursing in the first- (F1) and second- (F2) generation adolescent offspring of oral nicotine-treated female C57BL/6J mice, we have previously reported that DNE precipitates intergenerational transmission of nicotine preference, hyperactivity and impulsivity-like behaviors, altered rhythmicity of home cage activity, corticostriatal nicotinic acetylcholine receptor and dopamine transporter dysfunction, and corticostriatal global DNA methylome deficits. In aggregate, these DNE-evoked behavioral, neuropharmacological, and epigenomic anomalies mirror fundamental etiological aspects of neurodevelopmental disorders including ADHD, autism, and schizophrenia. Expanding this line of research, the current study profiled the multigenerational neurotrophic and neuroendocrine consequences of DNE. Results reveal impaired proBDNF proteolysis as indicated by proBDNF-BDNF imbalance, downregulation of the proBDNF processing enzyme furin, atypical glucocorticoid receptor (GR) activity as implied by decreased relative nuclear GR localization, and deficient basal plasma corticosterone (CORT) levels in adolescent DNE offspring and grandoffspring. Collectively, these data recapitulate the BDNF deficits and HPA axis dysregulation characteristic of neurodevelopmental disorders such as ADHD, autism, and schizophrenia as well as the children of maternal smokers. Notably, as BDNF is a quintessential mediator of neurodevelopment, our prior findings of multigenerational DNE-induced behavioral and neuropharmacological abnormalities may stem from neurodevelopmental insults conferred by the proBDNF-BDNF imbalance detected in DNE mice. Similarly, our findings of multigenerational GR hypoactivity may contribute to the increased risk-taking behaviors and aberrant circadian rhythmicity of home cage activity that we previously documented in first- and second-generation DNE mice.
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Affiliation(s)
- Jordan M Buck
- Institute for Behavioral Genetics, University of Colorado, Boulder, United States; Department of Integrative Physiology, University of Colorado, Boulder, United States.
| | - Heidi C O'Neill
- Institute for Behavioral Genetics, University of Colorado, Boulder, United States
| | - Jerry A Stitzel
- Institute for Behavioral Genetics, University of Colorado, Boulder, United States; Department of Integrative Physiology, University of Colorado, Boulder, United States
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