title: The extra-adrenal effects of metyrapone and oxazepam on ongoing cocaine self-administration.
abstract: Investigation of the role of stress in cocaine addiction has yielded an efficacious combination of metyrapone and oxazepam, hypothesized to decrease relapse to cocaine use by reducing stress-induced craving. However, recent data suggest an extra-adrenal role for metyrapone in mediating stress- and addiction-related behaviors. The interactions between the physiological stress response and cocaine self-administration were characterized in rodents utilizing surgical adrenalectomy and pharmacological treatment. Male Wistar rats were trained to self-administer cocaine (0.25mg/kg/infusion) and food pellets under a concurrent alternating fixed-ratio schedule of reinforcement. Surgical removal of the adrenal glands resulted in a significant decrease in plasma corticosterone and a consequent increase in ACTH, as expected. However, adrenalectomy did not significantly affect ongoing cocaine self-administration. Pretreatment with metyrapone, oxazepam and their combinations in intact rats resulted in a significant decrease in cocaine-reinforced responses. These same pharmacological treatments were still effective in reducing cocaine- and food-reinforced responding in adrenalectomized rats. The results of these experiments demonstrate that adrenally-derived steroids are not necessary to maintain cocaine-reinforced responding in cocaine-experienced rats. These results also demonstrate that metyrapone may produce effects outside of the adrenal gland, presumably in the central nervous system, to affect cocaine-related behaviors.
authors.affiliation: Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Highway, Box 33932, Shreveport, LA 71130, USA.
authors.forename: Glenn F
authors.initials: GF
authors.lastname: Guerin
authors.affiliation: Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Highway, Box 33932, Shreveport, LA 71130, USA. Electronic address: cschm1@lsuhsc.edu.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Schmoutz
authors.affiliation: Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Highway, Box 33932, Shreveport, LA 71130, USA.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Goeders
mesh_terms: D000313:Adrenal Medulla / Q000502:physiology*; D000315:Adrenalectomy; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D003042:Cocaine / Q000633:toxicity*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003345:Corticosterone / Q000097:blood; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology*; D005108:Extinction, Psychological / Q000187:drug effects; D008297:Male; D008797:Metyrapone / Q000494:pharmacology*; D010076:Oxazepam / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D014151:Anti-Anxiety Agents; D010076:Oxazepam; D003042:Cocaine; D003345:Corticosterone; D008797:Metyrapone
keywords: Addiction; Adrenalectomy; Benzodiazepine; Cocaine; Metyrapone; Self-administration