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Chagraoui A, Thibaut F, Skiba M, Thuillez C, Bourin M. 5-HT2C receptors in psychiatric disorders: A review. Prog Neuropsychopharmacol Biol Psychiatry 2016; 66:120-135. [PMID: 26739950 DOI: 10.1016/j.pnpbp.2015.12.006] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 12/25/2015] [Accepted: 12/26/2015] [Indexed: 12/26/2022]
Abstract
5-HT2Rs have a different genomic organization from other 5-HT2Rs. 5HT2CR undergoes post-transcriptional pre-mRNA editing generating diversity among RNA transcripts. Selective post-transcriptional editing could be involved in the pathophysiology of psychiatric disorders through impairment in G-protein interactions. Moreover, it may influence the therapeutic response to agents such as atypical antipsychotic drugs. Additionally, 5-HT2CR exhibits alternative splicing. Central serotonergic and dopaminergic systems interact to modulate normal and abnormal behaviors. Thus, 5HT2CR plays a crucial role in psychiatric disorders. 5HT2CR could be a relevant pharmacological target in the treatment of neuropsychiatric disorders. The development of drugs that specifically target 5-HT2C receptors will allow for better understanding of their involvement in the pathophysiology of psychiatric disorders including schizophrenia, anxiety, and depression. Among therapeutic means currently available, most drugs used to treat highly morbid psychiatric diseases interact at least partly with 5-HT2CRs. Pharmacologically, 5HT2CRs, have the ability to generate differentially distinct response signal transduction pathways depending on the type of 5HT2CR agonist. Although this receptor property has been clearly demonstrated, in vitro, the eventual beneficial impact of this property opens new perspectives in the development of agonists that could activate signal transduction pathways leading to better therapeutic efficiency with fewer adverse effects.
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Affiliation(s)
- A Chagraoui
- Inserm U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, Normandy University, France; Department of Medical Biochemistry, Rouen University Hospital, Rouen, France.
| | - F Thibaut
- Department of Psychiatry, University Hospital Cochin (site Tarnier), University of Paris-Descartes and INSERM U 894 Laboratory of Psychiatry and Neurosciences, Paris, France
| | - M Skiba
- Inserm U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, Normandy University, France
| | - C Thuillez
- Department of Pharmacology, Rouen University Hospital, Rouen, France; INSERM U1096, Laboratory of New Pharmacological Targets for Endothelial Protection and Heart Failure, Institute for Research and Innovation in Biomedicine, Normandy University, France
| | - M Bourin
- EA 3256 Neurobiology of Anxiety and Depression, Faculté de Médecine, BP 53508, 1 rue Gaston Veil, F44035 Nantes Cedex 01, France
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De Deurwaerdère P, Di Giovanni G. Serotonergic modulation of the activity of mesencephalic dopaminergic systems: Therapeutic implications. Prog Neurobiol 2016; 151:175-236. [PMID: 27013075 DOI: 10.1016/j.pneurobio.2016.03.004] [Citation(s) in RCA: 114] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 03/13/2016] [Accepted: 03/14/2016] [Indexed: 12/14/2022]
Abstract
Since their discovery in the mammalian brain, it has been apparent that serotonin (5-HT) and dopamine (DA) interactions play a key role in normal and abnormal behavior. Therefore, disclosure of this interaction could reveal important insights into the pathogenesis of various neuropsychiatric diseases including schizophrenia, depression and drug addiction or neurological conditions such as Parkinson's disease and Tourette's syndrome. Unfortunately, this interaction remains difficult to study for many reasons, including the rich and widespread innervations of 5-HT and DA in the brain, the plethora of 5-HT receptors and the release of co-transmitters by 5-HT and DA neurons. The purpose of this review is to present electrophysiological and biochemical data showing that endogenous 5-HT and pharmacological 5-HT ligands modify the mesencephalic DA systems' activity. 5-HT receptors may control DA neuron activity in a state-dependent and region-dependent manner. 5-HT controls the activity of DA neurons in a phasic and excitatory manner, except for the control exerted by 5-HT2C receptors which appears to also be tonically and/or constitutively inhibitory. The functional interaction between the two monoamines will also be discussed in view of the mechanism of action of antidepressants, antipsychotics, anti-Parkinsonians and drugs of abuse.
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Affiliation(s)
- Philippe De Deurwaerdère
- Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5293, 33076 Bordeaux Cedex, France.
| | - Giuseppe Di Giovanni
- Department of Physiology & Biochemistry, Faculty of Medicine and Surgery, University of Malta, Malta; Neuroscience Division, School of Biosciences, Cardiff University, Cardiff, UK.
