The midbrain raphe nuclei mediate primary reinforcement via GABA(A) receptors

Because rats learn to lever-press for brief electrical stimulation of the median and dorsal raphe nuclei (MRN and DRN, respectively), these brain sites have long been implicated in reward processes. However, it is not clear whether the MRN and DRN integrate reward-related signals or merely contain fibers of passage involved in reward processes. To shed light on this issue, the present study employed chemicals that selectively modulate neurotransmission, in particular the GABA(A) receptor agonist muscimol. Rats quickly learned to lever-press for muscimol infusions (50 and 100 microM) into the MRN or DRN. Muscimol was not self-administered when cannulae were placed just outside these nuclei. The reinforcing effects of muscimol appeared to be greater when the drug was administered into the MRN than into the DRN, as demonstrated by higher infusion rates and better response discrimination. These observations are consistent with the additional finding that muscimol administration into the MRN, but not the DRN, induced conditioned place preference. The reinforcing effects of muscimol administration into the MRN were blocked by coadministration of the GABA(A) antagonist picrotoxin (100 microM) and by pretreatment with the dopamine receptor antagonist SCH 23390 (0.025 mg/kg, i.p.). The present results suggest that median and dorsal raphe neurons presumably inhibited by muscimol via GABA(A) receptors are involved in integration of primary reinforcement, and that median raphe neurons exert tonic inhibition over dopamine-dependent reward circuitry. The midbrain raphe nuclei may be involved in a variety of reward-related phenomena including drug addiction.