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Bangasser DA, Wicks B, Waxler DE, Eck SR. Touchscreen Sustained Attention Task (SAT) for Rats. J Vis Exp 2017. [PMID: 28994786 DOI: 10.3791/56219] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Sustained attention is the ability to monitor intermittent and unpredictable events over a prolonged period of time. This attentional process subserves other aspects of cognition and is disrupted in certain neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Thus, it is clinically important to identify mechanisms that impair and improve sustained attention. Such mechanisms are often first discovered using rodent models. Therefore, several behavior procedures for testing aspects of sustained attention have been developed for rodents. One, first described by McGaughy and Sarter (1995), called the sustained attention task (SAT), trains rats to distinguish between signal (i.e., brief light presentation) and non-signal trials. The signals are short and thus require careful attention to be perceived. Attentional demands can be increased further by introducing a distractor (e.g., flashing houselight). We have modified this task for touchscreen operant chambers, which are configured with a touchscreen on one wall that can present stimuli and record responses. Here we detail our protocol for SAT in touchscreen chambers. Additionally, we present standard measures of performance in male and female Sprague-Dawley rats. Comparable performance on this task in both sexes highlights its use for attention studies, especially as more researchers are including female rodents in their experimental design. Moreover, the easy implementation of SAT for the increasingly popular touchscreen chambers increases its utility.
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Affiliation(s)
- Debra A Bangasser
- Psychology Department, Temple University; Neuroscience Program, Temple University;
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2
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Auger ML, Meccia J, Floresco SB. Regulation of sustained attention, false alarm responding and implementation of conditional rules by prefrontal GABA A transmission: comparison with NMDA transmission. Psychopharmacology (Berl) 2017. [PMID: 28646451 DOI: 10.1007/s00213-017-4670-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
RATIONALE Both prefrontal cortex (PFC) GABAA and NMDA transmission regulate attentional processes, yet how they may differentially regulate signal detection or other aspects of attention is unclear. OBJECTIVES We examined PFC GABAA and NMDA receptor regulation of attention using a sustained attention task (SAT) permitting identification of distinct forms of impairments. As this task requires implementation of conditional rules, we also investigated how reducing PFC GABA transmission affected performance of visual and auditory conditional discriminations. METHODS Male rats were well-trained on the SAT that required identifying whether a brief visual stimulus (500-50 ms) was present/absent by pressing one of two levers. They then received intra-PFC infusions of the GABAA antagonist bicuculline (12.5-50 ng), the NMDA antagonist MK-801 (6 μg), and i.p. injections of MK-801 (0.1-0.3 mg/kg) prior to testing. Separate groups were trained either on a similar task where the visual stimulus was presented for 2.5 s, or a task where presentation of one of two auditory cues required responding on a left or right lever. RESULTS Both doses of bicuculline impaired vigilance, selectively increasing errors during nonsignal trials. Intra-PFC MK-801 induced subtle impairments at short signal durations. Systemic MK-801 impaired performance and increased response latencies. Visual and auditory conditional discrimination was impaired by 50 ng, but not 12.5 ng of bicuculline. CONCLUSIONS These findings highlight a key role for PFC GABA transmission in reducing sensitivity to distractors during attentional performance. Furthermore, they reveal that disruption of GABA signaling can interfere with the ability to implement conditional rules.
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Affiliation(s)
- Meagan L Auger
- Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
| | - Juliet Meccia
- Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
| | - Stan B Floresco
- Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.
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Hahn B, Riegger KE, Elmer GI. Strain dependency of the effects of nicotine and mecamylamine in a rat model of attention. Psychopharmacology (Berl) 2016; 233:1427-34. [PMID: 26875755 PMCID: PMC4814296 DOI: 10.1007/s00213-016-4236-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 02/03/2016] [Indexed: 11/30/2022]
Abstract
RATIONALE Processes of attention have a heritable component, suggesting that genetic predispositions may predict variability in the response to attention-enhancing drugs. Among lead compounds with attention-enhancing properties are nicotinic acetylcholine receptor (nAChR) agonists. OBJECTIVES This study aims to test, by comparing three rat strains, whether genotype may influence the sensitivity to nicotine in the 5-choice serial reaction time task (5-CSRTT), a rodent model of attention. METHODS Strains tested were Long Evans (LE), Sprague Dawley (SD), and Wistar rats. The 5-CSRTT requires responses to light stimuli presented randomly in one of five locations. The effect of interest was an increased percentage of responses in the correct location (accuracy), the strongest indicator of improved attention. RESULTS Nicotine (0.05-0.2 mg/kg s.c.) reduced omission errors and response latency and increased anticipatory responding in all strains. In contrast, nicotine dose-dependently increased accuracy in Wistar rats only. The nAChR antagonist mecamylamine (0.75-3 mg/kg s.c.) increased omissions, slowed responses, and reduced anticipatory responding in all strains. There were no effects on accuracy, which was surprising giving the clear improvement with nicotine in the Wistar group. CONCLUSIONS The findings suggest strain differences in the attention-enhancing effects of nicotine, which would indicate that genetic predispositions predict variability in the efficacy of nAChR compounds for enhancing attention. The absence of effect of mecamylamine on response accuracy may suggest a contribution of nAChR desensitization to the attention-enhancing effects of nicotine.
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Affiliation(s)
- Britta Hahn
- University of Maryland School of Medicine, Maryland Psychiatric Research Center, P.O. Box 21247, Baltimore, MD, 21228, USA.
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Parikh V, Cole RD, Patel PJ, Poole RL, Gould TJ. Cognitive control deficits during mecamylamine-precipitated withdrawal in mice: Possible links to frontostriatal BDNF imbalance. Neurobiol Learn Mem 2016; 128:110-6. [PMID: 26775017 DOI: 10.1016/j.nlm.2016.01.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 12/02/2015] [Accepted: 01/10/2016] [Indexed: 02/06/2023]
Abstract
Nicotine is a major psychoactive and addictive component of tobacco. Although cessation of tobacco use produces various somatic and affective symptoms, withdrawal-related cognitive deficits are considered to be a critical symptom that predict relapse. Therefore, delineating the cognitive mechanisms of nicotine withdrawal may likely provide gainful insights into the neurobiology of nicotine addiction. The present study was designed to examine the effects of nicotine withdrawal induced by mecamylamine, a non-specific nicotinic receptor (nAChR) antagonist, on cognitive control processes in mice using an operant strategy switching task. Brain-derived neurotrophic factor (BDNF) modulates synaptic transmission in frontostriatal circuits, and these circuits are critical for executive functions. Thus, we examined the effects of mecamylamine-precipitated nicotine withdrawal on prefrontal and striatal BDNF protein expression. Mice undergoing precipitated nicotine withdrawal required more trials to attain strategy switching criterion as compared to the controls. Error analysis indicated that impaired performance in these animals was mostly related to their inability to execute the new strategy. The striatal/prefrontal BDNF ratios robustly increased following precipitated nicotine withdrawal. Moreover, higher BDNF ratios were associated with longer task acquisition. Collectively, our findings illustrate that mecamylamine-induced nicotine withdrawal disrupts cognitive control processes and that these changes are possibly linked to perturbations in frontostriatal BDNF signaling.
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Affiliation(s)
- Vinay Parikh
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA 19122, United States.
| | - Robert D Cole
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA 19122, United States
| | - Purav J Patel
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA 19122, United States
| | - Rachel L Poole
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA 19122, United States
| | - Thomas J Gould
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA 19122, United States
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5
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Abstract
The ability to focus one's attention on important environmental stimuli while ignoring irrelevant stimuli is fundamental to human cognition and intellectual function. Attention is inextricably linked to perception, learning and memory, and executive function; however, it is often impaired in a variety of neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, depression, and attention deficit hyperactivity disorder (ADHD). Accordingly, attention is considered as an important therapeutic target in these disorders. The purpose of this chapter is to provide an overview of the most common behavioral paradigms of attention that have been used in animals (particularly rodents) and to review the literature where these tasks have been employed to elucidate neurobiological substrates of attention as well as to evaluate novel pharmacological agents for their potential as treatments for disorders of attention. These paradigms include two tasks of sustained attention that were developed as rodent analogues of the human Continuous Performance Task (CPT), the Five-Choice Serial Reaction Time Task (5-CSRTT) and the more recently introduced Five-Choice Continuous Performance Task (5C-CPT), and the Signal Detection Task (SDT) which was designed to emphasize temporal components of attention.
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Affiliation(s)
- Patrick M Callahan
- Department of Pharmacology and Toxicology, CB-3545, Georgia Regents University, 1120 Fifteenth Street, Augusta, GA, 30912-2450, USA
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6
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Abstract
Facilitation of different attentional functions by nicotinic acetylcholine receptor (nAChR) agonists may be of therapeutic potential in disease conditions such as Alzheimer's disease or schizophrenia. For this reason, the neuronal mechanisms underlying these effects have been the focus of research in humans and in preclinical models. Attention-enhancing effects of the nonselective nAChR agonist nicotine can be observed in human nonsmokers and in laboratory animals, suggesting that benefits go beyond a reversal of withdrawal deficits in smokers. The ultimate aim is to develop compounds acting with greater selectivity than nicotine at a subset of nAChRs, with an effects profile narrowly matching the targeted cognitive deficits and minimizing unwanted effects. To date, compounds tested clinically target the nAChR subtypes most abundant in the brain. To help pinpoint more selectively expressed subtypes critical for attention, studies have aimed at identifying the secondary neurotransmitter systems whose stimulation mediates the attention-enhancing properties of nicotine. Evidence indicates that noradrenaline and glutamate, but not dopamine release, are critical mediators. Thus, attention-enhancing nAChR agents could spare the system central to nicotine dependence. Neuroimaging studies suggest that nAChR agonists act on a variety of brain systems by enhancing activation, reducing activation, and enhancing deactivation by attention tasks. This supports the notion that effects on different attentional functions may be mediated by distinct central mechanisms, consistent with the fact that nAChRs interact with a multitude of brain sites and neurotransmitter systems. The challenge will be to achieve the optimal tone at the right subset of nAChR subtypes to modulate specific attentional functions, employing not just direct agonist properties, but also positive allosteric modulation and low-dose antagonism.