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Di Giovanni G, De Deurwaerdère P. New therapeutic opportunities for 5-HT2C receptor ligands in neuropsychiatric disorders. Pharmacol Ther 2015; 157:125-62. [PMID: 26617215 DOI: 10.1016/j.pharmthera.2015.11.009] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The 5-HT2C receptor (R) displays a widespread distribution in the CNS and is involved in the action of 5-HT in all brain areas. Knowledge of its functional role in the CNS pathophysiology has been impaired for many years due to the lack of drugs capable of discriminating among 5-HT2R subtypes, and to a lesser extent to the 5-HT1B, 5-HT5, 5-HT6 and 5-HT7Rs. The situation has changed since the mid-90s due to the increased availability of new and selective synthesized compounds, the creation of 5-HT2C knock out mice, and the progress made in molecular biology. Many pharmacological classes of drugs including antipsychotics, antidepressants and anxiolytics display affinities toward 5-HT2CRs and new 5-HT2C ligands have been developed for various neuropsychiatric disorders. The 5-HT2CR is presumed to mediate tonic/constitutive and phasic controls on the activity of different central neurobiological networks. Preclinical data illustrate this complexity to a point that pharmaceutical companies developed either agonists or antagonists for the same disease. In order to better comprehend this complexity, this review will briefly describe the molecular pharmacology of 5-HT2CRs, as well as their cellular impacts in general, before addressing its central distribution in the mammalian brain. Thereafter, we review the preclinical efficacy of 5-HT2C ligands in numerous behavioral tests modeling human diseases, highlighting the multiple and competing actions of the 5-HT2CRs in neurobiological networks and monoaminergic systems. Notably, we will focus this evidence in the context of the physiopathology of psychiatric and neurological disorders including Parkinson's disease, levodopa-induced dyskinesia, and epilepsy.
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Affiliation(s)
- Giuseppe Di Giovanni
- Department of Physiology & Biochemistry, Faculty of Medicine and Surgery, University of Malta; Neuroscience Division, School of Biosciences, Cardiff University, Cardiff, UK.
| | - Philippe De Deurwaerdère
- Centre National de la Recherche Scientifique (Unité Mixte de Recherche 5293) 33076 Bordeaux Cedex, France.
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Luo M, Zhou J, Liu Z. Reward processing by the dorsal raphe nucleus: 5-HT and beyond. ACTA ACUST UNITED AC 2015; 22:452-60. [PMID: 26286655 PMCID: PMC4561406 DOI: 10.1101/lm.037317.114] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 07/06/2015] [Indexed: 12/20/2022]
Abstract
The dorsal raphe nucleus (DRN) represents one of the most sensitive reward sites in the brain. However, the exact relationship between DRN neuronal activity and reward signaling has been elusive. In this review, we will summarize anatomical, pharmacological, optogenetics, and electrophysiological studies on the functions and circuit mechanisms of DRN neurons in reward processing. The DRN is commonly associated with serotonin (5-hydroxytryptamine; 5-HT), but this nucleus also contains neurons of the neurotransmitter phenotypes of glutamate, GABA and dopamine. Pharmacological studies indicate that 5-HT might be involved in modulating reward- or punishment-related behaviors. Recent optogenetic stimulations demonstrate that transient activation of DRN neurons produces strong reinforcement signals that are carried out primarily by glutamate. Moreover, activation of DRN 5-HT neurons enhances reward waiting. Electrophysiological recordings reveal that the activity of DRN neurons exhibits diverse behavioral correlates in reward-related tasks. Studies so far thus demonstrate the strong power of DRN neurons in reward signaling and at the same time invite additional efforts to dissect the roles and mechanisms of different DRN neuron types in various processes of reward-related behaviors.
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Affiliation(s)
- Minmin Luo
- National Institute of Biological Sciences, Beijing 102206, China School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Jingfeng Zhou
- National Institute of Biological Sciences, Beijing 102206, China
| | - Zhixiang Liu
- National Institute of Biological Sciences, Beijing 102206, China
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Multiple controls exerted by 5-HT2C receptors upon basal ganglia function: from physiology to pathophysiology. Exp Brain Res 2013; 230:477-511. [PMID: 23615975 DOI: 10.1007/s00221-013-3508-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 03/28/2013] [Indexed: 10/26/2022]
Abstract
Serotonin2C (5-HT2C) receptors are expressed in the basal ganglia, a group of subcortical structures involved in the control of motor behaviour, mood and cognition. These receptors are mediating the effects of 5-HT throughout different brain areas via projections originating from midbrain raphe nuclei. A growing interest has been focusing on the function of 5-HT2C receptors in the basal ganglia because they may be involved in various diseases of basal ganglia function notably those associated with chronic impairment of dopaminergic transmission. 5-HT2C receptors act on numerous types of neurons in the basal ganglia, including dopaminergic, GABAergic, glutamatergic or cholinergic cells. Perhaps inherent to their peculiar molecular properties, the modality of controls exerted by 5-HT2C receptors over these cell populations can be phasic, tonic (dependent on the 5-HT tone) or constitutive (a spontaneous activity without the presence of the ligand). These controls are functionally organized in the basal ganglia: they are mainly localized in the input structures and preferentially distributed in the limbic/associative territories of the basal ganglia. The nature of these controls is modified in neuropsychiatric conditions such as Parkinson's disease, tardive dyskinesia or addiction. Most of the available data indicate that the function of 5-HT2C receptor is enhanced in cases of chronic alterations of dopamine neurotransmission. The review illustrates that 5-HT2C receptors play a role in maintaining continuous controls over the basal ganglia via multiple diverse actions. We will discuss their interest for treatments aimed at ameliorating current pharmacotherapies in schizophrenia, Parkinson's disease or drugs abuse.
