title: Glutamate Receptors within the Mesolimbic Dopamine System Mediate Alcohol Relapse Behavior.
abstract: Glutamatergic input within the mesolimbic dopamine (DA) pathway plays a critical role in the development of addictive behavior. Although this is well established for some drugs of abuse, it is not known whether glutamate receptors within the mesolimbic system are involved in mediating the addictive properties of chronic alcohol use. Here we evaluated the contribution of mesolimbic NMDARs and AMPARs in mediating alcohol-seeking responses induced by environmental stimuli and relapse behavior using four inducible mutant mouse lines lacking the glutamate receptor genes Grin1 or Gria1 in either DA transporter (DAT) or D1R-expressing neurons. We first demonstrate the lack of GluN1 or GluA1 in either DAT- or D1R-expressing neurons in our mutant mouse lines by colocalization studies. We then show that GluN1 and GluA1 receptor subunits within these neuronal subpopulations mediate the alcohol deprivation effect, while having no impact on context- plus cue-induced reinstatement of alcohol-seeking behavior. We further validated these results pharmacologically by demonstrating similar reductions in the alcohol deprivation effect after infusion of the NMDAR antagonist memantine into the nucleus accumbens and ventral tegmental area of control mice, and a rescue of the mutant phenotype via pharmacological potentiation of AMPAR activity using aniracetam. In conclusion, dopamine neurons as well as D1R-expressing medium spiny neurons and their glutamatergic inputs via NMDARs and AMPARs act in concert to influence relapse responses. These results provide a neuroanatomical and molecular substrate for relapse behavior and emphasize the importance of glutamatergic drugs in modulating relapse behavior.
  
  
  CONCLUSIONS
  Here we provide genetic and pharmacological evidence that glutamate receptors within the mesolimbic dopamine system play an essential role in alcohol relapse. Using various inducible and site-specific transgenic mouse models and pharmacological validation experiments, we show that critical subunits of NMDARs and AMPARs expressed either in dopamine neurons or in dopamine receptor D1-containing neurons play an important role in the alcohol deprivation effect (the increase in alcohol intake after a period of abstinence) while having no impact on context- plus cue-induced reinstatement of alcohol-seeking responses. Medications targeting glutamatergic neurotransmission by selective inactivation of these glutamate receptors might have therapeutic efficacy.
authors.affiliation: Institute of Psychopharmacology and Behavioral Genetics Research Group, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, J5, 68159 Mannheim, Germany, and.
authors.forename: Manuela
authors.initials: M
authors.lastname: Eisenhardt
authors.affiliation: Institute of Psychopharmacology and Behavioral Genetics Research Group, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, J5, 68159 Mannheim, Germany, and.
authors.forename: Sarah
authors.initials: S
authors.lastname: Leixner
authors.affiliation: Instituto de Investigación en Discapacidades Neurológicas, Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha, Campus Biosanitario, 02006 Albacete, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Luján
authors.affiliation: Institute of Psychopharmacology and.
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanagel
authors.affiliation: Institute of Psychopharmacology and Behavioral Genetics Research Group, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, J5, 68159 Mannheim, Germany, and ainhoa.bilbao@zi-mannheim.de.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Bilbao
mesh_terms: D000437:Alcoholism / Q000378:metabolism*; D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism*; D004298:Dopamine / Q000502:physiology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000172:deficiency / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D011954:Receptors, Dopamine / Q000172:deficiency / Q000502:physiology*; D017470:Receptors, Glutamate / Q000172:deficiency / Q000502:physiology*; D012008:Recurrence; D017557:Ventral Tegmental Area / Q000378:metabolism*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D011954:Receptors, Dopamine; D017470:Receptors, Glutamate; D004298:Dopamine
keywords: addiction; alcohol; dopamine; glutamate; relapse