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Affiliation(s)
- Britta Hahn
- Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA,
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Burk JA. Roles of cholinergic receptors during attentional modulation of cue detection. World J Pharmacol 2013; 2:84-91. [DOI: 10.5497/wjp.v2.i4.84] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2013] [Revised: 08/17/2013] [Accepted: 09/13/2013] [Indexed: 02/06/2023] Open
Abstract
Basal forebrain corticopetal cholinergic neurons are known to be necessary for normal attentional processing. Alterations of cholinergic system functioning have been associated with several neuropsychiatric diseases, such as Alzheimer’s disease and schizophrenia, in which attentional dysfunction is thought to be a key contributing factor. Loss of cortical cholinergic inputs impairs performance in attention-demanding tasks. Moreover, measures of acetylcholine with microdialysis and, more recently, of choline with enzyme-coated microelectrodes have begun to elucidate the precise cognitive demands that activate the cholinergic system on distinct time scales. However, the receptor actions following acetylcholine release under attentionally-challenging conditions are only beginning to be understood. The present review is designed to summarize the evidence regarding the actions of acetylcholine at muscarinic and nicotinic receptors under cognitively challenging conditions in order to evaluate the functions mediated by these two different cholinergic receptor classes. Moreover, evidence that supports beneficial effects of muscarinic muscarinic-1 receptor agonists and selective nicotinic receptor subtype agonists for cognitive processing will be discussed. Finally, some challenges and limitations of targeting the cholinergic system for treating cognitive deficits along with future research directions will be mentioned. In conclusion, multiple aspects of cholinergic neurotransmission must be considered when attempting to restore function of this neuromodulatory system.
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Lustig C, Kozak R, Sarter M, Young JW, Robbins TW. CNTRICS final animal model task selection: control of attention. Neurosci Biobehav Rev 2013; 37:2099-110. [PMID: 22683929 PMCID: PMC3490036 DOI: 10.1016/j.neubiorev.2012.05.009] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Revised: 04/14/2012] [Accepted: 05/24/2012] [Indexed: 02/05/2023]
Abstract
Schizophrenia is associated with impaired attention. The top-down control of attention, defined as the ability to guide and refocus attention in accordance with internal goals and representations, was identified by the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative as an important construct for task development and research. A recent CNTRICS meeting identified three tasks commonly used with rodent models as having high construct validity and promise for further development: The 5-choice serial reaction time task, the 5-choice continuous performance task, and the distractor condition sustained attention task. Here we describe their current status, including data on their neural substrates, evidence for sensitivity to neuropharmacological manipulations and genetic influences, and data from animal models of the cognitive deficits of schizophrenia. A common strength is the development of parallel human tasks to facilitate connections to the neural circuitry and drug development research done in these animal models. We conclude with recommendations for the steps needed to improve testing so that it better represents the complex biological and behavioral picture presented by schizophrenia.
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Affiliation(s)
- C Lustig
- Department of Psychology, University of Michigan, Ann Arbor, MI, USA.
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Young JW, Meves JM, Geyer MA. Nicotinic agonist-induced improvement of vigilance in mice in the 5-choice continuous performance test. Behav Brain Res 2013; 240:119-33. [PMID: 23201359 PMCID: PMC3538919 DOI: 10.1016/j.bbr.2012.11.028] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Revised: 11/16/2012] [Accepted: 11/20/2012] [Indexed: 12/12/2022]
Abstract
Impaired attentional processing is prevalent in numerous neuropsychiatric disorders and may negatively impact other cognitive and functional domains. Nicotine - a nonspecific nicotinic acetylcholine receptor (nAChR) agonist - improves vigilance in healthy subjects and schizophrenia patients as measured by continuous performance tests (CPTs), but the nAChR mediating this effect remains unclear. Here we examine the effects of: (a) nicotine; (b) the selective α7 nAChR agonist PNU 282987; and (c) the selective α4β2 nAChR agonist ABT-418 alone and in combination with scopolamine-induced disruption of mouse 5-choice (5C-)CPT performance. This task requires the inhibition of responses to non-target stimuli as well as active responses to target stimuli, consistent with human CPTs. C57BL/6N mice were trained to perform the 5C-CPT. Drug effects were examined in extended session and variable stimulus-duration challenges of performance. Acute drug effects on scopolamine-induced disruption in performance were also investigated. Nicotine and ABT-418 subtly but significantly improved performance of normal mice and attenuated scopolamine-induced disruptions in the 5C-CPT. PNU 282-987 had no effects on performance. The similarity of nicotine and ABT-418 effects provides support for an α4β2 nAChR mechanism of action for nicotine-induced improvement in attention/vigilance. Moreover, the data provide pharmacological predictive validation for the 5C-CPT because nicotine improved and scopolamine disrupted normal performance of the task, consistent with healthy humans in the CPT. Future studies using more selective agonists may result in more robust improvements in performance.
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Affiliation(s)
- Jared W Young
- Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, United States.
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Demeter E, Sarter M. Leveraging the cortical cholinergic system to enhance attention. Neuropharmacology 2013; 64:294-304. [PMID: 22796110 PMCID: PMC3445745 DOI: 10.1016/j.neuropharm.2012.06.060] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2012] [Revised: 06/18/2012] [Accepted: 06/28/2012] [Indexed: 12/26/2022]
Abstract
Attentional impairments are found in a range of neurodegenerative and neuropsychiatric disorders. However, the development of procognitive enhancers to alleviate these impairments has been hindered by a lack of comprehensive hypotheses regarding the circuitry mediating the targeted attentional functions. Here we discuss the role of the cortical cholinergic system in mediating cue detection and attentional control and propose two target mechanisms for cognition enhancers: stimulation of prefrontal α4β2* nicotinic acetylcholine receptors (nAChR) for the enhancement of cue detection and augmentation of tonic acetylcholine levels for the enhancement of attentional control. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
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Affiliation(s)
- Elise Demeter
- Psychiatry Department, 4250 Plymouth Road, University of Michigan, Ann Arbor, MI 48109-5765, USA.
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Robinson AM, Mangini DF, Burk JA. Task demands dissociate the effects of muscarinic M1 receptor blockade and protein kinase C inhibition on attentional performance in rats. J Psychopharmacol 2012; 26:1143-50. [PMID: 21890584 PMCID: PMC3251644 DOI: 10.1177/0269881111415732] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The cholinergic system is known to be necessary for normal attentional processing. However, the receptors and mechanisms mediating the effects of acetylcholine on attention remain unclear. Previous work in our laboratory suggested that cholinergic muscarinic receptors are critical for maintaining performance in an attention-demanding task in rats. We examined the role of the muscarinic M(1) receptor and protein kinase C (PKC), which is activated by the M(1) receptor, in attention task performance. Rats were trained in an attention-demanding task requiring discrimination of brief (500, 100, 25 ms) visual signals from trials with no signal presentation. The effects of muscarinic M(1) receptor blockade were assessed by administering dicyclomine (0-5.0 mg/kg). The effects of PKC inhibition were assessed by administering chelerythrine chloride (0-2.0 mg/kg). Dicyclomine decreased the accuracy of detecting longer signals in this attention task, including when attentional demands were increased by flashing a houselight throughout the session. Chelerythrine chloride decreased the accuracy of signal detection in the standard version of the task but not when the houselight was flashed throughout the session. The present findings indicate that muscarinic M(1) receptors are critical for maintaining performance when attentional demands are increased, and that PKC activity may contribute to some aspects of attentional performance.
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Affiliation(s)
- Andrea M Robinson
- Department of Psychology, College of William and Mary, Williamsburg, VA, USA
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Abstract
Cognitive dysfunction is a core aspect of schizophrenia that constitutes a major obstacle toward reintegration of patients into society. Although multiple cognitive deficits are evident in schizophrenia patients, no medication is currently approved for their amelioration. Although consensus clinical test batteries have been developed for the assessment of putative cognition enhancers in patients with schizophrenia, parallel animal tests remain to be validated. Having no approved treatment for cognitive symptoms means no positive control can be used to examine pharmacological predictive validity of animal models. Thus, focus has been placed on animal paradigms that have demonstrable construct validity for the cognitive domain being assessed.This review describes the growing arsenal of animal paradigms under development that have putative construct validity to cognitive domains affected in schizophrenia. We discuss (1) the construct validity of the paradigms; (2) compounds developed to investigate putative treatment targets; and (3) manipulations used to first impair task performance. Focus is placed on the paradigm design, including how the use of multivariate assessments can provide evidence that main effects of treatment are not confounded by extraneous effects.
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Olincy A, Freedman R. Nicotinic mechanisms in the treatment of psychotic disorders: a focus on the α7 nicotinic receptor. Handb Exp Pharmacol 2012:211-32. [PMID: 23027417 PMCID: PMC3692393 DOI: 10.1007/978-3-642-25758-2_8] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Nicotine is heavily abused by persons with schizophrenia. Nicotine better enables people with schizophrenia to filter out extraneous auditory stimuli. Nicotine also improves prepulse inhibition when compared to placebo. Nicotine similarly increases the amplitude of patients' duration mismatch negativity. The 15q13-14 region of the genome coding for the α7 nicotinic receptor is linked to schizophrenia. Multiple single nucleotide polymorphisms have been identified in this 15q13-14 gene promoter region that are more frequently present in people with schizophrenia than in normal controls. Abnormalities in expression and regulation of central nicotinic cholinoceptors with decreased α7 binding in multiple brain regions are also present. Nicotine enhances cognition in schizophrenia. Alternative agents that activate the nicotinic receptor have been tested including 3-[2,4-dimethoxybenzylidene]anabaseine (DMXB-A). This compound improved attention, working memory, and negative symptoms in an add-on study in nonsmoking patients with schizophrenia. There are multiple other nicotinic agents, including positive allosteric modulators, in the preclinical stages of development. Finally, the effects of varenicline and clozapine and their relation to smoking cessation are discussed.
