RU 24969, a 5-HT1A/1B agonist, elevates brain stimulation reward thresholds: an effect reversed by GR 127935, a 5-HT1B/1D antagonist.

Recent studies suggest that serotonergic neurotransmission through the serotonin-1B (5-HT1B) receptor is involved in reward processes. The purpose of the present studies was to investigate the effects of 5-HT(1B) receptor activation and antagonism on intracranial self-stimulation (ICSS) reward using a current-threshold ICSS task. Male Wistar rats were prepared with bipolar electrodes in the lateral hypothalamus. When stable baseline thresholds were established, the effects of the mixed 5-HT(1A)/1B receptor agonist, RU 24969 (0-1 mg/kg, SC), on ICSS behavior were assessed. Administration of this compound elevated ICSS thresholds without affecting response latencies, a measure of general motoric activity. The 5-HT(1B/1D) receptor antagonist, GR 127935 (0-10 mg/kg, SC), had no significant effect on ICSS behavior. However, pretreatment with an intermediate dose of GR 127935 (3 mg/kg), which was previously without effect on ICSS behavior, reversed the threshold-elevating effects of RU 24969 (1 mg/kg), suggesting the involvement of the 5-HT1B receptor in this effect of RU 24969 administration. Furthermore, pretreatment with RU 24969 (0.3 and 0.6 mg/kg), prior to 10 mg/kg cocaine hydrochloride, dose-dependently attenuated the threshold-reducing effects of cocaine. This result is interpreted as two opposing drug effects canceling each other out rather than a specific pharmacological antagonism. In conclusion, the results suggest that activation of 5-HT(1B) receptors reduces brain stimulation reward.