Effects of the CRF receptor antagonist D-Phe CRF(12-41) and the alpha2-adrenergic receptor agonist clonidine on stress-induced reinstatement of nicotine-seeking behavior in rats.
Tobacco dependence is a chronic disorder that is characterized by relapse after periods of abstinence. It has been hypothesized that the activation of brain stress systems mediates stress-induced relapse to smoking. The aim of these experiments was to investigate the role of corticotropin-releasing factor (CRF) and norepinephrine in stress-induced reinstatement of extinguished nicotine-seeking behavior. Rats were allowed to self-administer nicotine under a fixed-ratio 5 schedule for 14 days and then nicotine-seeking behavior was extinguished by substituting saline for nicotine. In experiment 1, footshocks reinstated extinguished nicotine-seeking behavior. In experiment 2, there was a trend for the CRF(1/2) receptor antagonist D-Phe CRF((12-41)) (5, 25microg, icv) to decrease stress-induced reinstatement of nicotine-seeking behavior. Footshock-induced reinstatement of nicotine-seeking behavior was observed only in a subset of stress-responsive rats (71%). D-Phe CRF((12-41)) significantly attenuated stress-induced reinstatement of nicotine-seeking behavior in this subset of rats. In experiment 3, the alpha2-adrenergic receptor agonist clonidine (20, 40microg/kg, sc) attenuated footshock-induced reinstatement of nicotine-seeking behavior. In experiment 4, the effects of D-Phe CRF((12-41)) and clonidine on responding for chocolate-flavored food pellets was investigated in order to determine if these compounds have sedative effects. D-Phe CRF((12-41)) did not affect responding for food pellets. Clonidine slightly, but significantly, decreased responding for food pellets. Clonidine decreased responding for food to a lesser degree than it decreased stress-induced reinstatement of nicotine-seeking behavior. These data provide support for the hypothesis that an increased activity of brain CRF and norepinephrine systems mediates stress-induced relapse to nicotine-seeking behavior.
Zislis
George
G
University of Florida, Department of Psychiatry, Gainesville, FL 32610, USA.
Desai
Tina V
TV
Prado
Melissa
M
Shah
Hina P
HP
Bruijnzeel
Adrie W
AW
D000316:Adrenergic alpha-Agonists / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003000:Clonidine / Q000627:therapeutic use*; D003216:Conditioning, Operant / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000379:methods; D005108:Extinction, Psychological / Q000187:drug effects; D005518:Food Preferences / Q000187:drug effects; D008297:Male; D009538:Nicotine / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D012646:Self Administration; D013315:Stress, Psychological / Q000150:complications*; D014029:Tobacco Use Disorder / Q000188:drug therapy* / Q000209:etiology*
D000316:Adrenergic alpha-Agonists; C113202:phenylalanyl corticotropin-releasing factor (12-41); D009538:Nicotine; D003346:Corticotropin-Releasing Hormone; D003000:Clonidine