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Affiliation(s)
- Ann Olincy
- Department of Psychiatry, University of Colorado, Denver, 13001 East 17th Place, Mail Stop, F546, Aurora, CO 80045, USA
| | - Robert Freedman
- Department of Psychiatry, University of Colorado, Denver, 13001 East 17th Place, Mail Stop, F546, Aurora, CO 80045, USA
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Sazetidine-A, a selective α4β2 nicotinic acetylcholine receptor ligand: effects on dizocilpine and scopolamine-induced attentional impairments in female Sprague-Dawley rats. Psychopharmacology (Berl) 2011; 215:621-30. [PMID: 21274704 DOI: 10.1007/s00213-010-2161-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2010] [Accepted: 12/18/2010] [Indexed: 01/03/2023]
Abstract
BACKGROUND Neuronal nicotinic receptor systems have been shown to play key roles in cognition. Nicotine and nicotinic analogs improve attention and nicotinic antagonists impair it. This study was conducted to investigate the role of α4β2 nicotinic receptors in sustained attention using a novel selective α4β2 nicotinic receptor ligand, sazetidine-A. METHODS Female rats were trained to perform the signal detection task to a stable baseline of accuracy. The rats were injected with saline, sazetidine-A (0.01, 0.03, and 0.1 mg/kg), dizocilpine (0.05 mg/kg), or their combination; or, in another experiment, the rats were injected with the same doses of sazetidine-A, scopolamine (0.02 mg/kg), or their combination. RESULTS Percent hit and percent correct rejection showed that dizocilpine caused significant (p < 0.025) impairments in performance, which were significantly reversed by each of the sazetidine-A doses. Response omissions were significantly (p < 0.05) increased by dizocilpine, and this was also significantly reversed by each of the sazetidine-A doses. None of the sazetidine-A doses had significant effects on hit, correct rejection, or response omissions when given alone. Scopolamine also caused significant (p < 0.0005) impairments in percent hit and percent correct rejection and increased response omissions, which were significantly attenuated by all the sazetidine-A doses for percent hit and response omissions and by the highest dose of sazetidine-A for percent correct rejection. Both scopolamine and dizocilpine significantly (p < 0.0005) increased response latency, an effect which was significantly attenuated by sazetidine-A coadministration. CONCLUSIONS These studies imply an important role for α4β2 nicotinic receptors in improving sustained attention under conditions that disrupt it. Very low doses of sazetidine-A or drugs with a similar profile may provide therapeutic benefit for reversing attentional impairment in patients suffering from mental disorders and/or cognitive impairment.
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D'Souza MS, Markou A. Schizophrenia and tobacco smoking comorbidity: nAChR agonists in the treatment of schizophrenia-associated cognitive deficits. Neuropharmacology 2011; 62:1564-73. [PMID: 21288470 DOI: 10.1016/j.neuropharm.2011.01.044] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2010] [Revised: 01/19/2011] [Accepted: 01/24/2011] [Indexed: 12/22/2022]
Abstract
Tobacco smoking is a preventable cause of morbidity and mortality throughout the world. Very high rates of tobacco smoking are seen in patients with schizophrenia. Importantly, smokers with schizophrenia generally have higher nicotine dependence scores, experience more severe withdrawal symptoms upon smoking cessation, have lower cessation rates than healthy individuals, and suffer from significant smoking-related morbidity and premature mortality compared with the general population. Interestingly, significant disturbances in cholinergic function are reported in schizophrenia patients. The high smoking-schizophrenia comorbidity observed in schizophrenia patients may be an attempt to compensate for this cholinergic dysfunction. Cholinergic neurotransmission plays an important role in cognition and is hypothesized to play an important role in schizophrenia-associated cognitive deficits. In this review, preclinical evidence highlighting the beneficial effects of nicotine and subtype-selective nicotinic receptor agonists in schizophrenia-associated cognitive deficits, such as working memory and attention, is discussed. Furthermore, some of the challenges involved in the development of procognitive medications, particularly subtype-selective nicotinic receptor agonists, are also discussed. Amelioration of schizophrenia-associated cognitive deficits may help in the treatment of schizophrenia-smoking comorbidity by promoting smoking cessation and thus help in the better management of schizophrenia patients.
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Affiliation(s)
- Manoranjan S D'Souza
- Department of Psychiatry, M/C 0603, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
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Howe WM, Ji J, Parikh V, Williams S, Mocaër E, Trocmé-Thibierge C, Sarter M. Enhancement of attentional performance by selective stimulation of alpha4beta2(*) nAChRs: underlying cholinergic mechanisms. Neuropsychopharmacology 2010; 35:1391-401. [PMID: 20147893 PMCID: PMC2855755 DOI: 10.1038/npp.2010.9] [Citation(s) in RCA: 135] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Impairments in attention are a major component of the cognitive symptoms of neuropsychiatric and neurodegenerative disorders. Using an operant sustained attention task (SAT), including a distractor condition (dSAT), we assessed the putative pro-attentional effects of the selective alpha4beta2(*) nicotinic acetylcholine receptor (nAChR) agonist S 38232 in comparison with the non-selective agonist nicotine. Neither drug benefited SAT performance. However, in interaction with the increased task demands implemented by distractor presentation, the selective agonist, but not nicotine, enhanced the detection of signals during the post-distractor recovery period. This effect is consistent with the hypothesis that second-long increases in cholinergic activity ('transients') mediate the detection of cues and that nAChR agonists augment such transients. Electrochemical recordings of prefrontal cholinergic transients evoked by S 38232 and nicotine indicated that the alpha4beta2(*) nAChR agonist evoked cholinergic transients that were characterized by a faster rise time and more rapid decay than those evoked by nicotine. Blockade of the alpha7 nAChR 'sharpens' nicotine-evoked transients; therefore, we determined the effects of co-administration of nicotine and the alpha7 nAChR antagonist methyllycaconitine on dSAT performance. Compared with vehicle and nicotine alone, this combined treatment significantly enhanced the detection of signals. These results indicate that compared with nicotine, alpha4beta2(*) nAChR agonists significantly enhance attentional performance and that the dSAT represents a useful behavioral screening tool. The combined behavioral and electrochemical evidence supports the hypothesis that nAChR agonist-evoked cholinergic transients, which are characterized by rapid rise time and fast decay, predict robust drug-induced enhancement of attentional performance.
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Affiliation(s)
- William M Howe
- Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, MI, USA
| | - Jinzhao Ji
- Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, MI, USA
| | - Vinay Parikh
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA, USA
| | - Sarah Williams
- Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, MI, USA
| | - Elisabeth Mocaër
- Institut de Recherches Internationales Servier, Courbevoie, France
| | | | - Martin Sarter
- Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, MI, USA,Department of Psychology, University of Michigan, 530 Church Street, 4032 East Hall, Ann Arbor, MI 48109-1043, USA, Tel: +1 734 764 6392, Fax: +1 734 763 7480, E-mail:
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Pasumarthi RK, Fadel J. Stimulation of lateral hypothalamic glutamate and acetylcholine efflux by nicotine: implications for mechanisms of nicotine-induced activation of orexin neurons. J Neurochem 2010; 113:1023-35. [PMID: 20236223 DOI: 10.1111/j.1471-4159.2010.06666.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The hypothalamus is a prominent target of nicotine action. We have previously shown that acute systemic nicotine treatment induces Fos expression in the lateral hypothalamus and perifornical area (LH/PFA), with orexin/hypocretin neurons being particularly responsive. However, the neurochemical correlates of acute nicotine treatment in the LH/PFA have not been described. Anatomical studies have revealed that this area receives afferents from cholinergic, glutamatergic, and GABAergic telencephalic brain regions, suggesting a potential role for these neurotransmitters in mediating the hypothalamic component of nicotine effects on homeostatic phenomena, such as arousal and appetite. Here, we used in vivo microdialysis to determine the effect of acute systemic or local nicotine on glutamate, acetylcholine, and GABA efflux in the LH/PFA of rats. Local administration of nicotine significantly increased acetylcholine and glutamate, but not GABA, in the LH/PFA. Thus, we further tested the role of afferent sources of glutamate and acetylcholine in mediating acute nicotine-induced activation of orexin neurons by unilaterally lesioning the prefrontal cortex or basal forebrain cholinergic regions. Lesioned animals showed reduced Fos-positive orexin neurons following nicotine treatment. These data suggest that both acetylcholine and glutamate may mediate the effects of acute nicotine on the activity of hypothalamic neurons, including orexin/hypocretin cells. Changes in cholinergic or glutamatergic transmission in this region with chronic nicotine may contribute to long-term alterations in functions mediated by LH/PFA neurons, including feeding and arousal.
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Affiliation(s)
- Ravi K Pasumarthi
- Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USA
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ABT-594 improves performance in the 5-choice serial reaction time task under conditions of increased difficulty, sub-chronic dosing, and in poorly-performing subjects. Pharmacol Biochem Behav 2010; 95:146-57. [PMID: 20064548 DOI: 10.1016/j.pbb.2009.12.019] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2009] [Revised: 12/08/2009] [Accepted: 12/23/2009] [Indexed: 11/21/2022]
Abstract
Several studies have tested nicotinic receptor ligands in the 5-Choice Serial Reaction Time Task (5-CSRTT) with varying results. Some investigators have increased attentional demands by modifying task parameters or using aged or poor performing rats to observe treatment effects. This study examined the alpha4beta2 nicotinic agonist ABT-594 in the 5-CSRTT using a variety of manipulations to determine optimal conditions for observing enhancement. ABT-594 had no effect in drug-naïve adult rats that self-initiated trials. Constant trial presentation decreased accuracy and omissions, with the latter significantly attenuated by acute administration of ABT-594 (0.019-0.062 micromol/kg). Sub-chronic treatment (0.019 micromol/kg) initially impaired drug-naïve subjects, but significant improvements in accuracy and decreased omissions were observed after 5 days of dosing. In 18-22 month-old rats, attentional demands were altered by interspersing blocks of trials with different stimulus durations. Acute ABT-594 (0.062 micromol/kg) enhanced accuracy performance in poor performing rats (<70% accuracy) but not in those that performed well (>80% accuracy), while omissions were decreased in both groups. Sub-chronic treatment with (0.019 micromol/kg) decreased omissions in all rats, but enhanced accuracy primarily in poor performing rats. These experiments demonstrate that an alpha4beta2 nicotinic agonist can enhance attention, but accuracy effects may only be observed under specific conditions. Moreover, a reduction in omissions was more reliably observed than improvements in accuracy, resulting in a net increase in signals successfully detected.
