title: Ethanol-mediated facilitation of AMPA receptor function in the dorsomedial striatum: implications for alcohol drinking behavior.
abstract: We found previously that acute ex vivo as well as repeated cycles of in vivo ethanol exposure and withdrawal, including excessive voluntary consumption of ethanol, produces a long-lasting increase in the activity of NR2B-containing NMDA receptors (NR2B-NMDARs) in the dorsomedial striatum (DMS) of rats (Wang et al., 2010a). Activation of NMDARs is required for the induction of long-term potentiation (LTP) of AMPA receptor (AMPAR)-mediated synaptic response. We therefore examined whether the ethanol-mediated upregulation of NMDAR activity alters the induction of LTP in the DMS. We found that ex vivo acute exposure of striatal slices to, and withdrawal from, ethanol facilitates the induction of LTP in DMS neurons, which is abolished by the inhibition of NR2B-NMDARs. We also report that repeated systemic administration of ethanol causes an NR2B-NMDAR-dependent facilitation of LTP in the DMS. LTP is mediated by the insertion of AMPAR subunits into the synaptic membrane, and we found that repeated systemic administration of ethanol, as well as cycles of excessive ethanol consumption and withdrawal, produced a long-lasting increase in synaptic localization of the GluR1 and GluR2 subunits of AMPARs in the DMS. Importantly, we report that inhibition of AMPARs in the DMS attenuates operant self-administration of ethanol, but not of sucrose. Together, our data suggest that aberrant synaptic plasticity in the DMS induced by repeated cycles of ethanol exposure and withdrawal contributes to the molecular mechanisms underlying the development and/or maintenance of excessive ethanol consumption.
authors.affiliation: Ernest Gallo Research Center and Department of Neurology, University of California at San Francisco, Emeryville, California 94608, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Sami
authors.initials: S
authors.lastname: Ben Hamida
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Darcq
authors.forename: Wenheng
authors.initials: W
authors.lastname: Zhu
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Gibb
authors.forename: Maria Fe
authors.initials: MF
authors.lastname: Lanfranco
authors.forename: Sebastien
authors.initials: S
authors.lastname: Carnicella
authors.forename: Dorit
authors.initials: D
authors.lastname: Ron
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002755:Choice Behavior / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004558:Electric Stimulation; D000431:Ethanol / Q000494:pharmacology*; D005071:Evoked Potentials / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005518:Food Preferences / Q000187:drug effects; D018756:GABA Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage; D013469:Sulpiride / Q000494:pharmacology; D013549:Sweetening Agents / Q000008:administration & dosage; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D002492:Central Nervous System Depressants; D018492:Dopamine Antagonists; D000431:Ethanol; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D016202:N-Methylaspartate; D010852:Picrotoxin; D011810:Quinoxalines; D018091:Receptors, AMPA; D013395:Sucrose; D013469:Sulpiride; D013549:Sweetening Agents; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline