Differential regulation of the mesoaccumbens circuit by serotonin 5-hydroxytryptamine (5-HT)_2A and 5-HT_2C receptors

Serotonin [5-hydroxytryptamine (5-HT)] 5-HT_2A and 5-HT_2C receptors (5-HT_2ARs and 5-HT_2CRs), which innervate the dopamine mesoaccumbens pathway, may play an important role in the behavioral effects of cocaine. To test this hypothesis, the present study measured cocaine-evoked locomotor activity after bilateral microinjection of selective 5-HT_2AR and 5-HT_2CR antagonists into the ventral tegmental area (VTA) or the nucleus accumbens (NAc) shell. Locomotor activity was measured after intracranial microinjection of saline (0.2 μl/ side), the selective 5-HT_2AR antagonist R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine methanol (M100907) (0.1 or 0.3/μg · 0.2 μl^-1 · side^-1), or the selective 5-HT_2CR 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 μg · 0.2 μl^-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 μg/side) into the VTA or RS 102221 (0.15-0.5 μg/side) into the NAc shell attenuated cocaine-induced hyperactivity in a dose-related manner. However, hyperactivity 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 observed after microinjection of M100907 or RS 102221 into either brain region. These findings are the first to demonstrate that the behavioral effects of cocaine are generated in part by activation of 5-HT_2ARs in the VTA and by activation of 5-HT_2CRs in the NAc shell. The selective regulation of the mesoaccumbens circuit by 5-HT_2ARs and 5-HT_2CRs implicates these 5-HT receptors as important in the behavioral outcomes of systemic cocaine administration.