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Sarter M, Parikh V, Howe WM. nAChR agonist-induced cognition enhancement: integration of cognitive and neuronal mechanisms. Biochem Pharmacol 2009; 78:658-67. [PMID: 19406107 DOI: 10.1016/j.bcp.2009.04.019] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2009] [Revised: 04/14/2009] [Accepted: 04/16/2009] [Indexed: 01/04/2023]
Abstract
The identification and characterization of drugs for the treatment of cognitive disorders has been hampered by the absence of comprehensive hypotheses. Such hypotheses consist of (a) a precisely defined cognitive operation that fundamentally underlies a range of cognitive abilities and capacities and, if impaired, contributes to the manifestation of diverse cognitive symptoms; (b) defined neuronal mechanisms proposed to mediate the cognitive operation of interest; (c) evidence indicating that the putative cognition enhancer facilitates these neuronal mechanisms; (d) and evidence indicating that the cognition enhancer facilitates cognitive performance by modulating these underlying neuronal mechanisms. The evidence on the neuronal and attentional effects of nAChR agonists, specifically agonists selective for alpha4beta2* nAChRs, has begun to support such a hypothesis. nAChR agonists facilitate the detection of signals by augmenting the transient increases in prefrontal cholinergic activity that are necessary for a signal to gain control over behavior in attentional contexts. The prefrontal microcircuitry mediating these effects include alpha4beta2* nAChRs situated on the terminals of thalamic inputs and the glutamatergic stimulation of cholinergic terminals via ionotropic glutamate receptors. Collectively, this evidence forms the basis for hypothesis-guided development and characterization of cognition enhancers.
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Affiliation(s)
- Martin Sarter
- Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, MI 48109-1043, USA.
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Rezvani AH, Kholdebarin E, Brucato FH, Callahan PM, Lowe DA, Levin ED. Effect of R3487/MEM3454, a novel nicotinic alpha7 receptor partial agonist and 5-HT3 antagonist on sustained attention in rats. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:269-75. [PMID: 19110025 DOI: 10.1016/j.pnpbp.2008.11.018] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2008] [Revised: 11/25/2008] [Accepted: 11/26/2008] [Indexed: 11/16/2022]
Abstract
It is well established that nicotinic systems in the brain are critically involved in attentional processes in both animals and humans. The current study assessed the effects of a novel nicotinic alpha7 receptor partial agonist and 5-HT3 antagonist, R3487/MEM3454 (also referred to as R3487 or MEM 3454) on sustained attention in rats performing an operant visual signal detection task. The effects of R3487/MEM3454 were compared to those of the acetylcholinesterase inhibitor/nicotinic alpha7 allosteric positive modulator galanthamine. Adult female Sprague-Dawley rats were injected subcutaneously with R3487/MEM3454 (0.03, 0.1, 0.15, 0.3 and 0.6 mg/kg), galanthamine (0.25, 0.5, 1, 2 mg/kg) or vehicle 30 min before the attentional test. In the second study, the time-dependent effects of R3487/MEM3454 were assessed by injecting the compound (0.6 mg/kg, s.c.) at different pretreatment intervals (30, 60 or 90 min) before the start of the attentional task. Our results show a significant dose-effect for R3487/MEM3454 on percent hit accuracy performance without any significant alteration on percent correct rejection performance. In the time-dependent test, R3487/MEM3454 significantly increased the percent hit accuracy performance when animals were injected 60 min before the start of the attentional task. Administration of galanthamine failed to significantly increase percent hit accuracy performance and increasing the dose of galanthamine produced a decrease in percent correct rejection performance. The present findings with R3487/MEM3454 suggest that nicotinic alpha7 receptors and/or 5-HT3 receptors may play an important role in modulating sustained attention and that R3487/MEM3454 may have therapeutic potential in improving sustained attention in humans.
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Affiliation(s)
- Amir H Rezvani
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
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Using the MATRICS to guide development of a preclinical cognitive test battery for research in schizophrenia. Pharmacol Ther 2009; 122:150-202. [PMID: 19269307 DOI: 10.1016/j.pharmthera.2009.02.004] [Citation(s) in RCA: 259] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2009] [Accepted: 02/17/2009] [Indexed: 12/29/2022]
Abstract
Cognitive deficits in schizophrenia are among the core symptoms of the disease, correlate with functional outcome, and are not well treated with current antipsychotic therapies. In order to bring together academic, industrial, and governmental bodies to address this great 'unmet therapeutic need', the NIMH sponsored the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. Through careful factor analysis and consensus of expert opinion, MATRICS identified seven domains of cognition that are deficient in schizophrenia (attention/vigilance, working memory, reasoning and problem solving, processing speed, visual learning and memory, verbal learning and memory, and social cognition) and recommended a specific neuropsychological test battery to probe these domains. In order to move the field forward and outline an approach for translational research, there is a need for a "preclinical MATRICS" to develop a rodent test battery that is appropriate for drug development. In this review, we outline such an approach and review current rodent tasks that target these seven domains of cognition. The rodent tasks are discussed in terms of their validity for probing each cognitive domain as well as a brief overview of the pharmacology and manipulations relevant to schizophrenia for each task.
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Newman LA, Darling J, McGaughy J. Atomoxetine reverses attentional deficits produced by noradrenergic deafferentation of medial prefrontal cortex. Psychopharmacology (Berl) 2008; 200:39-50. [PMID: 18568443 PMCID: PMC10719959 DOI: 10.1007/s00213-008-1097-8] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2007] [Accepted: 02/01/2008] [Indexed: 02/02/2023]
Abstract
BACKGROUND The majority of studies assessing executive function in attention deficit disorder (ADD) have shown deficits in attentional set shifting using either the Wisconsin card sorting task or the intra-dimensional/extra-dimensional set-shifting task (ID/ED). Damage to the prefrontal cortex in humans, primates, and rodents impairs extra-dimensional (ED) shifts. Noradrenergic depletion of the medial prefrontal cortex in rats is sufficient to impair attentional set shifting. Atomoxetine, a selective norepinephrine (NE) re-uptake inhibitor, is hypothesized to produce beneficial effects in patient with ADD by augmenting NE release in prefrontal cortex. MATERIALS AND METHODS We assessed the effects of systemic administration of atomoxetine (0.0, 0.1, 0.3, and 0.9 mg/kg/ml) in normal and noradrenergically lesioned (NE-LX) rats on attentional-set shifts. We replicated findings showing NE-LX rats are selectively impaired on the ED shifts but not reversals or other discriminations. RESULTS Atomoxetine remediated the attentional set-shifting impairments in NE-LX rats but impaired ED performance of non-lesioned rats. DISCUSSION Though atomoxetine is neurochemically selective, it is not wholly specific at doses >0.3 mg/kg. All doses of the drug were similar in their efficacy in reversing the ED deficit, but the effectiveness of the 0.1 mg/kg dose supports the hypothesis that increases in prefrontal NE alone are sufficient to improve attention in NE-LX rats. Moreover, the detrimental effects of the drug in non-lesioned rats support the hypothesis that optimal levels of NE in prefrontal cortex are critical to attentional set shifting with both supra- and sub-optimal levels producing attentional impairments.
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Affiliation(s)
- Lori A Newman
- Department of Psychology, University of New Hampshire, Conant Hall, Durham, NH 03824, USA
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Williams M, Arneric SP. Monthly Updates: Monthly Update Central & Peripheral Nervous Systems: Beyond the tobacco debate: Dissecting out the therapeutic potential of nicotine. Expert Opin Investig Drugs 2008. [DOI: 10.1517/13543784.5.8.1035] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Michael Williams
- Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL, 60064–3500, USA
| | - Stephen P Arneric
- Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL, 60064–3500, USA
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Arneric SP, Holladay MW, Sullivan JP. Section Review: Central & Peripheral Nervous Systems: Cholinergic channel modulators as a novel therapeutic strategy for Alzheimer's disease. Expert Opin Investig Drugs 2008. [DOI: 10.1517/13543784.5.1.79] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Rezvani AH, Kholdebarin E, Dawson E, Levin ED. Nicotine and clozapine effects on attentional performance impaired by the NMDA antagonist dizocilpine in female rats. Int J Neuropsychopharmacol 2008; 11:63-70. [PMID: 17295931 DOI: 10.1017/s1461145706007528] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Cognitive impairment is very prevalent in schizophrenia and is currently undertreated in most patients. Attentional deficit is one of the hallmark symptoms of schizophrenia. Antipsychotic drugs, which can be quite effective in combating hallucinations are often ineffective in reducing cognitive impairment and can potentiate cognitive impairment. Previously, we found that the antipsychotic drug clozapine impaired, while nicotine improved, the accuracy of rats performing a visual signal detection attentional task in normal rats. For the current study, in a model of cognitive impairment of schizophrenia with the NMDA antagonist dizocilpine (0.05 mg/kg), we examined the effects of clozapine and nicotine on significantly impaired attentional hit accuracy. This dizocilpine-induced impairment was significantly (p<0.05) reversed by either clozapine (1.25 mg/kg) or nicotine (0.025 mg/kg). Interestingly, when clozapine and nicotine were given together, they blocked each other's beneficial effects. When the effective doses of 1.25 mg/kg clozapine and 0.025 mg/kg nicotine were given together the combination no longer significantly reversed the dizocilpine-induced hit-accuracy impairment. Given that the great majority of people with schizophrenia smoke, the potential beneficial effects of clozapine on attentional function may be largely blocked by self-administered nicotine. In addition, there are promising results concerning the development of nicotinic treatments to reverse cognitive deficits including attentional impairment. This is supported in the current study by the reversal of the dizocilpine-induced attentional impairment by nicotine. However, in schizophrenia the efficacy of nicotinic treatments may be limited by co-treatment with antipsychotic drugs like clozapine. It will be important to determine which of the complex effects of clozapine and nicotine are key in reversing attentional impairment and how they block each other's effects for the development of therapy to combat the attentional impairment of schizophrenia.