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Chenu F, El Mansari M, Blier P. Electrophysiological effects of repeated administration of agomelatine on the dopamine, norepinephrine, and serotonin systems in the rat brain. Neuropsychopharmacology 2013; 38:275-84. [PMID: 22871919 PMCID: PMC3527117 DOI: 10.1038/npp.2012.140] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Agomelatine is a melatonergic MT1/MT2 agonist and a serotonin (5-HT) 5-HT(2C) antagonist. The effects of 2-day and 14-day administration of agomelatine were investigated on the activity of ventral tegmental area (VTA) dopamine (DA), locus coeruleus (LC) norepinephrine (NE), and dorsal raphe nucleus (DRN) 5-HT neurons using in vivo electrophysiology in rats. The 5-HT(1A) transmission was assessed at hippocampus CA3 pyramidal neurons. After a 2-day regimen of agomelatine (40 mg/kg/day, i.p.), an increase in the number of spontaneously active VTA-DA neurons (p<0.001) and in the firing rate of LC-NE neurons (p<0.001) was observed. After 14 days, the administration of agomelatine induced an increase in: (1) the number of spontaneously active DA neurons (p<0.05), (2) the bursting activity of DA neurons (bursts/min, p<0.01 and percentage of spikes occurring in bursts, p<0.05), (3) the firing rate of DRN-5-HT neurons (p<0.05), and (4) the tonic activation of postsynaptic 5-HT(1A) receptors located in the hippocampus. The increase in 5-HT firing rate was D2 dependent, as it was antagonized by the D2 receptor antagonist paliperidone. The enhancement of NE firing was restored by the 5-HT(2A) receptor antagonist MDL-100,907 after the 14-day regimen. All the effects of agomelatine were antagonized by a single administration of the melatonergic antagonist S22153 (except for the increase in the percentage of spikes occurring in burst for DA neurons). The present results suggest that (1) agomelatine exerts direct (2 days) and indirect (14 days) modulations of monoaminergic neuronal activity and (2) the melatonergic agonistic activity of agomelatine contributes to the enhancement of DA and 5-HT neurotransmission.
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Affiliation(s)
- Franck Chenu
- Institute of Mental Health Research, University of Ottawa, Ottawa, ON, Canada
| | - Mostafa El Mansari
- Institute of Mental Health Research, University of Ottawa, Ottawa, ON, Canada
| | - Pierre Blier
- Institute of Mental Health Research, University of Ottawa, Ottawa, ON, Canada,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada,Institute of Mental Health Research (IMHR), 1145 Carling Avenue, University of Ottawa, Room 6412, Ottawa K1Z 7K4, ON, Canada, Tel: +1 613 722 6521 (ext 6944), Fax: +1 613 761 3610, E-mail:
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Rosenzweig-Lipson S, Comery TA, Marquis KL, Gross J, Dunlop J. 5-HT(2C) agonists as therapeutics for the treatment of schizophrenia. Handb Exp Pharmacol 2012:147-165. [PMID: 23027415 DOI: 10.1007/978-3-642-25758-2_6] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
The 5-HT(2C) receptor is a highly complex, highly regulated receptor which is widely distributed throughout the brain. The 5-HT(2C) receptor couples to multiple signal transduction pathways leading to engagement of a number of intracellular signaling molecules. Moreover, there are multiple allelic variants of the 5-HT(2C) receptor and the receptor is subject to RNA editing in the coding regions. The complexity of this receptor is further emphasized by the studies suggesting the utility of either agonists or antagonists in the treatment of schizophrenia. While several 5-HT(2C) agonists have demonstrated clinical efficacy in obesity (lorcaserin, PRX-000933), the focus of this review is on the therapeutic potential of 5-HT(2C) agonists in schizophrenia. To this end, the preclinical profile of 5-HT(2C) agonists from a neurochemical, electrophysiological, and a behavioral perspective is indicative of antipsychotic-like efficacy without extrapyramidal symptoms or weight gain. Recently, the selective 5-HT(2C) agonist vabicaserin demonstrated clinical efficacy in a Phase II trial in schizophrenia patients without weight gain and with low EPS liability. These data are highly encouraging and suggest that 5-HT(2C) agonists are potential therapeutics for the treatment of psychiatric disorders.
