Effects of the 5-HT2C/2B Antagonist SB 206553 on Hyperactivity Induced by Cocaine

McCreary, Andrew C.; Cunningham, Kathryn A.

doi:10.1016/s0893-133x(98)00087-6

Cited by 77 publications

(49 citation statements)

References 31 publications

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“…Both pharmacological blockade of the 5-HT 2C receptor (McCreary and Cunningham, 1999;Fletcher et al, 2002), as well as elimination of the expression of this receptor through 5-HT 2C receptor gene deletion (Rocha et al, 2002), can enhance the stimulant and reinforcing effects of cocaine. This suggests that the expression of the behavioral effects of cocaine may depend to some extent upon the endogenous tone of 5-HT acting upon this receptor.…”

Section: Discussionmentioning

confidence: 99%

Injection of the 5-HT2C Receptor Agonist Ro60-0175 into the Ventral Tegmental Area Reduces Cocaine-Induced Locomotor Activity and Cocaine Self-Administration

Fletcher

Chintoh

Sinyard

et al. 2003

Neuropsychopharmacol

122

100

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Previously, we have shown that systemic administration of the 5-HT 2C receptor agonist Ro60-0175 reduces cocaine-induced locomotor activity and cocaine self-administration. Ro60-0175 also alters the activity of midbrain dopamine (DA) neurons of the ventral tegmental area (VTA), a region where 5-HT 2C receptors are expressed. The present experiments investigated whether microinjections of Ro60-0175 into the VTA would alter the locomotor stimulant effect of cocaine and cocaine self-administration. In the tests for locomotor activity injection of 3 and 10, but not 1 mg, Ro60-0175 into the VTA reduced the locomotor stimulation resulting from injection of 10 mg/ kg cocaine. In tests of cocaine self-administration, rats were trained to lever press for intravenous infusions of 0.25 mg cocaine delivered on either a fixed ratio 5 (FR5) or a progressive ratio schedule. Intra-VTA injection of Ro60-0175 at doses of 3 and 10 mg reduced responding for cocaine on both schedules without significantly altering the latency to initiate responding or the rate of responding. A subsequent experiment determined that the suppressant effect of intra-VTA Ro60-0175 (3 mg) on responding for cocaine was prevented by pretreatment with the selective 5-HT 2C receptor antagonist SB242,084 (0.5 mg/kg). In a final experiment, intra-VTA injection of Ro60-0175 reduced responding for food reinforcement on the same progressive ratio schedule as used for cocaine selfadministration. These results demonstrate that stimulation of 5-HT 2C receptors in the VTA is sufficient to attenuate the stimulant and reinforcing effects of cocaine. These effects complement electrophysiological and neurochemical findings, and indicate that 5-HT 2C receptors localized within the VTA modulate the activity of mesolimbic DA neurons.

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Section: Discussionmentioning

confidence: 99%

Injection of the 5-HT2C Receptor Agonist Ro60-0175 into the Ventral Tegmental Area Reduces Cocaine-Induced Locomotor Activity and Cocaine Self-Administration

Fletcher

Chintoh

Sinyard

et al. 2003

Neuropsychopharmacol

122

100

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“…Blockade of 5-HT 2A or 5-HT 2C receptors had opposite effects on cocaine-induced locomotor activity. Thus, 5-HT 2A receptor blockade with M100,907 attenuated cocaine-induced locomotion, whereas 5-HT 2C blockade with SB 242084 or SB 206553 enhanced cocaine-induced activity [216,[218][219][220]. It has been found that RO 60-0175 reduces cocaine-reinforced behaviour by stimulating 5-HT 2C receptors [221].…”

Section: -Ht 2c Receptors and Drug Of Abusementioning

confidence: 99%

Central Serotonin2C Receptor: From Physiology to Pathology

Giovanni¹,

Matteo²,

Pierucci³

et al. 2006

CTMC

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Since the 1950s, when serotonin (5-HT) was discovered in the mammalian central nervous system (CNS), an enormous amount of experimental evidence has revealed the pivotal role of this biogenic amine in a number of cognitive and behavioural functions. Although 5-HT is synthesized by a small group of neurons within the raphe nuclei of the brain stem, almost all parts of the CNS receive serotonergic projections. Furthermore, the importance of 5-HT modulation and the fine-tuning of its action is underlined by the large number of 5-HT binding sites found in the CNS. Hitherto, up to 15 different 5-HT receptors subtypes have been identified. This review was undertaken to summarize the work that has explored the pathophysiological role of one of these receptors, the 5-HT 2C receptor, that has been emerged as a prominent central serotonin receptor subtype. The physiology, pharmacology and anatomical distribution of the 5-HT 2C receptors in the CNS will be firstly reviewed. Finally, their potential involvement in the pathophysiology of depression, schizophrenia, Parkinson's disease and drug abuse will be also discussed.Keywords: Serotonergic receptors, Depression, Schizophrenia, Drug of abuse, selective 5-HT 2C drugs. BASIC ANATOMY OF 5-HT SYSTEMMore than fifty years have passed since Twarog and Page [1] isolated an indole, identified as serotonin (5-HT), in the mammalian brain. Subsequently, Brodie and colleagues [2] suggested that 5-HT might serve as a neurotransmitter in the central nervous system (CNS). The result was one of the most important discoveries in science, giving birth to a new branch of neuroscience [3]. Serotonin is one of the oldest biologically active compound on earth, found in a variety of plants and animals. In vertebrates, the majority of the neurons containing 5-HT are grouped in 9 nuclei named B1 to B9, located in the medial part of the brainstem, generically called the raphe nuclei [4] (Fig. 1). These midline clusters can be divided into two major groups. The caudal or inferior group, localized in the medulla, contains the three nuclei projecting essentially to the grey matter of the spinal cord: the nucleus raphe magnus (NRM, cell group B5), nucleus raphe obscurus (NRO, cell groups B1-B2-B3), and nucleus raphe pallidus (NRP, cell group B4). The rostral or superior group, situated in the pons/mesenchephalon, contains the dorsal raphe nucleus (DRN, cell groups B6 and B7) and the median raphe nucleus (MRN, cell group B8). These nuclei supply about 80% of the serotonergic innervation of the forebrain. Even if in many brain areas, the innervation coming from the two nuclei overlaps, in certain regions the innervation comes exclusively or prevalently from one nucleus only. For example, the dorsal hippocampus receives a serotonergic innervation only from MRN, other areas innervated preferentially from this nucleus are: the medial preoptic area, the suprachiasmatic nucleus, the olfactory bulb *Address correspondence to this author at the Istituto di Ricerche Farmacologiche "Mario Negri", Consor...

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“…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%

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

100

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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Effects of the 5-HT2C/2B Antagonist SB 206553 on Hyperactivity Induced by Cocaine

Cited by 77 publications

References 31 publications

Injection of the 5-HT2C Receptor Agonist Ro60-0175 into the Ventral Tegmental Area Reduces Cocaine-Induced Locomotor Activity and Cocaine Self-Administration

Injection of the 5-HT2C Receptor Agonist Ro60-0175 into the Ventral Tegmental Area Reduces Cocaine-Induced Locomotor Activity and Cocaine Self-Administration

Central Serotonin2C Receptor: From Physiology to Pathology

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

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