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Affiliation(s)
- Amir H Rezvani
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 3412, USA.
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Characterization of the effects of inhaled perchloroethylene on sustained attention in rats performing a visual signal detection task. Neurotoxicol Teratol 2008; 30:167-74. [PMID: 18299185 DOI: 10.1016/j.ntt.2008.01.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2007] [Revised: 12/06/2007] [Accepted: 01/05/2008] [Indexed: 11/23/2022]
Abstract
The aliphatic hydrocarbon perchloroethylene (PCE) has been associated with neurobehavioral dysfunction including reduced attention in humans. The current study sought to assess the effects of inhaled PCE on sustained attention in rats performing a visual signal detection task (SDT). Due to its similarities in physiological effect to toluene and trichloroethylene (TCE), two other commonly used volatile organic compounds (VOCs) known to reduce attention in rats, we hypothesized (1) that acute inhalation of PCE (0, 500, 1000, 1500 ppm) would disrupt performance of the SDT in rats; (2) that impaired accuracy would result from changes in attention to the visual signal; and (3) that these acute effects would diminish upon repetition of exposure. PCE impaired performance of the sustained attention task as evidenced by reduced accuracy [P(correct): 500 to 1500 ppm], elevated response time [RT: 1000 and 1500 ppm] and reduced number of trials completed [1500 ppm]. These effects were concentration-related and either increased (RT and trial completions) or remained constant [P(correct)] across the 60-min test session. The PCE-induced reduction in accuracy was primarily due to an increase in false alarms, a pattern consistent with reduced attention to the signal. A repeat of the exposures resulted in smaller effects on these performance measures. Thus, like toluene and TCE, inhaled PCE acutely impaired sustained attention in rats, and its potency weakened upon repetition of the exposure.
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Briand LA, Gritton H, Howe WM, Young DA, Sarter M. Modulators in concert for cognition: modulator interactions in the prefrontal cortex. Prog Neurobiol 2007; 83:69-91. [PMID: 17681661 PMCID: PMC2080765 DOI: 10.1016/j.pneurobio.2007.06.007] [Citation(s) in RCA: 138] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2006] [Revised: 04/06/2007] [Accepted: 06/22/2007] [Indexed: 12/19/2022]
Abstract
Research on the regulation and function of ascending noradrenergic, dopaminergic, serotonergic, and cholinergic systems has focused on the organization and function of individual systems. In contrast, evidence describing co-activation and interactions between multiple neuromodulatory systems has remained scarce. However, commonalities in the anatomical organization of these systems and overlapping evidence concerning the post-synaptic effects of neuromodulators strongly suggest that these systems are recruited in concert; they influence each other and simultaneously modulate their target circuits. Therefore, evidence on the regulatory and functional interactions between these systems is considered essential for revealing the role of neuromodulators. This postulate extends to contemporary neurobiological hypotheses of major neuropsychiatric disorders. These hypotheses have focused largely on aberrations in the integrity or regulation of individual ascending modulatory systems, with little regard for the likely possibility that dysregulation in multiple ascending neuromodulatory systems and their interactions contribute essentially to the symptoms of these disorders. This review will paradigmatically focus on neuromodulator interactions in the PFC and be further constrained by an additional focus on their role in cognitive functions. Recent evidence indicates that individual neuromodulators, in addition to their general state-setting or gating functions, encode specific cognitive operations, further substantiating the importance of research concerning the parallel recruitment of neuromodulator systems and interactions between these systems.
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Affiliation(s)
- Lisa A Briand
- University of Michigan, Department of Psychology and Neuroscience Program, Ann Arbor, MI 48109, USA.
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Chess AC, Simoni MK, Alling TE, Bucci DJ. Elevations of endogenous kynurenic acid produce spatial working memory deficits. Schizophr Bull 2007; 33:797-804. [PMID: 16920787 PMCID: PMC2526148 DOI: 10.1093/schbul/sbl033] [Citation(s) in RCA: 175] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Kynurenic acid (KYNA) is a tryptophan metabolite that is synthesized and released by astrocytes and acts as a competitive antagonist of the glycine site of N-methyl-D-aspartate receptors at high concentrations and as a noncompetitive antagonist of the alpha7-nicotinic acetylcholine receptor at low concentrations. The discovery of increased cortical KYNA levels in schizophrenia prompted the hypothesis that elevated KYNA concentration may underlie the working memory dysfunction observed in this population that has been attributed to altered glutamatergic and/or cholinergic transmission. The present study investigated the effect of elevated endogenous KYNA on spatial working memory function in rats. Increased KYNA levels were achieved with intraperitoneal administration of kynurenine (100 mg/kg), the precursor of KYNA synthesis. Rats were treated with either kynurenine or a vehicle solution prior to testing in a radial arm maze task at various delays. Elevations of endogenous KYNA resulted in increased errors in the radial arm maze. In separate experiments, assessment of locomotor activity in an open field and latency to retrieve food reward from one of the maze arms ruled out the possibility that deficits in the maze were attributable to altered locomotor activity or motivation to consume food. These results provide evidence that increased KYNA levels produce spatial working memory deficits and are among the first to demonstrate the influence of glia-derived molecules on cognitive function. The implications for psychopathological conditions such as schizophrenia are discussed.
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Affiliation(s)
- Amy C Chess
- Department of Psychological and Brain Sciences, Dartmouth College, 6207 Moore Hall, Hanover, NH 03755, USA.
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Hahn B, Ross TJ, Yang Y, Kim I, Huestis MA, Stein EA. Nicotine enhances visuospatial attention by deactivating areas of the resting brain default network. J Neurosci 2007; 27:3477-89. [PMID: 17392464 PMCID: PMC2707841 DOI: 10.1523/jneurosci.5129-06.2007] [Citation(s) in RCA: 149] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Nicotine-induced attentional enhancement is of potential therapeutic value. To investigate the precise attentional function(s) affected and their neuronal mechanisms, the current functional magnetic resonance imaging (fMRI) study used an attention task in which subjects responded to stimuli of high (INT(high)) or low intensity presented randomly in one of four peripheral locations. Central cues of varying precision predicted the target location. In some trials, the cue was not followed by a target, allowing separate analysis of blood oxygenation level-dependent (BOLD) responses to cue. Minimally deprived smokers underwent fast event-related fMRI twice: once with a nicotine patch (21 mg) and once with a placebo patch. Matched nonsmokers were scanned twice without a patch. Behaviorally, nicotine reduced omission errors and reaction time (RT) of valid and invalid cue trials and intra-individual variability of RT and did so preferentially in trials with INT(high). The BOLD signal related to cue-only trials, regardless of cue precision, demonstrated nicotine-induced deactivation in anterior and posterior cingulate, angular gyrus, middle frontal gyrus, and cuneus. These regions overlapped with the so-called "default network," which activates during rest and deactivates with attention-demanding activities. Partial correlations controlling for nicotine plasma levels indicated associations of deactivation by nicotine in posterior cingulate and angular gyrus with performance improvements under INT(high). Performance and regional activity in the absence of nicotine never differed between smokers and nonsmokers, ruling out a simple reversal of a deprivation-induced state. These findings suggest that nicotine improved attentional performance by downregulating resting brain function in response to task-related cues. Together with the selectivity of effects for INT(high), this suggests a nicotine-induced potentiation of the alerting properties of external stimuli.
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Affiliation(s)
- Britta Hahn
- Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA.
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McQuail JA, Burk JA. Evaluation of muscarinic and nicotinic receptor antagonists on attention and working memory. Pharmacol Biochem Behav 2006; 85:796-803. [PMID: 17196638 DOI: 10.1016/j.pbb.2006.11.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2006] [Revised: 11/09/2006] [Accepted: 11/21/2006] [Indexed: 02/05/2023]
Abstract
Cholinergic receptor antagonists are commonly used to model attentional and mnemonic impairments associated with neuropsychiatric disorders such as Alzheimer's disease. However, few studies have systematically assessed the effects of these drugs following manipulations that affect attention or working memory within the same task. In the present experiment, rats were trained to discriminate visual signals from "blank" trials when no signal was presented. This task was modified to include retention intervals on some trials to tax working memory. During standard task performance, rats received systemic injections of the muscarinic receptor antagonist, scopolamine, or of the nicotinic receptor antagonist, mecamylamine. A second experiment tested the effects on this task of co-administering doses of scopolamine and mecamylamine that, when administered alone, did not significantly affect task performance. Scopolamine (0.3 and 1.0 mg/kg) decreased detection of 500 ms signals but did not affect accurate identification of non-signals. Scopolamine did not differentially affect performance across the retention interval. Elevated omission rates were associated with high doses of scopolamine or mecamylamine. Combination drug treatment was associated with decreased signal detection and elevated omission rates. Collectively, the data suggest that muscarinic and nicotinic receptor antagonists do not exclusively impair working memory.
