title: Upregulation of dopamine D2 receptors in the nucleus accumbens indirect pathway increases locomotion but does not reduce alcohol consumption.
abstract: Brain imaging studies performed in humans have associated low striatal dopamine release and D2R binding with alcohol dependence. Conversely, high striatal D2R binding has been observed in unaffected members of alcoholic families suggesting that high D2R function may protect against alcohol dependence. A possible protective role of increased D2R levels in the striatum is further supported by preclinical studies in non-human primates and rodents. Here, we determined whether there is a causal relationship between D2R levels and alcohol intake. To this end, we upregulated D2R expression levels in the nucleus accumbens of the adult mouse, but selectively restricted the upregulation to the indirect striatal output pathway, which endogenously expresses D2Rs. After overexpression was established, mice were tested in two models of free-choice alcohol drinking: the continuous and intermittent access two-bottle choice models. As anticipated, we found that D2R upregulation leads to hyperactivity in the open field. Contrary to our expectation, D2R upregulation did not reduce alcohol intake during continuous or intermittent access or when alcohol drinking was tested in the context of aversive outcomes. These data argue against a protective role of accumbal indirect pathway D2Rs in alcohol consumption but emphasize their importance in promoting locomotor activity.
authors.affiliation: 1] Departments of Psychiatry and Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY, USA [2] Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Eduardo F
authors.initials: EF
authors.lastname: Gallo
authors.affiliation: Departments of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Salling
authors.affiliation: 1] Departments of Psychiatry and Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY, USA [2] Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Feng
authors.affiliation: Departments of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Morón
authors.affiliation: 1] Departments of Psychiatry and Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY, USA [2] Departments of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Neil L
authors.initials: NL
authors.lastname: Harrison
authors.affiliation: 1] Departments of Psychiatry and Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY, USA [2] Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Javitch
authors.affiliation: 1] Departments of Psychiatry and Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY, USA [2] Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kellendonk
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics*; D000438:Alcohols / Q000008:administration & dosage*; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D005106:Exploratory Behavior / Q000502:physiology; D008124:Locomotion / Q000187:drug effects / Q000235:genetics*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D000438:Alcohols; D008164:Luminescent Proteins; D017448:Receptors, Dopamine D2