title: Mechanisms of withdrawal-associated increases in heroin self-administration: pharmacologic modulation of heroin vs food choice in heroin-dependent rhesus monkeys.
abstract: Opioid withdrawal can produce a constellation of physiological and behavioral signs, including an increase in opioid self-administration. Different mechanisms mediate different withdrawal signs, and the present study used pharmacologic tools to assess mechanisms underlying withdrawal-associated increases in opioid reinforcement. Five rhesus monkeys were rendered heroin dependent via daily 21-h heroin self-administration sessions. One hour after each heroin self-administration session, monkeys chose between heroin (0-0.1 mg/kg per injection) and food (1 g pellets) during 2-h choice sessions. Under these conditions, heroin maintained a dose-dependent increase in heroin choice, such that monkeys responded primarily for food when low heroin doses were available (0-0.01 mg/kg per injection) and primarily for heroin when higher heroin doses were available (0.032-0.1 mg/kg per injection). Periods of spontaneous withdrawal were intermittently introduced by omitting one 21-h heroin self-administration session, and test drugs were administered during these withdrawal periods. Untreated withdrawal robustly increased heroin choice during choice sessions. Withdrawal-associated increases in heroin choice were completely suppressed by the mu opioid agonist morphine (0.032-0.32 mg/kg/h, i.v.), but not by the alpha-2 noradrenergic agonist clonidine (0.01-0.1 mg/kg/h, i.v.), the dopamine/norepinephrine releaser amphetamine (0.032-0.1 mg/kg/h, i.v.), or the kappa-opioid antagonist 5'-guanidinonaltrindole (1.0 mg/kg, i.m.). The corticotropin-releasing factor 1 antagonist antalarmin (1.0-10 mg/kg per day, i.m.) produced a morphine-like suppression of withdrawal-associated increases in heroin choice in one of three monkeys. These results suggest that mechanisms of withdrawal-associated increases in the relative reinforcing efficacy of opioid agonists may be different from mechanisms of many other somatic, mood-related, and motivational signs of opioid withdrawal.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA. ssnegus@vcu.edu
authors.forename: S Stevens
authors.initials: SS
authors.lastname: Negus
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D018663:Adrenergic Agents / Q000493:pharmacokinetics; D000322:Adrenergic Agonists / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy / Q000523:psychology*; D002755:Choice Behavior / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005502:Food; D003932:Heroin / Q000008:administration & dosage*; D006556:Heroin Dependence / Q000188:drug therapy / Q000523:psychology*; D008253:Macaca mulatta; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000523:psychology*
chemical_list: D018663:Adrenergic Agents; D000322:Adrenergic Agonists; D015259:Dopamine Agents; D009292:Narcotic Antagonists; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; C103016:antalarmin; D003932:Heroin; D009020:Morphine; D000661:Amphetamine; D003000:Clonidine