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Affiliation(s)
- Joseph A McQuail
- Department of Psychology, College of William and Mary, P.O. Box 8795, Williamsburg, VA 23187, USA
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Rezvani AH, Caldwell DP, Levin ED. Chronic nicotine interactions with clozapine and risperidone and attentional function in rats. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30:190-7. [PMID: 16310917 DOI: 10.1016/j.pnpbp.2005.10.017] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2005] [Indexed: 10/25/2022]
Abstract
Although antipsychotic drugs are therapeutically effective in attenuating the hallmark symptoms of schizophrenia, these improvements do not return most patients to normative standards of cognitive function. Thus, complementary drug treatment may be needed to treat the attentional deficits of schizophrenia as well as to counteract the potential attentional impairments caused by some antipsychotic drugs. Nicotine, a drug commonly self-administered by a great majority of individuals with schizophrenia, has been shown to significantly improve cognitive function in some studies. The current study was conducted to determine the interactive effects of the atypical antipsychotic drugs clozapine and risperidone with chronic nicotine administration on attentional performance. Adult female Sprague-Dawley rats (N=35) were trained to perform an attentional task using an operant visual signal detection task. After training, rats were infused with a dose of 5 mg/kg/day (s.c.) nicotine base (n=18) or saline (n=17) for 28 consecutive days via osmotic pump. In Exp. 1, while being administered chronic nicotine or saline, rats were given acute doses of clozapine (0, 0.625, 1.25 and 2.5 mg/kg, s.c.) and were tested for attentional function. In Exp. 2, while on chronic nicotine or saline, other rats were challenged with acute doses of risperidone (0, 0.025, 0.05 and 0.1 mg/kg, s.c.) and were tested for attentional function. Results showed that acute administration of clozapine caused a significant dose-dependent impairment in choice accuracy (percent hit) in animals treated with chronic saline. Chronic nicotine treatment itself lowered accuracy, but attenuated further declines with acute clozapine treatment. Acute administration of risperidone at high dose significantly reduced performance (percent correct rejection) in chronically saline-treated rats, but in a similar fashion as in Exp. 1, chronic nicotine lowered accuracy but attenuated further impairment with acute risperidone. In summary, atypical antipsychotic drugs clozapine and risperidone significantly impaired choice accuracy in the visual signal detection task. Clozapine was more detrimental than risperidone but the adverse effects of both clozapine and risperidone on attentional performance were masked in rats chronically treated with nicotine.
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Affiliation(s)
- Amir H Rezvani
- Department of Psychiatry and Behavioral Sciences, 341 Bell Building, Box 3412 Duke University Medical Center, Durham, NC 27710, USA.
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Rezvani AH, Caldwell DP, Levin ED. Nicotinic-serotonergic drug interactions and attentional performance in rats. Psychopharmacology (Berl) 2005; 179:521-8. [PMID: 15682310 DOI: 10.1007/s00213-004-2060-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2003] [Accepted: 10/01/2004] [Indexed: 10/25/2022]
Abstract
RATIONALE Both central serotonergic and nicotinic systems play important roles in a variety of neurobehavioral functions; however, the interactions of these two systems have not been fully characterized. The current study served to determine the impact of a relatively selective 5-HT2A receptor antagonist, ketanserin, on attentional function in rats and the interactions of ketanserin with nicotine administration. METHODS A standard operant visual signal detection task was used to assess sustained attention. In expt 1, adult female Sprague-Dawley rats (n = 39) were injected subcutaneously (SC) with a dose range of ketanserin (0, 0.25, 0.5 and 1 mg/kg). In expt 2, the interactions of acute ketanserin (0, 1 and 2 mg/kg, SC) and acute nicotine (0, 25 and 50 microg/kg, SC) were assessed. In expt 3, the interaction of acute ketanserin (0, 1 and 2 mg/kg, SC) and chronic nicotine (5 mg/kg per day, SC for 4 weeks via osmotic pump) was characterized. Using an operant visual signal detection task, three possible outcomes (dependent variables) were measured in each trial: percent hit, percent correct rejection, and response omissions. RESULTS Ketanserin, when given alone, did not have a significant effect on either percent hit or percent correct rejection. Acute administration of 25 microg/kg nicotine significantly improved percent hit (i.e. improvement in choice accuracy), an effect that was reversed by acute administration of 1 mg/kg ketanserin. Chronic nicotine infusion for 28 consecutive days significantly increased percent correct rejection (i.e. improvement in choice accuracy) without development of tolerance, an effect which was reversed by an acute dose of 2 mg/kg ketanserin. CONCLUSIONS These data suggest a functional interaction between nicotine and 5-HT2A receptor antagonist ketanserin.
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Affiliation(s)
- Amir H Rezvani
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
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Abstract
Acetylcholine release in sensory neocortex contributes to higher-order sensory function, in part by activating nicotinic acetylcholine receptors (nAChRs). Molecular studies have revealed a bewildering array of nAChR subtypes and cellular actions; however, there is some consensus emerging about the major nAChR subtypes and their functions in sensory cortex. This review first describes the systems-level effects of activating nAChRs in visual, somatosensory, and auditory cortex, and then describes, as far as possible, the underlying cellular and synaptic mechanisms. A related goal is to examine if sensory cortex can be considered a model system for cortex in general, because the use of sensory stimuli to activate neural circuits physiologically is helpful for understanding mechanisms of systems-level function and plasticity. A final goal is to highlight the emerging role of nAChRs in developing sensory cortex, and the adverse impact of early nicotine exposure on subsequent sensory-cognitive function.
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Affiliation(s)
- Raju Metherate
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697, USA.
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Oshiro WM, Krantz QT, Bushnell PJ. A search for residual behavioral effects of trichloroethylene (TCE) in rats exposed as young adults. Neurotoxicol Teratol 2004; 26:239-51. [PMID: 15019957 DOI: 10.1016/j.ntt.2003.12.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2003] [Revised: 12/16/2003] [Accepted: 12/16/2003] [Indexed: 10/26/2022]
Abstract
Trichloroethylene (TCE) is an organic solvent with robust acute effects on the nervous system, but poorly documented long-term effects. This study employed a signal detection task (SDT) to assess the persistence of effects of repeated daily inhalation of TCE on sustained attention in rats. Adult male Long-Evans rats inhaled TCE at 0, 1600, or 2400 ppm, 6 h/day for 20 days (n=8/group) and began learning the SDT 3 weeks later. Rats earned food by pressing one retractable response lever in a signal trial and a second lever in a blank (no signal) trial. TCE did not affect acquisition of the response rule or performance of the SDT after the intertrial interval (ITI) was changed from a constant value to a variable one. Increasing the trial presentation rate reduced accuracy equivalently in all groups. Injections of ethanol (0, 0.5, 1.0, 1.5 g/kg ip) and d-amphetamine (0, 0.1, 0.3, 1.0 mg/kg sc) systematically impaired performance as functions of drug dose. d-Amphetamine (1.0 mg/kg) reduced P(hit) more in the 2400-ppm TCE group than in the other groups. All rats required remedial training to learn a reversal of the response contingencies, which TCE did not interfere with. Thus, a history of exposure to TCE did not significantly alter learning or sustained attention in the absence of drugs. Although ethanol did not differentially affect the TCE groups, the effect of d-amphetamine is consistent with solvent-induced changes in dopaminergic functions in the CNS. Calculations indicated power values of 0.5 to 0.8 to detect main effects of TCE for the three primary endpoints.
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Affiliation(s)
- Wendy M Oshiro
- Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, B105-04, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
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Rezvani AH, Levin ED. Nicotine–antipsychotic drug interactions and attentional performance in female rats. Eur J Pharmacol 2004; 486:175-82. [PMID: 14975706 DOI: 10.1016/j.ejphar.2003.12.021] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2003] [Accepted: 12/10/2003] [Indexed: 11/23/2022]
Abstract
Schizophrenia is marked by pronounced cognitive impairments in addition to the hallmark psychotic symptoms like hallucinations. Antipsychotic drugs can effectively reduce these hallucinations; however, the drugs have not resolved the cognitive impairment. Interestingly, nicotine, a drug commonly self-administered by people with schizophrenia, has been shown to significantly improve cognitive function of people with schizophrenia. The current study was conducted to determine the effect of typical (haloperidol) and atypical (clozapine and risperidone) antipsychotic drug treatment on sustained attention in rats performing a visual signal detection task. In addition, the interaction of haloperidol with chronic nicotine administration was assessed. Female Sprague-Dawley rats were injected subcutaneously with clozapine (0, 0.6, 1.25 and 2.5 mg/kg), risperidone (0, 0.025, 0.05 and 0.1 mg/kg) or haloperidol (0, 0.01, 0.02 and 0.04 mg/kg). In the second part of the study, the interaction of acute haloperidol (0, 0.005, 0.01 and 0.02 mg/kg) and chronic nicotine (5 mg/kg/day, for 4 weeks via osmotic minipump) was characterized. Clozapine, risperidone and haloperidol all caused dose-related impairments in percent hit performance. There was a significant linear dose-related impairment in percent hit caused by risperidone. All the doses of clozapine caused a significant impairment in percent hit at the higher luminance intensities in the visual signal detection task. The 0.01 and 0.02 mg/kg haloperidol doses caused significant decreases in percent hit. The 0.04 mg/kg haloperidol dose impaired performance of the task to the point that reliable choice accuracy measurements could not be made. Chronic nicotine infusion significantly diminished the impairing effects of haloperidol on performance during weeks 1-2. In summary, both typical and atypical antipsychotic drugs significantly impaired sustained attention in rats. Haloperidol was more detrimental than clozapine and risperidone. Chronic nicotine diminished the adverse effects of haloperidol on performance. This study establishes a paradigm to reliably determine the attentional impairment caused by antipsychotic drugs.
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Affiliation(s)
- Amir H Rezvani
- Department of Psychiatry and Behavioral Sciences, Box 3412, Duke University Medical Center, Durham, NC 27710, USA.
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Simon BB, Knuckley B, Powell DA. Galantamine facilitates acquisition of a trace-conditioned eyeblink response in healthy, young rabbits. Learn Mem 2004; 11:116-22. [PMID: 14747525 PMCID: PMC321322 DOI: 10.1101/lm.66204] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2003] [Accepted: 11/24/2003] [Indexed: 11/25/2022]
Abstract
Previous work has demonstrated that drugs increasing brain concentrations of acetylcholine can enhance cognition in aging and brain-damaged organisms. The present study assessed whether galantamine (GAL), an allosteric modulator of nicotinic cholinergic receptors and weak acetylcholinesterase inhibitor, could improve acquisition and retention of an eyeblink (EB) classical conditioning task in healthy, young animals. We trained 24 rabbits (n = 8/group) in a 1000-msec trace Pavlovian EB conditioning paradigm in which a tone conditioned stimulus (CS) was presented for 500 msec, followed by a 500-msec trace period in which no stimuli were presented. A 100-msec corneal airpuff was the unconditioned stimulus (US). Acquisition sessions, consisting of 100 trials each, occurred daily for 10 consecutive days, followed by 3 d of extinction training. Animals were treated with one of three doses of GAL (0.0-3.0 mg/kg) prior to each session. Animals that received 3.0 mg/kg GAL showed significantly more EB conditioned responses (CRs) in fewer training trials than animals receiving either 1.5 mg/kg GAL or vehicle injections. GAL had no effect on CR performance during extinction. Pseudoconditioning control experiments, consisting of 200 explicitly unpaired tone-puff presentations indicated that GAL did not increase reactivity to the CS or US. These findings indicate that GAL may improve acquisition of moderately difficult associative learning tasks in healthy young organisms.
