The 5-HT3 antagonist Y-25130 blocks cocaine-induced lowering of ICSS reward thresholds in the rat.

Serotonin-3 (5-HT(3)) receptor antagonists have been shown to attenuate drug-induced increases in mesolimbic dopamine (DA), locomotor activation, and drug self-administration. In the present study, we tested whether the selective 5-HT(3) antagonist Y-25130 would attenuate cocaine-induced lowering of intracranial self-stimulation (ICSS) reward thresholds. Rats (n=6) were surgically prepared with bipolar stimulation electrodes and trained to self-administer electrical stimulation delivered to the medial forebrain bundle-lateral hypothalamus (MFB-LH). A discrete-trial, rate-free threshold determination procedure was used to detect pharmacologically induced changes from baseline reward thresholds. Four doses of Y-25130 (0.0, 0.03, 0.3, and 3.0 mg/kg ip) were given alone and in combination with cocaine (4.0 mg/kg ip). Y-25130 did not significantly alter reward thresholds or response latencies when given alone as compared to baseline measures. While there were no significant effects at lower doses, the middle and highest doses of Y-25130 (0.3 and 3.0 mg/kg) did attenuate the threshold-lowering effect of cocaine. These findings suggest that the rewarding effects of cocaine are mediated through 5-HT(3) receptor activity.