title: A therapeutic combination of metyrapone and oxazepam increases brain levels of GABA-active neurosteroids and decreases cocaine self-administration in male rats.
abstract: In rodents, the behavioral and neurochemical effects resulting from the pharmacological blockade of the hypothalamo-pituitary-adrenal (HPA) axis are unclear. Metyrapone, a corticosterone synthesis inhibitor, has been demonstrated to reduce cocaine-related behaviors, especially in a low-dose combination with oxazepam, a benzodiazepine. Although this combination therapy (MET/OX) also reduces drug-taking and drug-seeking behaviors in both rodents and cocaine-dependent humans, these effects are not correlated with plasma glucocorticoid levels. In this brief report, we present data demonstrating that this MET/OX combination enhances brain levels of the GABA-active steroid metabolites, tetrahydrodeoxycorticosterone (THDOC) and allopregnanolone. Male rats, trained to self-administer cocaine or that received yoked-saline infusions, were pretreated with MET/OX, at doses that reduced cocaine-motivated responding, or vehicle. Allopregnanolone and THDOC were measured using liquid chromatography-mass spectroscopy (LC-MS/MS) in the prefrontal cortex and amygdala in the brains from these rats. THDOC levels were enhanced following MET/OX pretreatment in both brain regions, regardless of cocaine self-administration experience. However, allopregnanolone was selectively enhanced in the rats that self-administered cocaine, but not in rats in the yoked-saline group. Thus, the MET/OX combination increased neurosteroid content in brain regions important for drug addiction. These neurosteroids have been shown to reduce cocaine-related behaviors and may contribute to the behavioral effects of MET/OX combination therapy.
authors.affiliation: Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA. Electronic address: cschm1@lsuhsc.edu.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Schmoutz
authors.affiliation: Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA. Electronic address: ggueri@lsuhsc.edu.
authors.forename: Glenn F
authors.initials: GF
authors.lastname: Guerin
authors.affiliation: Organic and Medicinal Chemistry, Research Triangle Institute, 3040 Cornwallis Drive, Research Triangle Park, NC 27709, USA. Electronic address: srunyon@rti.org.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Runyon
authors.affiliation: Organic and Medicinal Chemistry, Research Triangle Institute, 3040 Cornwallis Drive, Research Triangle Park, NC 27709, USA. Electronic address: sdhungana@rti.org.
authors.forename: Suraj
authors.initials: S
authors.lastname: Dhungana
authors.affiliation: Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA. Electronic address: ngoede@lsuhsc.edu.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Goeders
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism; D003900:Desoxycorticosterone / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology; D018757:GABA Modulators / Q000494:pharmacology*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology*; D009042:Motivation / Q000187:drug effects / Q000502:physiology; D010076:Oxazepam / Q000494:pharmacology*; D011280:Pregnanolone / Q000378:metabolism; D017208:Rats, Wistar; D012646:Self Administration
chemical_list: D018765:Dopamine Uptake Inhibitors; D018757:GABA Modulators; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D010076:Oxazepam; D011280:Pregnanolone; D003042:Cocaine; D008797:Metyrapone
keywords: Allopregnanolone; Cocaine; Metyrapone; Neurosteroids; Oxazepam; Tetrahydrodeoxycorticosterone