Dual synaptic sites of D(1)-dopaminergic regulation of ethanol sensitivity of NMDA receptors in nucleus accumbens

Abstract

Regulation of NMDAreceptor-mediated synaptic transmission onto accumbal medium spiny neurons (MSN) may constitute an important site in drug reward and reinforcement in mesolimbic structures. Previously, we reported that D(1)-like dopamine receptors activate a postsynaptic cAMP/PKA/DARPP-32 signaling cascade culminating in phosphorylation of SER897-NR1 subunits and a reduction in the sensitivity to ethanol of NMDA receptor-mediated synaptic transmission. Here, we use a detailed electrophysiological analysis of D(1)-like receptor regulation of the ethanol sensitivity of accumbal NMDA receptors (NMDARs) through recordings of quantal Sr(2+)-supported NMDA miniature synaptic currents (mEPSCs) in reduced Mg(2+) (0.6 mM) and report dual presynaptic and postsynaptic components of D(1)-like regulation of ethanol sensitivity of NMDARs. Ethanol inhibited NMDA mEPSC amplitude and frequency in a dose-dependent manner (25-75 mM), indicating inhibitory effects on presynaptic and postsynaptic components NMDA receptor-mediated synaptic transmission. The presynaptic inhibitory effect was corroborated by analysing the ratio of paired-pulse facilitation (PPF) of Ca(2+)-supported NMDA EPSCs. Activation of D(1) receptors with the agonist, SKF 38393 (25 microM), reversed ethanol suppression of NMDA mEPSC frequency and amplitude. Furthermore, the Mg(2+)-dependent decay off-rate of NMDA mEPSCs was substantially reduced by ethanol in a manner strongly reversed by the D(1) agonist. D(1) receptor-mediated attenuation of both the presynaptic and postsynaptic actions of ethanol was completely blocked by a D(1) selective antagonist (SCH 23390). These data suggest that D(1)-like receptors modulate both the presynaptic and postsynaptic effects of ethanol on NMDA receptor-mediated synaptic transmission in nucleus accumbens (NAc) and that these interactions may contribute to ethanol-induced neuroadaptation of the reward pathway.