title: Role of GABA-active neurosteroids in the efficacy of metyrapone against cocaine addiction.
abstract: Previous research has demonstrated a complicated role for stress and HPA axis activation in potentiating various cocaine-related behaviors in preclinical models of drug dependence. However, the investigation of several antiglucocorticoid therapies has yielded equivocal results in reducing cocaine-related behaviors, possibly because of varying mechanisms of actions. Specifically, research suggests that metyrapone (a corticosterone synthesis inhibitor) may reduce cocaine self-administration in rats via a nongenomic, extra-adrenal mechanism without altering plasma corticosterone. In the current experiments, male rats were trained to self-administer cocaine infusions and food pellets in a multiple, alternating schedule of reinforcement. Metyrapone pretreatment dose-dependently decreased cocaine self-administration as demonstrated previously. Pharmacological inhibition of neurosteroid production by finasteride had significant effects on cocaine self-administration, regardless of metyrapone pretreatment. However, metyrapone's effects on cocaine self-administration were significantly attenuated with bicuculline pretreatment, suggesting a role for GABA-active neurosteroids in cocaine-reinforced behaviors. In vitro binding data also confirmed that metyrapone does not selectively bind to GABA-related proteins. The results of these experiments support the hypothesis that metyrapone may increase neurosteroidogenesis to produce effects on cocaine-related behaviors.
authors: 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: Christopher D
authors: CD
authors: Schmoutz
authors: Department of Pharmacology, Toxicology & Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Highway, Box 33932, Shreveport, LA 71130, USA.
authors: Glenn F
authors: GF
authors: Guerin
authors: Department of Pharmacology, Toxicology & Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Highway, Box 33932, Shreveport, LA 71130, USA.
authors: Nicholas E
authors: NE
authors: Goeders
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000008:administration & dosage / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy / Q000378:metabolism*; D003216:Conditioning, Operant / Q000187:drug effects; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018120:Finasteride / Q000008:administration & dosage / Q000494:pharmacology; D005502:Food; D058787:GABA-A Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012054:Reinforcement, Psychology; D012646:Self Administration / Q000379:methods
chemical_list: D058891:5-alpha Reductase Inhibitors; D004791:Enzyme Inhibitors; D058787:GABA-A Receptor Antagonists; D018120:Finasteride; D003042:Cocaine; D001640:Bicuculline; D008797:Metyrapone
keywords: Bicuculline; Cocaine; Finasteride; GABA; Metyrapone; Neurosteroid