title: Altered ratio of D1 and D2 dopamine receptors in mouse striatum is associated with behavioral sensitization to cocaine.
abstract: BACKGROUND
  Drugs of abuse elevate brain dopamine levels, and, in vivo, chronic drug use is accompanied by a selective decrease in dopamine D2 receptor (D2R) availability in the brain. Such a decrease consequently alters the ratio of D1R:D2R signaling towards the D1R. Despite a plethora of behavioral studies dedicated to the understanding of the role of dopamine in addiction, a molecular mechanism responsible for the downregulation of the D2R, in vivo, in response to chronic drug use has yet to be identified.
  
  
  RESULTS
  ETHICS STATEMENT: All animal work was approved by the Gallo Center IACUC committee and was performed in our AAALAC approved facility. In this study, we used wild type (WT) and G protein coupled receptor associated sorting protein-1 (GASP-1) knock out (KO) mice to assess molecular changes that accompany cocaine sensitization. Here, we show that downregulation of D2Rs or upregulation of D1Rs is associated with a sensitized locomotor response to an acute injection of cocaine. Furthermore, we demonstrate that disruption of GASP-1, that targets D2Rs for degradation after endocytosis, prevents cocaine-induced downregulation of D2Rs. As a consequence, mice with a GASP-1 disruption show a reduction in the sensitized locomotor response to cocaine.
  
  
  CONCLUSIONS
  Together, our data suggests that changes in the ratio of the D1:D2R could contribute to cocaine-induced behavioral plasticity and demonstrates a role of GASP-1 in regulating both the levels of the D2R and cocaine sensitization.
authors.affiliation: Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, California, USA.
authors.forename: Dawn
authors.initials: D
authors.lastname: Thompson
authors.forename: Lene
authors.initials: L
authors.lastname: Martini
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Whistler
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C479636:Gprasp1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D003042:Cocaine