A Therapeutic Combination of Metyrapone and Oxazepam Increases Brain Levels of GABA-active Neurosteroids and Decreases Cocaine Self-Administration in Male Rats

Behav Brain Res. 2015 Sep 15;291:108-111. doi: 10.1016/j.bbr.2015.05.019. Epub 2015 May 21.

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.

Keywords: Allopregnanolone; Cocaine; Metyrapone; Neurosteroids; Oxazepam; Tetrahydrodeoxycorticosterone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects*
  • Brain / metabolism
  • Cocaine / administration & dosage
  • Cocaine-Related Disorders / drug therapy*
  • Cocaine-Related Disorders / metabolism
  • Desoxycorticosterone / analogs & derivatives
  • Desoxycorticosterone / metabolism
  • Disease Models, Animal
  • Dopamine Uptake Inhibitors / administration & dosage
  • Drug-Seeking Behavior / drug effects*
  • Drug-Seeking Behavior / physiology
  • GABA Modulators / pharmacology*
  • Male
  • Metyrapone / pharmacology*
  • Motivation / drug effects
  • Motivation / physiology
  • Oxazepam / pharmacology*
  • Pregnanolone / metabolism
  • Rats, Wistar
  • Self Administration

Substances

  • Dopamine Uptake Inhibitors
  • GABA Modulators
  • Desoxycorticosterone
  • tetrahydrodeoxycorticosterone
  • Oxazepam
  • Pregnanolone
  • Cocaine
  • Metyrapone