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Dawson LA. The central role of 5-HT6 receptors in modulating brain neurochemistry. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2011; 96:1-26. [PMID: 21329782 DOI: 10.1016/b978-0-12-385902-0.00001-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Lee A Dawson
- Neurosciences Product Creation Unit, Eisai Limited, Hatfield, Hertfordshire, AL10 9SN, UK
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Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat. Psychopharmacology (Berl) 2009; 206:403-14. [PMID: 19629447 DOI: 10.1007/s00213-009-1618-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2009] [Accepted: 07/08/2009] [Indexed: 12/11/2022]
Abstract
RATIONALE 5-HT receptor mechanisms have been suggested to mediate improvements in cognition in schizophrenia. AIM The aim of this study was to investigate the involvement of 5-HT receptor mechanisms in sub-chronic phencyclidine (PCP)-induced reversal learning deficits in female rats, a task of relevance to schizophrenia. METHODS Adult female hooded Lister rats were trained to perform an operant reversal learning task and then received sub-chronic PCP (2 mg/kg) or vehicle intraperitoneally (i.p.) twice daily for 7 days, followed by 7-day washout. Rats then received an acute dose of the 5-HT(7) receptor antagonist SB-269970A (1.0, 3.0, and 10.0 mg/kg, i.p.) or vehicle. In experiment 2, PCP-treated rats received the selective 5-HT(2C) receptor antagonist, SB-243213A acutely (1.0, 3.0, and 10.0 mg/kg, i.p.) or vehicle. In experiment 3, PCP-treated rats received the 5-HT(1A) receptor partial agonist, buspirone (0.15625, 0.3125, and 0.625 mg/kg, i.p.) in combination with the selective 5-HT(1A) receptor antagonist WAY-100635 (0.3 and 1.0 mg/kg). RESULTS In all experiments, sub-chronic PCP significantly impaired reversal phase performance (P < 0.01-0.001), with no effect in the initial phase. SB-269970A at 3.0 and 10.0 mg/kg significantly improved the PCP-induced deficit (P < 0.05). SB-243213A also significantly attenuated the deficit at 10 mg/kg (P < 0.05). In experiment 3, buspirone attenuated the deficit with significant effects at 0.3125 and 0.625 mg/kg (P < 0.05). WAY-100635 at 0.3 and 1.0 mg/kg produced a partial attenuation of buspirone's effect as buspirone (0.3125 mg/kg) in the presence of WAY-100635 did not significantly reverse the PCP-induced deficit. CONCLUSIONS These studies implicate the role of 5-HT(7), 5-HT(2C), and 5-HT(1A) receptors in the improvement of cognitive dysfunction of relevance to schizophrenia.
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Abdallah L, Bonasera SJ, Hopf FW, O'Dell L, Giorgetti M, Jongsma M, Carra S, Pierucci M, Di Giovanni G, Esposito E, Parsons LH, Bonci A, Tecott LH. Impact of serotonin 2C receptor null mutation on physiology and behavior associated with nigrostriatal dopamine pathway function. J Neurosci 2009; 29:8156-65. [PMID: 19553455 PMCID: PMC3077993 DOI: 10.1523/jneurosci.3905-08.2009] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2008] [Revised: 12/19/2008] [Accepted: 01/12/2009] [Indexed: 11/21/2022] Open
Abstract
The impact of serotonergic neurotransmission on brain dopaminergic pathways has substantial relevance to many neuropsychiatric disorders. A particularly prominent role has been ascribed to the inhibitory effects of serotonin 2C receptor (5-HT(2C)R) activation on physiology and behavior mediated by the mesolimbic dopaminergic pathway, particularly in the terminal region of the nucleus accumbens. The influence of this receptor subtype on functions mediated by the nigrostriatal dopaminergic pathway is less clear. Here we report that a null mutation eliminating expression of 5-HT(2C)Rs produces marked alterations in the activity and functional output of this pathway. 5-HT(2C)R mutant mice displayed increased activity of substantia nigra pars compacta (SNc) dopaminergic neurons, elevated baseline extracellular dopamine concentrations in the dorsal striatum (DSt), alterations in grooming behavior, and enhanced sensitivity to the stereotypic behavioral effects of d-amphetamine and GBR 12909. These psychostimulant responses occurred in the absence of phenotypic differences in drug-induced extracellular dopamine concentration, suggesting a phenotypic alteration in behavioral responses to released dopamine. This was further suggested by enhanced behavioral responses of mutant mice to the D(1) receptor agonist SKF 81297. Differences in DSt D(1) or D(2) receptor expression were not found, nor were differences in medium spiny neuron firing patterns or intrinsic membrane properties following dopamine stimulation. We conclude that 5-HT(2C)Rs regulate nigrostriatal dopaminergic activity and function both at SNc dopaminergic neurons and at a locus downstream of the DSt.
