title: Previous ethanol experience enhances synaptic plasticity of NMDA receptors in the ventral tegmental area.
abstract: Alcohol addiction (alcoholism) is one of the most prevalent substance abuse disorders worldwide. Addiction is thought to arise, in part, from a maladaptive learning process in which enduring memories of drug experiences are formed. However, alcohol (ethanol) generally interferes with synaptic plasticity mechanisms in the CNS and thus impairs various types of learning and memory. Therefore, it is unclear how powerful memories associated with alcohol experience are formed during the development of alcoholism. Here, using brain slice electrophysiology in mice, we show that repeated in vivo ethanol exposure (2 g/kg, i.p., three times daily for 7 d) causes increased susceptibility to the induction of long-term potentiation (LTP) of NMDA receptor (NMDAR)-mediated transmission in mesolimbic dopamine neurons, a form of synaptic plasticity that may drive the learning of stimuli associated with rewards, including drugs of abuse. Enhancement of NMDAR plasticity results from an increase in the potency of inositol 1,4,5-trisphosphate (IP(3)) in producing facilitation of action potential-evoked Ca(2+) signals, which is critical for LTP induction. This increase in IP(3) effect, which lasts for a week but not a month after ethanol withdrawal, occurs through a protein kinase A (PKA)-dependent mechanism. Corticotropin-releasing factor, a stress-related neuropeptide implicated in alcoholism and other addictions, further amplifies the PKA-mediated increase in IP(3) effect in ethanol-treated mice. Finally, we found that ethanol-treated mice display enhanced place conditioning induced by the psychostimulant cocaine. These data suggest that repeated ethanol experience may promote the formation of drug-associated memories by enhancing synaptic plasticity of NMDARs in dopamine neurons.
authors.affiliation: Section of Neurobiology and Institute for Neuroscience, Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Texas 78712, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Bernier
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Whitaker
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Morikawa
mesh_terms: D029845:Amphibian Proteins / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D036361:Peptide Hormones / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012457:Salicylamides / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects*
chemical_list: D029845:Amphibian Proteins; D002492:Central Nervous System Depressants; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D036361:Peptide Hormones; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; D012457:Salicylamides; D005576:Colforsin; D000431:Ethanol; D008734:Methoxyhydroxyphenylglycol; C056723:FG 9041; C025727:sauvagine; D015544:Inositol 1,4,5-Trisphosphate; D003346:Corticotropin-Releasing Hormone; D003042:Cocaine; C045989:eticlopride; C010117:3,4-dihydroxyphenylglycol