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Affiliation(s)
- Barbara B Simon
- Shirley L. Buchanan Neuroscience Laboratory, WJB Dorn VA Medical Center, Columbia, South Carolina 29209, USA.
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Bizarro L, Stolerman IP. Attentional effects of nicotine and amphetamine in rats at different levels of motivation. Psychopharmacology (Berl) 2003; 170:271-277. [PMID: 12955304 DOI: 10.1007/s00213-003-1543-6] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2002] [Accepted: 05/17/2003] [Indexed: 10/26/2022]
Abstract
RATIONALE The effects of drugs on performance of tasks used to assess attention might be confounded with changes in motivation. Few studies have investigated the role of motivational factors in such situations. OBJECTIVES To determine how changes in motivation for food influence performance of the 5-choice serial reaction time task and whether the effects of nicotine and amphetamine can be explained by motivational changes. METHODS Male hooded Lister rats were trained to respond to a 1-s light stimulus presented randomly in one of five apertures in order to obtain food reinforcers. For three groups of rats (n=9-10), access to food was restricted to maintain body weights at 80, 90 or 95% of control weights. Saline and nicotine (0.025-0.2 mg/kg) were tested in each group, with and without pre-feeding (5 g). In a second experiment, saline and amphetamine (0.03-0.9 mg/kg s.c.) were tested without pre-feeding. RESULTS High levels of motivation for food were associated with increases in anticipatory responses, fewer omission errors, shorter response latencies and completion of more trials, without change in accuracy. Nicotine, but not amphetamine, increased accuracy and the number of trials completed; whereas amphetamine, but not nicotine, increased omission errors. Both drugs decreased anticipatory responding at the largest doses tested. There were few interactions of motivational level with drug effects. CONCLUSIONS The improvements in performance produced by nicotine did not resemble the effect of increased motivation, but some effects of amphetamine resembled those of reducing the level of motivation for food. Motivational levels did not confound assessments of the attentional effects of the drugs in terms of response accuracy.
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Affiliation(s)
- L Bizarro
- Section of Behavioural Pharmacology, Institute of Psychiatry P049, King's College London, De Crespigny Park, London, SE5 8AF, UK
| | - I P Stolerman
- Section of Behavioural Pharmacology, Institute of Psychiatry P049, King's College London, De Crespigny Park, London, SE5 8AF, UK.
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Bushnell PJ, Benignus VA, Case MW. Signal detection behavior in humans and rats: a comparison with matched tasks. Behav Processes 2003; 64:121-129. [PMID: 12915002 DOI: 10.1016/s0376-6357(03)00146-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Animal models of human cognitive processes are essential for studying the neurobiological mechanisms of these processes and for developing therapies for intoxication and neurodegenerative diseases. A discrete-trial signal detection task was developed for assessing sustained attention in rats; a previous study showed that rats perform as predicted from the human sustained attention literature. In this study, we measured the behavior of humans in a task formally homologous to the task for rats, varying two of the three parameters previously shown to affect performance in rats. Signal quality was manipulated by varying the increment in the intensity of a lamp. Trial rate was varied among values of 4, 7, and 10 trials/min. Accuracy of signal detection was quantified by the proportion of correct detections of the signal (P(hit)) and the proportion of false alarms (P(fa), i.e. incorrect responses on non-signal trials). As with rats, P(hit) in humans increased with increasing signal intensity whereas P(fa) did not. Like rats, humans were sensitive to the trial rate, though the change in behavior depended on the sex of the subject. These data show that visual signal detection behavior in rats and humans is controlled similarly by two important parameters, and suggest that this task assesses similar processes of sustained attention in the two species.
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Affiliation(s)
- Philip J. Bushnell
- Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, 27711, Research Triangle Park, NC, USA
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40
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Rezvani AH, Levin ED. Nicotinic-glutamatergic interactions and attentional performance on an operant visual signal detection task in female rats. Eur J Pharmacol 2003; 465:83-90. [PMID: 12650836 DOI: 10.1016/s0014-2999(03)01439-0] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Nicotinic systems have been shown to be critically involved in cognitive function including attention. Nicotine has been shown to improve performance on attentional tasks in humans with Alzheimer's disease, schizophrenia and attention deficit hyperactivity disorder. Nicotine has mixed effects on attentional accuracy in unimpaired rats with findings of increased, reduced or unaltered accuracy under different conditions. Nicotine effects on attentional function in rats might be more clearly seen in reversing impaired performance. The current study determined nicotine effects on attentional accuracy reduced by the NMDA receptor antagonist dizocilpine (MK-801). Sprague-Dawley rats (N=35) were trained on a food-motivated two-lever operant task with one lever correct after a brief visual signal (0.027-1.22 lx) for hits and the other lever correct after the absence of a signal for correct rejections. First, a dose response study of dizocilpine was conducted to determine the threshold for impairment. The rats were administered acute doses of dizocilpine (0, 12.5, 25 and 50 microg/kg, sc). The 50 microg/kg dose caused significant (p<0.0005) reduction in percent hit at the four highest signal intensities. Percent correct rejection was also significantly lowered by this dose (p<0.005). No effect was seen with 12.5 microg/kg and only minimal effect seen with 25 microg/kg. Then, nicotine-dizocilpine interactions were investigated. The rats were administered acute doses of dizocilpine (0, 37.5 and 50 microg/kg, sc) and nicotine (0, 25 and 50 microg/kg, sc), alone or in combination. Percent hit was affected by nicotine and dizocilpine in a complex fashion with only the nicotinexdizocilpinexsignal intensity interaction being significant (p<0.05). Percent correct rejection showed a more straightforward effect. Percent correct rejection was significantly reduced by 50 microg/kg dizocilpine (p<0.025). The addition of 25 microg/kg of nicotine significantly (p<0.025) reversed the dizocilpine-induced reduction of correct rejection. This study shows that dizocilpine reduces signal detection accuracy in a dose-dependent fashion. Nicotine can partially counteract an aspect of this reduction by reversing the dizocilpine-induced reduction of correct rejection.
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Affiliation(s)
- Amir H Rezvani
- Department of Psychiatry, Duke University Medical Center, 341 Bell Building, Box 3412, Durham, NC 27710, USA.
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41
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Hahn B, Shoaib M, Stolerman IP. Effects of dopamine receptor antagonists on nicotine-induced attentional enhancement. Behav Pharmacol 2002; 13:621-32. [PMID: 12478212 DOI: 10.1097/00008877-200212000-00003] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
An understanding of the neuropharmacological mechanisms mediating attentional enhancement by nicotine would indicate whether these effects could be dissociated pharmacologically from other behavioural effects of nicotine. The aim of the present study was to examine the involvement of dopamine neurotransmission in the effects of nicotine on different response indices of an attentional paradigm. The effects of the D2-type dopamine receptor antagonist raclopride (0.025-0.1 mg/kg) and the D1-type receptor antagonist SCH23390 (0.006-0.024 mg/kg) were tested, in both the presence and absence of nicotine (0.1 mg/kg), in rats trained in a modified version of the five-choice serial reaction time task (5-CSRTT). Nicotine robustly enhanced the accuracy of signal detection, reduced omission errors and shortened response latencies. Neither raclopride nor SCH23390 altered the effects of nicotine on accuracy and omissions, but raclopride augmented accuracy and SCH23390 increased omissions when given alone. By contrast, raclopride, but not SCH23390, reversed the nicotine-induced reductions in response latencies, at doses that had no effect on their own. In the presence of nicotine, both antagonists had rate-disruptive effects at the highest dose. Both antagonists also reduced responding in the intertrial interval, and this effect was additive to the nicotine-induced decrease in this measure. The data indicate that D2-type dopamine receptors may be involved in the effects of nicotine on response speed. Neither the D1- nor the D2-type dopamine receptor antagonist affected nicotine-induced improvements in signal detection, at doses that reversed dependence-related behavioural effects of nicotine in previous studies. Thus these effects may be pharmacologically dissociable.
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Affiliation(s)
- B Hahn
- Section of Behavioural Pharmacology, P049, Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, UK.
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42
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Redolat R, Oterino MC, Carrasco MC, Brain PF. A specific anti-aggressive effect of repeatedly administered lobeline. Addict Biol 2002; 7:301-6. [PMID: 12126489 DOI: 10.1080/13556210220139514] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The effects of chronic treatments with nicotinic agonists on agonistic encounters have received little attention. The effects of repeated (for 10 days) SC administration of (-)-lobeline (9.3, 18.6 and 37.2 micromol/kg) and (-)-nicotine (0.93, 1.86 and 3.72 micromol/kg) were evaluated using the mouse isolation-induced aggression model. Individually housed OF1 male mice served as experimental animals and were confronted by 'standard opponents'. Each mouse was tested only once on the last day of the repeated drug treatment. Videotaped agonistic encounters were analysed estimating the times allocated to 11 behavioural categories. Repeated treatment with the highest dose of lobeline diminished attack behaviour without significantly increasing immobility or changing any other behavioural category involving motor activity. In contrast, nicotine did not significantly alter time allocated to any behavioural category.
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Affiliation(s)
- Rosa Redolat
- Area de Psicobiología, Facultad de Psicología, Universitat de València, Spain.
