Long-Lasting Potentiation of GABAergic Synapses in Dopamine Neurons after a SingleIn VivoEthanol Exposure

The mesolimbic dopamine (DA) system originating in the ventral tegmental area (VTA) is involved in many drug-related behaviors, including ethanol self-administration. In particular, VTA activity regulating ethanol consummatory behavior appears to be modulated through GABA A receptors. Previous exposure to ethanol enhances ethanol self-administration, but the mechanisms underlying this phenomenon are not well understood. In this study, we examined changes occurring at GABA synapses onto VTA DA neurons after a single in vivo exposure to ethanol. We observed that evoked GABA A IPSCs in DA neurons of ethanol-treated animals exhibited paired-pulse depression (PPD) compared with saline-treated animals, which exhibited paired-pulse facilitation (PPF). Furthermore, PPD was still present 1 week after the single exposure to ethanol. An increase in frequency of spontaneous miniature GABA A IPSCs (mIPSCs) was also observed in the ethanol-treated animals. Additionally, the GABA B receptor antagonist (3-aminopropyl)(diethoxymethyl) phosphinic acid shifted PPD to PPF, indicating that presynaptic GABA B receptor activation, likely attributable to GABA spillover, might play a role in mediating PPD in the ethanol-treated mice. The activation of adenylyl cyclase by forskolin increased the amplitude of GABA A IPSCs and the frequency of mIPSCs in the saline- but not in the ethanol-treated animals. Conversely, the protein kinase A (PKA) inhibitor N -[z-( p -bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide significantly decreased both the frequency of spontaneous mIPSCs and the amplitude of GABA A IPSCs in the ethanol-treated mice but not in the saline controls. The present results indicate that potentiation of GABAergic synapses, via a PKA-dependent mechanism, occurs in the VTA after a single in vivo exposure to ethanol, and such potentiation might be a key synaptic modification underlying increased ethanol intake.