Immunohistochemical localisation of the 5-HT2C receptor protein in the rat CNS

Clemett, Delyth A; Punhani, Taniya; Duxon, Mark S.; Blackburn, Thomas P.; Fone, Kevin C. F.

doi:10.1016/s0028-3908(99)00086-6

Cited by 339 publications

(261 citation statements)

References 29 publications

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“…Specifically, although the role of NAc 5-HT 2C R remains to be unravelled because of the existence of opposite concentration-dependent effects, our findings do not support the previous proposal that the 5-HT 2C R resident in the VTA may primarily account for the central inhibitory control this receptor protein exerts over accumbal DA release . Conversely, our findings provide support to the idea that central 5-HT 2C R inhibitory control of mesoaccumbens DA pathway may be considered as a composite response Cunningham, 2002, 2003) involving different 5-HT 2C R populations located within multiple brain areas (Clemett et al, 2000;Pompeiano et al, 1994) which are known to provide important efferent control of this DA pathway, such as the prefrontal cortex (Carr et al, 1999;Carr and Sesack, 2000), the hippocampus (Sesack and Pickel, 1990), and the amygdala (McDonald, 1991). This conclusion is further supported by the fact that, in contrast to their systemic effects Gobert et al, 2000;Navailles et al, 2006a), intra-VTA or intra-NAc administration of 5-HT 2C R ligands has no influence on basal DA release in the NAc (Navailles et al, 2006b;present results).…”

Section: Discussionsupporting

confidence: 79%

“…Indeed, 5-HT 2C Rs are expressed at higher levels in the NAc shell compared to the core (Clemett et al, 2000) and they have been specifically targeted by using the most selective and injectable 5-HT 2C R compounds presently available (Kennett et al, 1997;Martin et al, 1998;Porter et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…During recent years, numerous studies have focused on the role of the serotonergic2C receptor (5-HT 2C R) in the modulation of this DA pathway and its potential to control cocaine dependence (Bubar and Cunningham, 2006;Di Matteo et al, 2002;Higgins and Fletcher, 2003). Indeed, 5-HT 2C Rs are densely localized in brain regions containing DA cell bodies (VTA) and terminals (NAc) (Bubar and Cunningham, 2006;Clemett et al, 2000;Pazos et al, 1985;Pompeiano et al, 1994), and are known to modulate DA-dependent behavioral and neurochemical effects induced by cocaine (Fletcher et al, 2002(Fletcher et al, , 2006Grottick et al, 2000;McCreary and Cunningham, 1999;Navailles et al, 2004). Specifically, the systemic administration of the 5-HT 2C R agonist Ro 60-0175, and the 5-HT 2C R antagonist SB 242084 has been shown to respectively inhibit and potentiate cocaineinduced behaviors including its hypermotive and rewarding effects (Fletcher et al, 2002(Fletcher et al, , 2006Grottick et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Differential Regulation of the Mesoaccumbens Dopamine Circuit by Serotonin2C Receptors in the Ventral Tegmental Area and the Nucleus Accumbens: An In Vivo Microdialysis Study with Cocaine

Navailles

Moison

Cunningham

et al. 2007

Neuropsychopharmacol

102

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Stimulation of central serotonin2C receptor (5-HT 2C R) inhibits dopamine (DA)-dependent neurochemical and behavioral effects of cocaine, while 5-HT 2C Rs locally expressed into the ventral tegmental area (VTA) and the nucleus accumbens (NAc) exert opposite functional control over cocaine-induced behavioral effects. Using in vivo microdialysis in halothane-anesthetized rats, we tested the hypothesis that this functionally opposite regulation of the mesoaccumbens DA pathway relies on the ability of 5-HT 2C Rs in the VTA and the NAc to inhibit and enhance respectively cocaine-induced accumbal DA outflow. Intra-VTA injection of the 5-HT 2C R agonist Ro 60-0175 at 5 mg/0.2 ml, but not 1 mg/0.2 ml, attenuated the increase in accumbal DA outflow induced by the systemic administration of 10 mg/ kg of cocaine. Intra-VTA injection of the 5-HT 2C R antagonist SB 242084 at either dose (0.1 or 0.5 mg/0.2 ml) did not modify the effects of cocaine. Intra-NAc application of Ro 60-0175 dose-dependently excited (0.1 mM) and inhibited (1 mM) cocaine-induced DA outflow. In contrast, intra-NAc application of SB 242084 resulted in diametrically opposite effects when applied at these concentrations. These results further support the idea that the overall action of central 5-HT 2C Rs on accumbal DA output is dependent, at least in part, on the functional balance between different 5-HT 2C R populations within the NAc and within the mesoaccumbens DA pathway (VTA vs NAc).