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Affiliation(s)
- Luna Abdallah
- Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158
| | - Stephen J. Bonasera
- Division of Geriatrics, Department of Medicine, University of California, San Francisco, San Francisco, California 94143
| | - F. Woodward Hopf
- Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville, California 94608
| | - Laura O'Dell
- Department of Psychology, University of Texas, El Paso, El Paso, Texas 79968
| | - Marco Giorgetti
- Division of Pharmacology, Amgen, South San Francisco, California 94080
| | | | - Scott Carra
- Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158
| | - Massimo Pierucci
- Istituto Di Ricerche Farmacologiche “Mario Negri,” Consorzio “Mario Negri Sud,” 66030 Santa Maria Imbaro, Chieti, Italy
| | - Giuseppe Di Giovanni
- Istituto Di Ricerche Farmacologiche “Mario Negri,” Consorzio “Mario Negri Sud,” 66030 Santa Maria Imbaro, Chieti, Italy
| | - Ennio Esposito
- Istituto Di Ricerche Farmacologiche “Mario Negri,” Consorzio “Mario Negri Sud,” 66030 Santa Maria Imbaro, Chieti, Italy
| | - Loren H. Parsons
- Committee on the Neurobiology of Addictive Disorders, SP30–2120, The Scripps Research Institute, La Jolla, California 92037, and
| | - Antonello Bonci
- Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville, California 94608
| | - Laurence H. Tecott
- Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158
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Preferential Modulation of the GABAergic vs. Dopaminergic Function in the Substantia Nigra by 5-HT2C Receptor. ACTA ACUST UNITED AC 2009. [DOI: 10.1007/978-1-4419-0340-2_22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
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12
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Berg KA, Navailles S, Sanchez TA, Silva YM, Wood MD, Spampinato U, Clarke WP. Differential effects of 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxyl]-5-pyridyl]carbamoyl]-6-trifluoromethylindone (SB 243213) on 5-hydroxytryptamine(2C) receptor-mediated responses. J Pharmacol Exp Ther 2006; 319:260-8. [PMID: 16807362 DOI: 10.1124/jpet.106.104448] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
5-Methyl-1-[[2-[(2-methyl-3-pyridyl)oxyl]-5-pyridyl]carbamoyl]-6-trifluoromethylindone (SB 243213) is a selective, high-affinity 5-hydroxytryptamine (serotonin)(2C) receptor ligand that has been previously characterized as a competitive 5-HT(2C) receptor antagonist that has a long duration of activity in vivo. It is active in two preclinical models of anxiety and has an improved anxiolytic profile compared with benzodiazepines. In this study, we further characterized the pharmacological properties of SB 243213 by measuring its effects on each of multiple responses coupled to the 5-HT(2C) receptor. In Chinese hamster ovary cells, SB 243213 was an inverse agonist for the phospholipase A(2) response, for guanosine 5'-O-(3-[(35)S]thio)triphosphate binding, for reduction of constitutive desensitization, and for enhancement of dopamine release in the rat nucleus accumbens, with relative efficacies of 0.6, 1, 1, and 0.6, respectively. However, for the phospholipase C (PLC) signaling cascade, SB 243213 behaved as an antagonist. Although SB 243213 was previously characterized as a competitive antagonist for the PLC response, the magnitude of the dextral shift of the 5-HT concentration-response curve was time-dependent, and the maximal PLC response to 5-HT was decreased, probably as a result of the slow dissociation rate of SB 243213 (initial dissociation rate was 3.2 times slower than SB206553, a prototypical 5-HT(2C) receptor inverse agonist). Taken together, these data show that the pharmacological characteristics of SB 243213 at the 5-HT(2C) receptor differ depending upon the response measured, and they support the hypothesis that different drugs, acting at the same receptor subtype, can differentially regulate multiple cellular signaling systems.
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Affiliation(s)
- Kelly A Berg
- Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900, USA.
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Navailles S, De Deurwaerdère P, Spampinato U. Clozapine and haloperidol differentially alter the constitutive activity of central serotonin2C receptors in vivo. Biol Psychiatry 2006; 59:568-75. [PMID: 16182256 DOI: 10.1016/j.biopsych.2005.07.035] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2005] [Revised: 07/18/2005] [Accepted: 07/25/2005] [Indexed: 11/16/2022]
Abstract
BACKGROUND Central serotonin2C (5-HT2C) receptors are known to play a role in the mechanism of action of the antipsychotic drugs (APDs) clozapine and haloperidol. However, evidence for the involvement of the constitutive activity of 5-HT2C receptors in the dopamine (DA)ergic effects of APDs is lacking in vivo. METHODS Using in vivo microdialysis in halothane-anesthetized rats, we assessed the ability of selective 5-HT2C compounds to modulate the release of DA induced by haloperidol and clozapine in the nucleus accumbens and striatum. RESULTS Both APDs induced a dose-dependent increase in accumbal and striatal DA extracellular levels. The effect of .01 mg/kg haloperidol was potentiated by the 5-HT2C inverse agonist SB 206553 (5 mg/kg) but unaltered by the 5-HT2C antagonists SB 243213 and SB 242084 (1 mg/kg). Conversely, the effect of 1 mg/kg clozapine, a dose able to reverse the decrease in DA outflow induced by the 5-HT2C agonist Ro 60-0175 (3 mg/kg), was unaffected by SB 206553 but blocked by SB 243213 (1 mg/kg) and SB 242084 (.3 and 1 mg/kg). CONCLUSIONS These results show that clozapine and haloperidol differentially alter the constitutive activity of 5-HT2C receptors and suggest that clozapine behaves as a 5-HT2C inverse agonist in vivo.
