Dopamine D1-like receptor-mediated regulation of NMDA receptor sensitivity to ethanol in the nucleus accumbens

dc.contributor.advisorMorrisett, Richard A.en
dc.creatorZhang, Taoen
dc.date.accessioned2008-08-28T22:38:03Zen
dc.date.available2008-08-28T22:38:03Zen
dc.date.issued2005en
dc.description.abstractDopaminergic regulation of NMDA receptor-mediated synaptic transmission onto medium spiny neurons (MSNs) in the nucleus accumbens (NAc) may constitute a critical site of ethanol action in mesolimbic structures. Here we investigated how dopaminergic inputs alter the ability of ethanol to inhibit NMDA receptor-mediated synaptic transmission onto accumbal MSNs in rats and mice. By using a variety of recording techniques such as patch-clamp recordings and field potential recordings, we demonstrated that prior activation of D1-like dopamine receptors (D1DRs) with the D1-agonist SKF 38393 (25 µM) significantly attenuated ethanol (75 mM) inhibition of NMDA receptor function. The D1-regulation of ethanol sensitivity was mediated largely by a postsynaptic mechanism involving D1-signaling cascade through the cAMP-regulated phosphoprotein-32 kD (DARPP-32) and protein phosphatase-1 (PP-1) pathway. D1/DARPP-32-dependent regulation of NMDA receptor sensitivity to ethanol was absent in DARPP-32 knockout mice. Coincident activation of regulator of calmodulin signaling (RCS) further amplified the effect of D1-DARPP-32 on ethanol inhibition of NMDA receptor function. In addition, we performed a detailed electrophysiological analysis of D1-regulation of the ethanol sensitivity of accumbal NMDA receptors through recordings of quantal Sr2+-supported NMDA mEPSCs in reduced Mg2+ (0.6 mM) and observed dual presynaptic and postsynaptic components of D1-regulation of ethanol sensitivity of NMDA receptors. Ethanol inhibited NMDA mEPSC amplitude and frequency in a dose-dependent manner (25-75 mM), indicating inhibitory effects on presynaptic and postsynaptic components of NMDA receptor-mediated synaptic transmission. The presynaptic effect of ethanol was corroborated by analyzing the ratio of paired-pulse facilitation (PPF) of Ca2+-supported NMDA EPSCs. Activation of D1DRs 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 D1DRs modulate both the presynaptic and postsynaptic effects of ethanol on NMDA receptor-mediated synaptic transmission in the NAc and that these interactions may contribute to ethanol-induced neuroadaptation of the reward pathway.
dc.description.departmentInstitute for Neuroscienceen
dc.format.mediumelectronicen
dc.identifierb60851454en
dc.identifier.oclc69250092en
dc.identifier.urihttp://hdl.handle.net/2152/2213en
dc.language.isoengen
dc.rightsCopyright is held by the author. Presentation of this material on the Libraries' web site by University Libraries, The University of Texas at Austin was made possible under a limited license grant from the author who has retained all copyrights in the works.en
dc.subject.lcshMethyl aspartate--Receptorsen
dc.subject.lcshDopamine--Physiological effecten
dc.subject.lcshAlcohol--Physiological effecten
dc.titleDopamine D1-like receptor-mediated regulation of NMDA receptor sensitivity to ethanol in the nucleus accumbensen
dc.type.genreThesisen
thesis.degree.departmentNeuroscience, Institute foren
thesis.degree.disciplineNeuroscienceen
thesis.degree.grantorThe University of Texas at Austinen
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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