Differential regulation of the mesoaccumbens circuit by serotonin 5-hydroxytryptamine (5-HT)(2A) and 5-HT2C receptors

Serotonin [5-hydroxytryptamine (5-HT)] 5-HT2A and 5-HT2C receptors (5-HT(2A )Rs and 5-HT(2C)Rs), which innervate the dopamine mesoaccumbens pathway, ma y play an important role in the behavioral effects of cocaine. To test this hypothesis, the present study measured cocaine-evoked locomotor activity a fter bilateral microinjection of selective 5-HT2AR and 5-HT2CR antagonists into the ventral tegmental area (VTA) or the nucleus accumbens (NAc) shell. Locomotor activity was measured after intracranial microinjection of salin e (0.2 mul/side), the selective 5-HT2AR antagonist R-(+)-alpha-(2,3-dimetho xyphenyl)-1-[2-(4-flucrophenylethyl)]-4-piperidine methanol (M100907) (0.1 or 0.3 mug.0.2 mul(-1).side(-1)), or the selective 5-HT2CR antagonist 8-[5- (2,4-dimethoxy-5-(4-trifluoromethylphenylsulfon-amido)phenyl-5-oxopentyl)]- 1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (RS 102221) (0.05-0.5 mug.0.2 mul(-1).side(-1)) followed by an injection of saline (1 ml/kg, i.p .) or cocaine (10 mg/kg, i.p.).Microinjection Of M100907 (0.1-0.3 mug/side) into the VTA or RS 102221 (0.15-0.5 mug/side) into the NAc shell attenuate d cocaine-induced hyperactivity in a dose-related manner. However, hyperact ivity evoked by cocaine was not altered by microinjection of RS 102221 into the VTA or M100907 into the NAc shell. No changes in basal activity were o bserved after microinjection of M100907 or RS 102221 into either brain regi on. These findings are the first to demonstrate that the behavioral effects of cocaine are generated in part by activation of 5-HT(2A)Rs in the VTA an d by activation of 5-HT(2C)Rs in the NAc shell. The selective regulation of the mesoaccumbens circuit by 5-HT(2A)Rs and 5-HT(2C)Rs implicates these 5- HT receptors as important in the behavioral outcomes of systemic cocaine ad ministration.