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Affiliation(s)
- Sylvia Navailles
- Unité Mixte de Recherche-Centre National de la Recherche Scientifique, Bordeaux Cedex, France
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Blackburn TP, Suzuki K, Ashby CR. The acute and chronic administration of the 5-HT2B/2C receptor antagonist SB-200646A significantly alters the activity of spontaneously active midbrain dopamine neurons in the rat: An in vivo extracellular single cell study. Synapse 2006; 59:502-12. [PMID: 16565966 DOI: 10.1002/syn.20263] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
This study examined the effect of the acute and chronic administration of the 5-HT(2B/2C) receptor antagonist N-(1-methyl-5-indolyl)-N'-(3-pyridyl) urea hydrochloride (SB-200646A) on the activity of spontaneously active DA cells in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, male Sprague-Dawley rats. This was accomplished using in vivo extracellular single cell recording. The i.v. administration of 4-16 mg/kg of SB-200646A significantly increased the firing rate and % events as bursts in spontaneously active VTA DA neurons and significantly increased the % events as burst in SNC DA neurons. The acute i.p. administration of 20 and 40 mg/kg of SB-200646A significantly increased the number of spontaneously active VTA DA neurons when compared with vehicle-treated controls. The acute administration of 10 mg/kg of SB-200646A significantly increased the coefficient of variation in spontaneously active SNC and DA neurons when compared with vehicle-treated controls. However, the acute i.p. administration of 20 mg/kg of SB-200646A significantly decreased the degree of bursting of VTA DA neurons. Similary, chronic i.p. administration of 10 mg/kg of SB-200646 did not significantly alter firing, whereas chronic administration of 20 mg/kg of SB-200646A or 20 mg/kg of clozapine significantly decreased the number of spontaneously active VTA DA neurons when compared with vehicle-treated controls. The SB-200646A-induced decrease in the number of spontaneously active VTA DA neurons was reversed by the i.v. administration of (+)-apomorphine or (-)-baclofen. The chronic i.p. administration of either 10 or 20 mg/kg of SB-200646A did not significantly alter the firing pattern of spontaneously active SNC DA neurons. However, the chronic administration of 20 mg/kg of SB-200646A significantly increased the degree of bursting in VTA DA neurons when compared with vehicle. Overall, the acute and chronic administration of SB-200646A produces in vivo electrophysiological effects, resembling that of atypical antipsychotic drugs.
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Affiliation(s)
- Thomas P Blackburn
- GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
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Shilliam CS, Dawson LA. The effect of clozapine on extracellular dopamine levels in the shell subregion of the rat nucleus accumbens is reversed following chronic administration: comparison with a selective 5-HT(2C) receptor antagonist. Neuropsychopharmacology 2005; 30:372-80. [PMID: 15562297 DOI: 10.1038/sj.npp.1300591] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The clinical onset of both the therapeutic and side effects of antipsychotic drugs can take days/weeks to develop. Therefore, it is likely that adaptive changes in neurotransmission of key systems may only manifest upon chronic administration. Thus, using in vivo microdialysis we have evaluated the acute and chronic (21 days) effects of the atypical antipsychotic clozapine on nucleus accumbens (NAcc) dopamine (DA) output in the rat. Clozapine (10 mg/kg p.o.) produced an acute 60% increase in extracellular levels of DA in the shell but not the core subregion of the NAcc. This clozapine-induced effect was also apparent on day 8 (59% increase) of chronic administration. However, on day 22 (following 21 days chronic administration), clozapine-induced a significant decrease in extracellular DA levels (44% decrease). Since clozapine possesses significant affinity for the 5-HT(2C) receptor these clozapine-induced effects were compared to those of SB-243213, a selective 5-HT(2C) receptor antagonist. SB-243213 (10 mg/kg p.o.) had no effect on NAcc DA levels either acutely or following 21 days chronic administration. These data demonstrate that the atypical neuroleptic clozapine is more effective at eliciting changes in the shell vs the core subregion of the NAcc. In contrast, chronic treatment produces a time-dependent reduction in clozapine-induced DA efflux in the shell subregion. This selective temporal change in dopaminergic neurotransmission may be associated with the delayed therapeutic onset of antipsychotic activity. However, since SB-243213 had no effect on DA levels in the NAcc, it is likely that 5-HT(2C) receptor antagonism alone is not the mechanism by which clozapine exerts is actions.
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Affiliation(s)
- Claire S Shilliam
- Department of Neuropharmacology, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.
