Increased extracellular glutamate in the nucleus accumbens promotes excessive ethanol drinking in ethanol dependent mice.
Using a well-established model of ethanol dependence and relapse, this study examined adaptations in glutamatergic transmission in the nucleus accumbens (NAc) and their role in regulating voluntary ethanol drinking. Mice were first trained to drink ethanol in a free-choice, limited access (2 h/day) paradigm. One group (EtOH mice) received repeated weekly cycles of chronic intermittent ethanol (CIE) exposure with intervening weeks of test drinking sessions, whereas the remaining mice (CTL mice) were similarly treated but did not receive CIE treatment. Over repeated cycles of CIE exposure, EtOH mice exhibited significant escalation in drinking (up to ∼3.5 g/kg), whereas drinking remained relatively stable at baseline levels (2-2.5 g/kg) in CTL mice. Using in vivo microdialysis procedures, extracellular glutamate (GLUEX) levels in the NAc were increased approximately twofold in EtOH mice compared with CTL mice, and this difference was observed 7 days after final CIE exposure, indicating that this hyperglutamatergic state persisted beyond acute withdrawal. This finding prompted additional studies examining the effects of pharmacologically manipulating GLUEX in the NAc on ethanol drinking in the CIE model. The non-selective glutamate reuptake antagonist, threo-β-benzyloxyaspartate (TBOA), was bilaterally microinjected into the NAc and found to dose-dependently increase drinking in nondependent (CTL) mice to levels attained by dependent (EtOH) mice. TBOA also further increased drinking in EtOH mice. In contrast, reducing glutamatergic transmission in the NAc via bilateral injections of the metabotropic glutamate receptor-2/3 agonist LY379268 reduced drinking in dependent (EtOH) mice to nondependent (CTL) levels, whereas having a more modest effect in decreasing ethanol consumption in CTL mice. Taken together, these data support an important role of glutamatergic transmission in the NAc in regulating ethanol drinking. Additionally, these results indicate that ethanol dependence produces adaptations that favor elevated glutamate activity in the NAc which, in turn, promote excessive levels of ethanol consumption associated with dependence.
Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Science, Medical University of South Carolina, Charleston, SC, USA.
William C
WC
Griffin
Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Science, Medical University of South Carolina, Charleston, SC, USA.
Harold L
HL
Haun
Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Science, Medical University of South Carolina, Charleston, SC, USA.
Callan L
CL
Hazelbaker
Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Science, Medical University of South Carolina, Charleston, SC, USA.
Vorani S
VS
Ramachandra
1] Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Science, Medical University of South Carolina, Charleston, SC, USA [2] Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA [3] Ralph H Johnson VA Medical Center, Charleston, SC, USA.
Howard C
HC
Becker
D000428:Alcohol Drinking / Q000473:pathology* / Q000503:physiopathology; D000437:Alcoholism / Q000150:complications*; D000596:Amino Acids / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D045604:Extracellular Fluid / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D008845:Microinjections; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*
D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018683:Excitatory Amino Acid Agents; C118218:LY 379268; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid