title: 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.
authors.affiliation: The Institute for Neuroscience, The University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Tao A
authors.initials: TA
authors.lastname: Zhang
authors.forename: Adam W
authors.initials: AW
authors.lastname: Hendricson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morrisett
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D000431:Ethanol / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D010852:Picrotoxin / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects
chemical_list: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D002492:Central Nervous System Depressants; D018491:Dopamine Agonists; D000431:Ethanol; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D008274:Magnesium; D010852:Picrotoxin; D011810:Quinoxalines; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; C098593:dopamine D1A receptor; C056723:FG 9041