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Bushnell PJ, Levin ED, Marrocco RT, Sarter MF, Strupp BJ, Warburton DM. Attention as a target of intoxication: insights and methods from studies of drug abuse. Neurotoxicol Teratol 2000; 22:487-502. [PMID: 10974587 DOI: 10.1016/s0892-0362(00)00077-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
A symposium was convened to discuss recent developments in the assessment of attention and the effects of drugs and toxic chemicals on attention at the 17th annual meeting of the Behavioral Toxicology Society on May 1, 1999, in Research Triangle Park, NC. Speakers addressed issues including the methodology of assessing cognitive function, the neurobiology of specific aspects of attention, the dual roles of attention as a target of intoxication and as a mediating variable in the development of addiction to psychoactive drugs, the changes in attention that accompany neuropsychological disorders of schizophrenia, senile dementia of the Alzheimer type and attention deficit hyperactivity disorder, and potential therapies for these disorders. This article provides an overview of the objectives of the symposium, followed by summaries of each of the talks given.
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Affiliation(s)
- P J Bushnell
- Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, 27711, Research Triangle Park, NC 27711, USA.
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44
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Grilly DM, Simon BB, Levin ED. Nicotine enhances stimulus detection performance of middle- and old-aged rats: a longitudinal study. Pharmacol Biochem Behav 2000; 65:665-70. [PMID: 10764920 DOI: 10.1016/s0091-3057(99)00259-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The effects of nicotine on sustained attention were tested in F344xBN male rats when they were chronologically middle and old aged. The rats (n = 11) were trained in a two-choice, stimulus detection task in which a press of one of two levers was reinforced with food, with the correct lever indicated by the position of a briefly illuminated light. They were tested when they were 24-25 and 34-35 months of age (i.e., at 60-68% and 85-95%, respectively of their expected median life span) after saline or 0.1-0.5 mg/kg doses of nicotine (SC). A significant dose-related improvement in percent correct choices and decrease in choice response times was found at both ages, and there was no significant main effect of age or an age by dose interaction. These results support the position that nicotine can enhance attentional processes in rats throughout their life span. Nicotine and other nicotinic agonists may have efficacy in the treatment of disorders such as Alzheimer's disease.
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Affiliation(s)
- D M Grilly
- Department of Psychology, Cleveland State University, Cleveland, OH 44114, USA
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Abstract
Studies in smokers have suggested that at least part of the improved psychomotor performance produced by nicotine is the result of an effect on attention. Many animal experiments have assessed the effects of nicotine and its antagonists on diverse types of learning and memory but relatively few have looked at it in tasks designed to assess attention. In a five-choice serial reaction time task (5-CSRTT), rats with restricted access to food were presented with an array of five holes; illumination of a randomly selected hole signalled that a nose-poke into it would be reinforced by food presentation. Initially, signal length and the inter-trial interval (ITI) were varied and the procedure was demonstrated to satisfy some criteria for a vigilance task. The effects of nicotine on deficits in performance induced by varying signal length and ITI were assessed. Under appropriate conditions, small doses of nicotine increased the percentage of correct responses (accuracy), decreased omission errors and reaction time, and increased anticipatory responses. Subsequently, the effects of varying the ITI were examined more extensively in a slightly modified task. Here, nicotine produced small but robust, highly significant dose-related increases in accuracy, as well as decreases in omission errors and reaction times. Nicotine also increased accuracy when light stimuli were presented in an unpredictable manner. The nicotine antagonist mecamylamine produced a modest deficit in reaction time only. It is concluded that appropriate doses of nicotine can produce robust improvements in performance of normal rats in an attentional task. The effect cannot be attributed easily to changes in sensory or motor capability, learning or memory and may provide the measures needed to investigate the neuropharmacological and neuroanatomical bases of the elusive attentional effect of nicotine.
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Affiliation(s)
- I P Stolerman
- Section of Behavioural Pharmacology, Institute of Psychiatry, De Crespigny Park, London, UK.
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46
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Redolat R, Oterino M, Carrasco M, Berry M, Brain P. Effects of acute administration of nicotine and lobeline on agonistic encounters in male mice. Aggress Behav 2000. [DOI: 10.1002/1098-2337(2000)26:5<376::aid-ab3>3.0.co;2-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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47
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Bushnell PJ, Rice DC. Behavioral assessments of learning and attention in rats exposed perinatally to 3,3',4,4',5-pentachlorobiphenyl (PCB 126). Neurotoxicol Teratol 1999; 21:381-92. [PMID: 10440482 DOI: 10.1016/s0892-0362(99)00006-9] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Evidence from humans suggests that cognitive dysfunction may result from perinatal exposure to polychlorinated biphenyls (PCBs), and the results of some animal research with PCBs have been interpreted in terms of possible impairment of attention. Long-Evans rats were fed 3,3',4,4',5-pentachlorobiphenyl (PCB 126), a coplanar congener, at doses of 0.25 or 1 microgram/kg/day [corrected] throughout gestation and nursing. Male offspring of these rats were trained as adults to perform 2 tests of attention for food reward. First, a cued target-detection task, modeled after Posner's covert orienting method for humans, was used to assess visuospatial attention. In this task, a visual target stimulus was presented in 1 visual hemifield on each trial, preceded either by a valid cue, an invalid cue, or no cue. A valid cue appeared in the same hemifield as the target, and an invalid cue appeared in the opposite hemifield. As expected, valid cues increased accuracy and speed of target detection and invalid cues decreased accuracy and speed; moreover, these effects were systematically related to changes in cue intensity and target duration. However, perinatal exposure to PCB 126 did not affect acquisition or performance of this task. The second task assessed sustained attention by means of a signal detection method in which a brief, spatially-constant but temporally unpredictable, visual signal indicated which of 2 responses would yield food. Varying the intensity of the signal greatly affected the probability of correctly reporting the signal. Perinatal exposure to PCB 126 did not affect acquisition of the response rule or performance of the task. Finally, all rats were challenged with chlordiazepoxide (CDP) at doses of 0, 3, 5, 8, or 12 mg/kg SC, 20 min before testing in the sustained attention task. In control rats, low doses (3, 5, and 8 mg/kg) of CDP reduced accuracy at low signal intensities only, suggesting an increase in visual threshold. The high dose of CDP reduced accuracy at all signal intensities and increased the false-alarm rate as well, suggesting an impairment of attention. The rats exposed perinatally to PCB 126 at 0.25 micrograms/kg [corrected] were unaffected by CDP, and those exposed to PCB 126 at 1 microgram/kg [corrected] showed a smaller decrement in performance after CDP than did the controls. Taken together, these data provide little support for the possibility that perinatal exposure to PCB 126 causes deficits in attention, but suggest that PCB 126 may alter GABA-mediated pathways in the CNS during development.
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Affiliation(s)
- P J Bushnell
- Neurotoxicology Division, United States Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
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48
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Bushnell PJ. Detection of visual signals by rats: effects of signal intensity, event rate, and task type. Behav Processes 1999; 46:141-50. [DOI: 10.1016/s0376-6357(99)00030-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/1998] [Revised: 02/22/1999] [Accepted: 02/23/1999] [Indexed: 11/30/2022]
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49
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Miner LA, Sarter M. Intra-accumbens infusions of antisense oligodeoxynucleotides to one isoform of glutamic acid decarboxylase mRNA, GAD65, but not to GAD67 mRNA, impairs sustained attention performance in the rat. BRAIN RESEARCH. COGNITIVE BRAIN RESEARCH 1999; 7:269-83. [PMID: 9838159 DOI: 10.1016/s0926-6410(98)00030-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The effects of bilateral infusions of antisense oligodeoxynucleotides (ODNs) for the two isoforms of glutamic acid decarboxylase (GAD65; GAD67) into the nucleus accumbens on the performance of intact rats in a task designed to assess sustained attention were tested. The task required the animals to discriminate between signal and non-signal events. Signals and non-signals were presented randomly and unpredictably. The task generated all four response types of a sustained attention task, i.e., hits, misses, correct rejections, false alarms. Infusions of the scrambled sequence ODNs did not affect performance. Likewise, infusions of the GAD67 ODNs failed to produce any effect. However, infusions of the GAD65 ODNs into the nucleus accumbens resulted in a robust and reliable decrease in the relative number of hits. Similarly, the combined infusion of GAD65+67 ODNs impaired the hit rate but did not affect the animals' ability to reject non-signals. Following each treatment series, performance rapidly returned to baseline, further indicating the specificity and reversibility of the effects of the infusions of the ODNs. While these data suggest that translation arrest of specifically the GAD65 isoform of the enzyme in the nucleus accumbens impairs attentional performance, the neuronal mechanisms mediating these effects remain unsettled.
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Affiliation(s)
- L A Miner
- Department of Psychology, The Ohio State University, 27 Townshend Hall, Columbus, OH 43210, USA
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Benwell ME, Balfour DJ. The influence of lobeline on nucleus accumbens dopamine and locomotor responses to nicotine in nicotine-pretreated rats. Br J Pharmacol 1998; 125:1115-9. [PMID: 9863636 PMCID: PMC1565682 DOI: 10.1038/sj.bjp.0702161] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
In vivo brain microdialysis was used to investigate the influence of lobeline on dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) overflow in the core of the nucleus accumbens of freely-moving rats pretreated with nicotine (0.4 mg x kg(-1), s.c., once per day for 5 days). Locomotion was also recorded. Lobeline, at doses of 0.7, 4.0 and 10.0 mg x kg(-1), i.p., failed to elicit any significant changes in extracellular dopamine or dihydroxyphenylacetic acid levels during the 60 min following its administration and did not stimulate locomotor. The dopamine responses to nicotine (0.4 mg x kg(-1), s.c.), were abolished (P<0.01) if the nicotine challenge was administered 10 min but not 60 min, after lobeline doses of 4.0 and 10.0 mg kg(-1), i.p., but were unaffected following lobeline at the lowest dose tested (0.7 mg x kg(-1), i.p.) at either time. The increase in locomotor activity was significantly attenuated (P<0.01), to a similar extent, when the nicotine was injected 10 min, but not 60 min, after all three doses of lobeline (0.7, 4.0 and 10.0 mg kg(-1), i.p.) when compared with the saline-treated rats. The results suggest that lobeline is a short-acting antagonist of the nicotinic AChRs which mediate the effects of nicotine on mesolimbic dopamine activity and locomotor stimulation.
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Affiliation(s)
- M E Benwell
- Department of Pharmacology and Neuroscience, Dundee University Medical School, Ninewells Hospital
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