Vol. 297, Issue 1, 316-325, April 2001

Serotonergic Manipulations Both Potentiate and Reduce Brain Stimulation Reward in Rats: Involvement of Serotonin-1A Receptors

Amanda A. Harrison¹ and Athina Markou

Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California

A discrete-trial current-threshold self-stimulation procedure was used to assess the effects of increased and decreased serotonergic neurotransmission, and 5-HT_1A receptor activation on brain stimulation reward. Systemic administration of the 5-HT_1A receptor agonist 8-OH-DPAT had a biphasic effect on brain reward thresholds, without affecting the latency to respond, a measure of performance. The low dose of 8-OH-DPAT (0.03 mg/kg) lowered reward thresholds, whereas higher doses (0.1 and 0.3 mg/kg) elevated thresholds. The 5-HT_1A receptor antagonist p-MPPI had no effect on brain stimulation behavior, but reversed both the 8-OH-DPAT-induced lowering and elevation of thresholds, indicating that both of these effects of 8-OH-DPAT are mediated through the 5-HT_1A receptor. Injections of 8-OH-DPAT into the median raphé nucleus also lowered brain reward thresholds, without affecting measures of performance, whereas injections of 8-OH-DPAT into the dorsal raphé nucleus had no effect. A high dose of the selective serotonin reuptake inhibitor fluoxetine (10 mg/kg) elevated reward thresholds and responses latencies, whereas lower doses (2.5 and 5.0 mg/kg) increased response latencies without affecting thresholds. Furthermore, the coadministration of a 5-HT_1A antagonist, p-MPPI, and a previously ineffective dose of fluoxetine, a drug combination that increases serotonin levels, significantly elevated thresholds. Thus, it is suggested here that the reward-potentiating effects of systemically administered low doses of 8-OH-DPAT may be the result of reduced serotonergic neurotransmission, mediated by activation of 5-HT_1A somatodendritic autoreceptors in the median, but not the dorsal, raphé nucleus. In conclusion, the present data support the hypothesis that serotonin exerts an inhibitory influence on reward processes.