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- Title
The effects of the 5-HT<sub>2C</sub> receptor antagonist SB242084 on locomotor activity induced by selective, or mixed, indirect serotonergic and dopaminergic agonists.
- Authors
Fletcher, Paul J.; Sinyard, Judy; Higgins, Guy A.
- Abstract
Rationale The 5-HT2C receptor modulates mesolimbic dopamine (DA) function and the expression of DA-dependent behaviors, including stimulant-induced hyperactivity. The 5-HT2C receptor may also be involved in drug-induced locomotion that is 5-HT-dependent. Objectives This study investigated the effects of the 5HT2C receptor antagonist 6-chloro-5-methyl-1-[[2-[(2methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline (SB242084) on hyperlocomotion induced by psychomotor stimulants with selective, or mixed, actions on serotonergic and/or dopaminergic systems. Materials and methods Male Sprague--Dawley rats were treated in the presence or absence of SB242084 with releasers/reuptake inhibitors of DA (amphetamine and methylphenidate), 5-HT (fenfluramine and citalopram), or both 5-HT and DA (MDMA and cocaine). In addition, the effects of SB242084 combined with nicotine, morphine, or the 5-HT1A/1B receptor agonist RU24969 were examined. Locomotor activity was recorded for 2 h. Results SB242084 potentiated hyperactivity induced by MDMA (2.5-5 mg/kg), amphetamine (0.5 mg/kg), fenfluramine (5 mg/kg), cocaine (10 mg/kg), and methylphenidate (5 mg/kg). SB242084 modestly potentiated nicotine-induced (0.2-0.4 mg/kg) and morphine-induced (2.5 mg/kg) hyperactivity. SB242084 failed to influence hyperactivity induced by RU24969 (0.5-1 mg/kg) or citalopram (10-20mg/kg). Conclusion SB242084 potentiated the locomotor stimulant effects of both indirect DA and 5-HT agonists. This potentiation may reflect two distinct mechanisms. The first involves direct enhancement of DA activity as shown by potentiation of the effects of amphetamine and methylphenidate. The second mechanism reflects an unmasking of stimulatory 5-HT receptors activated by 5-HT releasers (possibly 5-HT1B/2A) through blockade of inhibitory 5-HT2C receptors. The failure of SB242084 to potentiate the effect of citalopram might reflect differences between changes in synaptic levels of 5-HT produced by release compared to reuptake inhibition.
- Subjects
DOPAMINE; METHYLPHENIDATE; NICOTINE; MORPHINE; AMPHETAMINES
- Publication
Psychopharmacology, 2006, Vol 187, Issue 4, p515
- ISSN
0033-3158
- Publication type
Article
- DOI
10.1007/s00213-006-0453-9