Dual synaptic sites of D1‐dopaminergic regulation of ethanol sensitivity of NMDA receptors in nucleus accumbens

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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 D1‐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 D1‐like receptor regulation of the ethanol sensitivity of accumbal NMDA receptors (NMDARs) through recordings of quantal Sr2+‐supported NMDA miniature synaptic currents (mEPSCs) in reduced Mg2+ (0.6 mM) and report dual presynaptic and postsynaptic components of D1‐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 Ca2+‐supported NMDA EPSCs. Activation of D1 receptors with the agonist, SKF 38393 (25 μM), reversed ethanol suppression of NMDA mEPSC frequency and amplitude. Furthermore, the Mg2+‐dependent decay off‐rate of NMDA mEPSCs was substantially reduced by ethanol in a manner strongly reversed by the D1 agonist. D1 receptor‐mediated attenuation of both the presynaptic and postsynaptic actions of ethanol was completely blocked by a D1 selective antagonist (SCH 23390). These data suggest that D1‐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. Synapse 58:29–43, 2005.