M‐chlorophenylpiperazine (mCPP) attenuates the behavioral‐stimulant effects of cocaine via activation of the 5‐HT2C receptor in nonhuman primates

Abstract

Serotonin (5‐HT) indirect agonists have been shown to modulate the behavioral and neurochemical effects of cocaine in rodents and nonhuman primates, yet the specific receptors mediating these effects have not been fully elucidated. Recent evidence suggests that these actions may be partially mediated by the 5‐HT2C receptor in rodents, but this has not been systematically tested in nonhuman primates. In the present study, squirrel monkeys (n=3) were trained to lever‐press according to a fixed‐interval 300‐sec schedule of stimulus termination. Administration of cocaine (0.3 – 3.0 mg/kg) resulted in a typical inverted U‐shape dose‐response function with response rate as the dependent measure. Pretreatment with the preferential 5‐HT2C agonist mCPP (0.1 – 0.3 mg/kg) dose‐dependently and insurmountably attenuated the behavioral‐stimulant effects of cocaine, inducing a downward‐shift of the cocaine dose‐response curve. Moreover, the effects of mCPP were dose‐dependently reversed following pretreatment with the selective 5‐HT2C antagonist SB 242084 (0.01 – 0.3 mg/kg). These data are the first to demonstrate a modulatory effect of 5‐HT2C receptor activation on the behavioral effects of cocaine in nonhuman primates and warrant further investigation into the capacity of more selective compounds to alter cocaine's neurochemical and reinforcing effects. Support: F31DA026262, DA12514, DA00517 and RR00165.