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential Regulation of the Mesoaccumbens Dopamine Circuit by Serotonin2C Receptors in the Ventral Tegmental Area and the Nucleus Accumbens: An In Vivo Microdialysis Study with Cocaine

Navailles

Moison

Cunningham

et al. 2007

Neuropsychopharmacol

102

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“…The fact that this structure appears to have high density of 5-HT 2C receptors (Clemett et al, 2000) suggests that the BNST is an alternative site where 5-HT 2C receptor activation could alter the functioning of circuitry involved in mediating stressinduced reinstatement of drug-seeking behavior.…”

Section: Discussionmentioning

confidence: 99%

The 5-HT2C Receptor Agonist Ro60-0175 Reduces Cocaine Self-Administration and Reinstatement Induced by the Stressor Yohimbine, and Contextual Cues

Fletcher

Rizos

Sinyard

et al. 2007

Neuropsychopharmacol

112

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Previously, we showed that the 5-HT 2C receptor agonist Ro60-0175 reduces cocaine self-administration, and the ability of cocaine to reinstate responding after extinction of drug-seeking behavior. The present experiments extended these findings further by determining whether the effects of Ro60-0175 on self-administration were sustained with repeated treatment, and whether Ro60-0175 altered reinstatement induced by the pharmacological stressor yohimbine, or by the context in which self-administration occurred. In Experiment 1, Ro60-0175 (1 mg/kg, s.c.) reduced cocaine (0.25 mg/infusion) self-administration maintained by a progressive ratio schedule. This reduction was sustained over eight daily injections. In Experiment 2, rats self-administered cocaine in daily 2 h sessions for 15 days on a FR1 schedule. Following extinction, yohimbine (1 mg/kg, i.p.) reinstated responding, and this effect was reduced dose dependently by Ro60-0175 (0.3-3 mg/kg, s.c.). In Experiment 3, rats were trained to respond for cocaine on a FR1 schedule in a distinct environmental context (A); responding was then extinguished in a different context (B). Reinstatement tests occurred in either context A or B.Responding was reinstated only when rats were tested in the original self-administration context (A). This reinstatement was reduced dose dependently by Ro60-0175. All effects of Ro60-0175 were blocked by the 5-HT 2C receptor antagonist SB242084. Thus, Ro60-0175, acting via 5-HT 2C receptors, reduces cocaine self-administration and cocaine-seeking triggered by a stressor and by drug-associated cues. The effects of Ro60-0175 do not exhibit tolerance within the 8-day test period. These results indicate that selective 5-HT 2C receptor agonists may be a useful pharmacological strategy for treatment of drug abuse.

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“…Fewer studies have examined the localization of 5-HT2C receptor protein. Several immnunochemistry studies indicate the presence of 5-HT2C receptors in the striatum (Abramowski et al, 1995;Sharma et al, 1997;Clemett et al, 2000) with the most recent study also showing 5-HT2C receptors in the NA and cingulate cortex as well as the SNpr and SNpc (Clemett et al, 2000).…”

Section: -Ht2c Localizationmentioning

confidence: 98%

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Alex

Pehek

2007

Pharmacology & Therapeutics

525

311

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The neurotransmitter dopamine (DA) has a long association with normal functions such as motor control, cognition, and reward, as well as a number of syndromes including drug abuse, schizophrenia, and Parkinson's disease. Studies show that serotonin (5-HT) acts through several 5-HT receptors in the brain to modulate DA neurons in all three major dopaminergic pathways. There are at least 14 5-HT receptor subtypes, many of which have been shown to play some role in mediating 5-HT/DA interactions. Several subtypes, including the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4 receptors, act to facilitate DA release, while the 5-HT2C receptor mediates an inhibitory effect of 5-HT on DA release. Most 5-HT receptor subtypes only modulate DA release when 5-HT and/or DA neurons are stimulated, but the 5-HT2C receptor, characterized by high levels of constitutive activity, inhibits tonic as well as evoked DA release. This review summarizes the anatomical evidence for the presence of each 5-HT receptor subtype in dopaminergic regions of the brain and the neuropharmacological evidence demonstrating regulation of each DA pathway. The relevance of 5-HT receptor modulation of DA systems to the development of therapeutics used to treat schizophrenia, depression, and drug abuse is discussed. Lastly, areas are highlighted in which future research would be maximally beneficial to the treatment of these disorders.

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Immunohistochemical localisation of the 5-HT2C receptor protein in the rat CNS

Cited by 339 publications

References 29 publications

Differential Regulation of the Mesoaccumbens Dopamine Circuit by Serotonin2C Receptors in the Ventral Tegmental Area and the Nucleus Accumbens: An In Vivo Microdialysis Study with Cocaine

Differential Regulation of the Mesoaccumbens Dopamine Circuit by Serotonin2C Receptors in the Ventral Tegmental Area and the Nucleus Accumbens: An In Vivo Microdialysis Study with Cocaine

The 5-HT2C Receptor Agonist Ro60-0175 Reduces Cocaine Self-Administration and Reinstatement Induced by the Stressor Yohimbine, and Contextual Cues

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

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