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Filip M, Bubar MJ, Cunningham KA. Contribution of serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor subtypes to the hyperlocomotor effects of cocaine: acute and chronic pharmacological analyses. J Pharmacol Exp Ther 2004; 310:1246-54. [PMID: 15131246 DOI: 10.1124/jpet.104.068841] [Citation(s) in RCA: 108] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The role of serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor subtypes (5-HT2AR, 5-HT2BR, and 5-HT2CR) in acute cocaine-evoked hyperactivity was compared with their contribution to the development and expression of locomotor sensitization upon repeated, intermittent treatment with cocaine (10 mg/kg/day for 5 days) in male Wistar rats. Cocaine-evoked hyperactivity was significantly enhanced by pretreatment with the preferential 5-HT2AR agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT2CR antagonist SDZ SER-082 [(+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo(1,7-BC)(2,6) naphthyridine fumarate]. The 5-HT2AR antagonist SR 46349B [1(Z)-[2-(dimethylamino)ethoxyimino]-1(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene] and the preferential 5-HT2CR agonist MK 212 [6-chloro-2-(1-piperazinyl)pyrazine HCl] (2 mg/kg) significantly attenuated acute cocaine-evoked hyperactivity; however, a lower dose of MK 212 (0.3 mg/kg) enhanced cocaine-evoked hyperactivity. The 5-HT2BR agonist BW 723C86 (1-[5-(2-thienylmethoxy)-1H-3-indolyl]propan-2-amine HCl) and the 5-HT2BR antagonist SB 204741 [N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl) urea] had no effect on cocaine-evoked hyperactivity. Repeated treatment with cocaine alone resulted in a 2-fold increase in hyperactivity upon challenge with cocaine 5 days after termination of the cocaine regimen (sensitization). The 5-HT2AR antagonist SR 46349B also blocked cocaine-evoked hyperactivity following repeated cocaine treatment, whereas the other 5-HT2R ligands were ineffective. When any of the 5-HT2R ligands was coadministered with cocaine during the treatment regimen (10 mg/kg/day for 5 days), the development of sensitization was unchanged as measured by the level of cocaine-evoked hyperactivity upon challenge 5 days after termination of the treatment. The present study implies that 5-HT2AR and 5-HT2CR exert oppositional influence upon hyperactivity evoked by acute administration of cocaine; this balance is altered following repeated cocaine administration.
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Affiliation(s)
- Malgorzata Filip
- Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
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Olijslagers JE, Werkman TR, McCreary AC, Siarey R, Kruse CG, Wadman WJ. 5-HT2 receptors differentially modulate dopamine-mediated auto-inhibition in A9 and A10 midbrain areas of the rat. Neuropharmacology 2004; 46:504-10. [PMID: 14975674 DOI: 10.1016/j.neuropharm.2003.10.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2003] [Revised: 09/23/2003] [Accepted: 10/02/2003] [Indexed: 11/22/2022]
Abstract
5-HT (20 microM) enhanced dopamine (DA) D2-like receptor mediated reduction of the firing rate of DA neurons in the substantia nigra pars compacta (A9) and ventral tegmental area (A10) in a rat midbrain slice preparation. Quinpirole (30 nM) induced a mean reduction of the firing rate in A9 and A10 DA neurons to 64 +/- 4%, respectively, 71 +/- 5% of the baseline value. Bath application of 5-HT in the presence of quinpirole further reduced the firing rate to 37 +/- 7% in A9 and 33 +/- 13% in A10. The 5-HT2 receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI, 500 nM) enhanced quinpirole-induced reduction of firing rate of A10 DA neurons, but not of A9 DA neurons, suggesting that different 5-HT receptor subtypes are involved in modulation of dopamine D2-like receptor mediated inhibition in the two regions. The selective 5-HT2A receptor antagonist MDL100907 and the selective 5-HT2C receptor antagonist SB242084 (50 and 500 nM) both abolished the enhancement of quinpirole-induced reduction by either 5-HT or DOI, suggesting the involvement of direct and indirect (possibly via interneurons) modulation pathways in A10. The involvement of 5-HT and specific 5-HT2 receptors in augmentation of auto-inhibition in A10 could have important implications for our understanding of the mechanism of atypical antipsychotic drug action.
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Affiliation(s)
- J E Olijslagers
- Institute for Neurobiology, Swammerdam Institute for Life Sciences, University of Amsterdam, Kruislaan 320, 1098 SM Amsterdam, The Netherlands.
