Ethanol and Mesolimbic Serotonin/Dopamine Interactions via 5HT-1B Receptors

Abstract

Abstract : The experiments under Specific Aim 1 have been completed. Dual-probe microdialysis was performed as before. Ethanol (1 and 2 g/kg) or saline was injected ip to animals and extracellular dopamine (DA) and GABA in the ventral tegmental area (VTA), and DA in the ipsilateral nucleus accumbens (NACC) were measured. Then, SB 216641(10 micrometers, a 5-HT1B receptor antagonist), WAY 100635 (10 micrometers, a 5-HT1A receptor antagonist), BRL (10 micrometers, a 5-HT1D/1A receptor antagonist), or CP 94253 (10 micrometers, a 5-HT1B receptor antagonist) was infused into the VTA 20 min before ethanol administration (1 and 2 g/kg) until the end of the experiments. The results showed that administration of ethanol at the doses of 1 and 2 g/kg increased extracellular DA concentrations in both areas. The time course of extracellular DA in the VTA after ethanol is similar to that in the NACC. Administration of ethanol at the same doses did not produce significant changes in extracellular VTA GABA. Co-administration of SB 216641, but not WAY 100635 or BRL 15572, attenuated ethanol-evoked DA release in both areas. Co-administration of CP 94253 prolonged the effects of ethanol on extracellular NACC DA. The results are consistent with the hypothesis that activation and blockade of VTA 5-HT-1B receptors potentiates and attenuates ethanol's effects on DA transmission in the ipsilateral NACC, respectively. These observations may in part explain why 5-HT-1B receptors play a role in ethanol's behavioral effects. The experiments under Specific Aim 2 were also initiated in 5-HT1B receptor knockout (KO) and their counterparts wild-type (WT) mice. The results showed that the 5-HT-1B/1A receptor agonist RU 24969 increased extracellular NACC DA concentrations in the WT but not in the KO mice. The results provide additional support to the hypothesis that 5-HT-1B receptors are involved in modulation of mesolimbic dopaminergic neurotransmission.