title: Repeated exposure to the κ-opioid receptor agonist salvinorin A modulates extracellular signal-regulated kinase and reward sensitivity.
abstract: BACKGROUND
  Repeated exposure to drugs of abuse and stress increase dynorphin, a κ opioid receptor (KOR) ligand, in the nucleus accumbens (NAc). Acute KOR activation produces dysphoria that might contribute to addictive behavior. How repeated KOR activation modulates reward circuitry is not understood.
  
  
  METHODS
  We used intracranial self-stimulation (ICSS), a method that provides a behavioral index of reward sensitivity, to measure the effects of repeated administration of the KOR agonist salvinorin A (salvA) (2 mg/kg) on the reward-potentiating effects of cocaine (5.0 mg/kg). In separate rats, we measured the effects of salvA on activation of extracellular signal regulated kinase (ERK), cyclic adenosine monophosphate (cAMP) response element binding protein, and c-Fos within the NAc.
  
  
  RESULTS
  SalvA had biphasic effects on reward: an immediate effect was to decrease the rewarding impact of ICSS, whereas a delayed effect was to increase the rewarding impact of ICSS. Repeated salvA produced a net decrease in the reward-potentiating effects of cocaine. In the NAc, both acute and repeated salvA administration increased phosphorylated ERK, whereas only acute salvA increased c-Fos and repeated salvA increased phosphorylated cAMP response element binding protein. The KOR antagonist nor-binaltorphimine (20 mg/kg) blocked the immediate and delayed effects of salvA and prolonged the duration of cocaine effects in ICSS.
  
  
  CONCLUSIONS
  Repeated salvA might trigger opponent processes such that "withdrawal" from the dysphoric effects of KOR activation is rewarding and decreases the net rewarding valence of cocaine. The temporal effects of salvA on ERK signaling suggest KOR-mediated engagement of distinct signaling pathways within the NAc that might contribute to biphasic effects on reward sensitivity.
authors.affiliation: Behavioral Genetics Laboratory, Harvard Medical School, McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts.
authors.forename: David N
authors.initials: DN
authors.lastname: Potter
authors.affiliation: Molecular Pharmacology Laboratory, Harvard Medical School, McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts.
authors.forename: Diane
authors.initials: D
authors.lastname: Damez-Werno
authors.affiliation: Behavioral Genetics Laboratory, Harvard Medical School, McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts.
authors.forename: William A
authors.initials: WA
authors.lastname: Carlezon
authors.affiliation: Molecular Pharmacology Laboratory, Harvard Medical School, McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Cohen
authors.affiliation: Behavioral Genetics Laboratory, Harvard Medical School, McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts. Electronic address: echartoff@mclean.harvard.edu.
authors.forename: Elena H
authors.initials: EH
authors.lastname: Chartoff
mesh_terms: D000818:Animals; D003042:Cocaine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D045785:Diterpenes, Clerodane / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004347:Drug Interactions / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors; D012201:Reward; D012653:Self Stimulation / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D045785:Diterpenes, Clerodane; D016760:Proto-Oncogene Proteins c-fos; D017473:Receptors, Opioid, kappa; C051843:binaltorphimine; D009271:Naltrexone; D048049:Extracellular Signal-Regulated MAP Kinases; D003042:Cocaine; C090499:salvinorin A