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- Title
Dual synaptic sites of D<sub>1</sub>-dopaminergic regulation of ethanol sensitivity of NMDA receptors in nucleus accumbens.
- Authors
Zhang, Tao A.; Hendricson, Adam W.; Morrisett, Richard A.
- 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. © 2005 Wiley-Liss, Inc.
- Publication
Synapse, 2005, Vol 58, Issue 1, p30
- ISSN
0887-4476
- Publication type
Article
- DOI
10.1002/syn.20181