Inhibition of 5-HT2 receptor-mediated head-twitch response by cocaine via indirect stimulation of adrenergic alpha 2 and serotonergic 5-HT1A receptors.

Cocaine inhibits the 5-HT2-mediated (+/-)-DOI-induced head-twitch response (HTR) in mice in a dose-dependent manner. In order to investigate the possible inhibitory mechanism(s) of cocaine on 5-HT2 receptor function, we studied the effects of the selective adrenergic alpha 2 receptor antagonist yohimbine and the beta-adrenergic/5-HT1 receptor antagonist alprenolol, and the 5-HT3 antagonist ICS 205-930 on the inhibitory action of cocaine on the (+/-)-DOI-induced HTR. Neither yohimbine (0.1 and 0.5 mg/kg) nor alprenolol (10 mg/kg) pretreatment had any significant effect on the (+/-)-DOI-induced HTR. However, both antagonists prevented the inhibitory effects of cocaine on the (+/-)-DOI-induced HTR. The 5-HT3 antagonist ICS 205-930 neither produced HTR nor decreased the (+/-)-DOI-induced HTR frequency. The present results suggest that cocaine inhibits 5-HT2 receptor function by increasing the synaptic concentration of norepinephrine and serotonin via inhibition of their uptake and thus indirectly stimulating the respective inhibitory adrenergic alpha 2 and serotonergic 5-HT1A receptors. Furthermore, cocaine's 5-HT3 antagonist properties appear not to play a role in the inhibition of head-twitch behavior.