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Daniela E, Brennan K, Gittings D, Hely L, Schenk S. Effect of SCH 23390 on (±)-3,4-methylenedioxymethamphetamine hyperactivity and self-administration in rats. Pharmacol Biochem Behav 2004; 77:745-50. [PMID: 15099919 DOI: 10.1016/j.pbb.2004.01.008] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2003] [Revised: 12/22/2003] [Accepted: 01/23/2004] [Indexed: 10/26/2022]
Abstract
Recently, we demonstrated that (+/-)-3,4-methylenedioxymethamphetamine (MDMA; ecstasy) was reliably and dose-dependently self-administered by previously drug-naïve laboratory rats. The neurochemical basis of MDMA self-administration has not, however, been extensively studied. The present study investigated the role of dopamine in MDMA self-administration and hyperactivity. Pretreatment with the D1-like antagonist, SCH 23390 (0.01-0.08 mg/kg) produced a dose-dependent attenuation of MDMA (20.0 mg/kg)-produced hyperactivity. In self-administration tests, the baseline rate of responding maintained by intravenous infusions varied inversely with MDMA dose; as the dose available was changed, responding also changed so that about 10.0 mg/kg MDMA was self-administered during each daily 2-h session. Pretreatment with SCH 23390 (0.02 mg/kg) produced a rightward shift in the MDMA dose-response curve. These findings suggest that MDMA self-administration, like self-administration of other drugs of abuse, is dependent on the activation of dopaminergic substrates.
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Affiliation(s)
- Evangelene Daniela
- School of Psychology, Victoria University of Wellington, PO Box 600, Wellington, New Zealand
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Navailles S, De Deurwaerdère P, Porras G, Spampinato U. In vivo evidence that 5-HT2C receptor antagonist but not agonist modulates cocaine-induced dopamine outflow in the rat nucleus accumbens and striatum. Neuropsychopharmacology 2004; 29:319-26. [PMID: 14560323 DOI: 10.1038/sj.npp.1300329] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
During recent years, much attention has been devoted at investigating the modulatory role of central 5-HT(2C) receptors on dopamine (DA) neuron activity, and it has been proposed that these receptors modulate selectively DA exocytosis associated with increased firing of DA neurons. In the present study, using in vivo microdialysis in the nucleus accumbens (NAc) and the striatum of halothane-anesthetized rats, we addressed this hypothesis by assessing the ability of 5-HT(2C) agents to modulate the increase in DA outflow induced by haloperidol and cocaine, of which the effects on DA outflow are associated or not with an increase in DA neuron firing, respectively. The intraperitoneal administration of cocaine (10-30 mg/kg) induced a dose-dependent increase in DA extracellular levels in the NAc and the striatum. The effect of 15 mg/kg cocaine was potentiated by the mixed 5-HT(2C/2B) antagonist SB 206553 (5 mg/kg i.p.) and the selective 5-HT(2C) antagonist SB 242084 (1 mg/kg i.p.) in both brain regions. The mixed 5-HT(2C/2B) agonist, Ro 60-0175 (1 mg/kg i.p.), failed to affect cocaine-induced DA outflow, but reduced significantly the increase in DA outflow induced by the subcutaneous administration of 0.1 mg/kg haloperidol. The obtained results provide evidence that 5-HT(2C) receptors exert similar effects in both the NAc and the striatum, and they modulate DA exocytosis also when its increase occurs independently from an increase in DA neuron impulse activity. Furthermore, they show that 5-HT(2C) agonists, at variance with 5-HT(2C) antagonists, exert a preferential control on the impulse-stimulated release of DA.
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Affiliation(s)
- Sylvia Navailles
- UMR CNRS, 5541-Université Victor Segalen Bordeaux 2, Bordeaux Cedex, France
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Minabe Y, Hashimoto K, Shirayama Y, Ashby CR. Effect of the acute and chronic administration of the putative atypical antipsychotic drug Y-931 (8-fluoro-12- (4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3b][1,5] benzodiazepine maleate) on spontaneously active rat midbrain dopamine neurons: an in vivo electrophysiological study. Synapse 2004; 51:19-26. [PMID: 14579422 DOI: 10.1002/syn.10280] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
This study examined the effect of the p.o. administration of the putative atypical antipsychotic drug Y-931 (8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3b][1,5] benzodiazepine maleate) on the activity of spontaneously active dopamine (DA) neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) in anesthetized male Sprague-Dawley rats. This was accomplished using in vivo electrophysiology. The acute p.o. administration of Y-931 did not significantly alter the number of spontaneously active SNC DA neurons compared to vehicle-treated animals. A single p.o. administration of 3 and 10 mg/kg of Y-931 significantly increased and decreased, respectively, the number of spontaneously active VTA DA neurons compared to vehicle-treated animals. The acute administration of 3 mg/kg of Y-931 significantly altered the firing pattern parameters for all spontaneously active SNC DA. The 3 and 10 mg/kg doses of Y-931 significantly increased the degree of bursting and irregular activity of spontaneously active VTA and SNC DA neurons firing in a bursting pattern. The repeated p.o. administration (21 days) of 1, 3, or 10 mg/kg of Y-931 significantly decreased the number of spontaneously active VTA DA neurons but had no significant effect on SNC DA neurons compared to vehicle-treated animals. The repeated administration of Y-931 did not significantly alter the firing pattern of all spontaneously active SNC or VTA DA neurons. Our findings indicate that the acute and chronic administration of Y-931 significantly alters the activity of midbrain DA neurons in rats and the electrophysiological profile of chronic Y-931 resembles that of atypical antipsychotic agents.
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Affiliation(s)
- Yoshio Minabe
- Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, 431-3192 Japan
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