title: Blockade of mesolimbic dopamine D3 receptors inhibits stress-induced reinstatement of cocaine-seeking in rats.
abstract: BACKGROUND
  The dopamine (DA) D3 receptor is preferentially expressed in the mesolimbic system. We have previously shown that selective D3 receptor blockade by the novel D3 antagonist SB-277011A inhibits cocaine's reinforcing action and cocaine-induced reinstatement of cocaine-seeking behavior.
  
  
  OBJECTIVE
  In the present study, we investigated whether SB-277011A similarly inhibits stress-induced reinstatement of cocaine-seeking behavior.
  
  
  METHODS
  Rats were allowed to self-administer cocaine (0.5 mg/kg per infusion, 3 h per session) for 10-14 days, followed by a once-daily extinction session for 7-14 days during which saline was substituted for cocaine. Extinction criteria were fewer than ten lever-presses per 3-h session for at least 3 consecutive days. After cocaine-seeking behavior was extinguished, each animal was tested twice for footshock-stress-induced reinstatement, once with vehicle (25% hydroxypropyl-beta-cyclodextrin) and once with one of three doses of SB-277011A in counterbalanced fashion.
  
  
  RESULTS
  During the last 3 days of cocaine self-administration (SA), active lever-presses were approximately 100 per session under fixed-ratio 2 reinforcement (approximately 25 mg/kg cocaine per session). After extinction, intermittent footshock (10 min, 0.5 mA, 0.5 s on with a mean inter-shock interval of 40 s) robustly reinstated the cocaine-seeking behavior (8.4+/-3.6 active lever-presses in last extinction session to 35.3+/-5.2 in animals after footshock stress). Intraperitoneal (i.p.) injections of SB-277011A (3, 6, and 12 mg/kg) dose-dependently blocked stress-induced reinstatement of cocaine-seeking. Reinstatement was also blocked by microinjections of SB-277011A (1.5 microg/0.5 microl per side) bilaterally into the nucleus accumbens, but not into the dorsal striatum.
  
  
  CONCLUSIONS
  The mesolimic DA D3 receptor plays an important role in mediating stress-induced reinstatement.
authors.affiliation: Neuropsychopharmacology Section, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. zxi@intra.nida.nih.gov
authors.forename: Zheng-Xiong
authors.initials: ZX
authors.lastname: Xi
authors.forename: Jeremy
authors.initials: J
authors.lastname: Gilbert
authors.forename: Arlene C
authors.initials: AC
authors.lastname: Campos
authors.forename: Nicole
authors.initials: N
authors.lastname: Kline
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Hagan
authors.forename: Christian A
authors.initials: CA
authors.lastname: Heidbreder
authors.forename: Eliot L
authors.initials: EL
authors.lastname: Gardner
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000493:pharmacokinetics; D019970:Cocaine-Related Disorders / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects; D065127:Dopamine D2 Receptor Antagonists; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D007262:Infusions, Intravenous; D008297:Male; D008845:Microinjections; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D051381:Rats; D020318:Rats, Long-Evans; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000502:physiology*; D050637:Receptors, Dopamine D3; D012054:Reinforcement, Psychology; D055502:Secondary Prevention; D012646:Self Administration / Q000379:methods; D013315:Stress, Psychological / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*; D013375:Substance Withdrawal Syndrome / Q000150:complications / Q000517:prevention & control; D044005:Tetrahydroisoquinolines / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D065127:Dopamine D2 Receptor Antagonists; C493595:Drd3 protein, rat; D009570:Nitriles; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C409982:SB 277011; D044005:Tetrahydroisoquinolines; D003042:Cocaine