Abstract

Opioid receptor subtypes may have site-specific effects and play different roles in modulating serotonergic neurotransmission in the mammalian central nervous system. To test this hypothesis, we used in vivo microdialysis to measure changes in extracellular serotonin (5-hydroxytryptamine; 5-HT) in response to local infusion of μ-, δ-, and κ-opioid receptor ligands into the dorsal raphe nucleus (DRN), median raphe nucleus (MRN), and nucleus accumbens (NAcc) of freely behaving rats. The μ-opioids [d-Ala²-N-Me-Phe⁴,Gly⁵-ol]enkephalin (DAMGO), endomorphin-1, and endomorphin-2 were administered by reverse dialysis infusion into the DRN. In response, extracellular 5-HT was increased in the DRN, an effect that was blocked by the selective μ-receptor antagonist β-funaltrexamine, but not by the δ-receptor antagonistN,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI-174,864). Infusion of δ-receptor agonists, [d-Ala²,d-Len⁵]enkephalin (DADLE), [d-Pen^2,5]enkephalin (DPDPE), and deltophin-II into the DRN also increased extracellular 5-HT, an effect that was blocked by selective δ-receptor antagonists. In contrast to the DRN, local infusion of μ- and δ-opioids had no effect on 5-HT in the MRN or NAcc. These data indicate that μ- and δ-opioid ligands have a selective influence on serotonergic neurons in the DRN. Finally, the κ-receptor agonist U-50,488 [trans-(±)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide] produced similar decreases in 5-HT during local infusion into the DRN, MRN, and NAcc. These results provide evidence of differential regulation of 5-HT release by opioid receptor subtypes in the midbrain raphe and forebrain.