title: Locomotor sensitization to ethanol impairs NMDA receptor-dependent synaptic plasticity in the nucleus accumbens and increases ethanol self-administration.
abstract: Although alcoholism is a worldwide problem resulting in millions of deaths, only a small percentage of alcohol users become addicted. The specific neural substrates responsible for individual differences in vulnerability to alcohol addiction are not known. In this study, we used rodent models to study behavioral and synaptic correlates related to individual differences in the development of ethanol locomotor sensitization, a form of drug-dependent behavioral plasticity associated with addiction vulnerability. Male Swiss Webster mice were treated daily with saline or 1.8 g/kg ethanol for 21 d. Locomotor activity tests were performed once a week for 15 min immediately after saline or ethanol injections. After at least 11 d of withdrawal, cohorts of saline- or ethanol-treated mice were used to characterize the relationships between locomotor sensitization, ethanol drinking, and glutamatergic synaptic transmission in the nucleus accumbens. Ethanol-treated mice that expressed locomotor sensitization to ethanol drank significantly more ethanol than saline-treated subjects and ethanol-treated animals resilient to this form of behavioral plasticity. Moreover, ethanol-sensitized mice also had reduced accumbal NMDA receptor function and expression, as well as deficits in NMDA receptor-dependent long-term depression in the nucleus accumbens core after a protracted withdrawal. These findings suggest that disruption of accumbal core NMDA receptor-dependent plasticity may represent a synaptic correlate associated with ethanol-induced locomotor sensitization and increased propensity to consume ethanol.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
authors.forename: Karina Possa
authors.initials: KP
authors.lastname: Abrahao
authors.forename: Olusegun J
authors.initials: OJ
authors.lastname: Ariwodola
authors.forename: Tracy R
authors.initials: TR
authors.lastname: Butler
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Rau
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Skelly
authors.forename: Eugenia
authors.initials: E
authors.lastname: Carter
authors.forename: Nancy P
authors.initials: NP
authors.lastname: Alexander
authors.forename: Brian A
authors.initials: BA
authors.lastname: McCool
authors.forename: Maria Lucia O
authors.initials: ML
authors.lastname: Souza-Formigoni
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Weiner
mesh_terms: D000435:Alcoholic Intoxication / Q000209:etiology / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001703:Biophysics; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D000431:Ethanol / Q000008:administration & dosage*; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008124:Locomotion / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012646:Self Administration; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D002492:Central Nervous System Depressants; D058787:GABA-A Receptor Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D001640:Bicuculline