title: Catecholamine response to methamphetamine is related to glucocorticoid levels but not to pleasurable subjective response.
abstract: BACKGROUND
  Corticosteroids may modulate addiction. We previously described subjective, physiological, and endocrine effects of 0.5 mg/kg of intravenous methamphetamine after augmenting cortisol level with hydrocortisone or blocking cortisol response with the corticosteroid synthesis inhibitor metyrapone in a double-blind, balanced crossover study. Although the pharmacologic manipulations produced the expected hormonal changes, pleasurable subjective effects of methamphetamine were unchanged. Metyrapone was followed by frequent premature ventricular complexes (PVCs) in two subjects during methamphetamine administration. In order to better understand these results, we examined changes in two plasma catecholamine metabolites, homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), and their relationship to the previously reported hormonal changes and physiological and subjective responses.
  
  
  METHODS
  Plasma from 10 methamphetamine subjects from the earlier study was assayed for HVA and MHPG by high performance liquid chromatography.
  
  
  RESULTS
  HVA levels were greater after hydrocortisone or metyrapone pretreatment compared to placebo, and MHPG levels were greater after metyrapone pretreatment. Hydrocortisone pretreatment diminished HVA and MHPG increases after methamphetamine (perhaps explaining the lack of expected increase in pleasurable effects), but metyrapone did not. HVA and MHPG concentrations were not correlated with pleasurable drug effects but were inversely related to reports of "Bad Drug Effect." Increases in MHPG and DHEA concentrations were positively correlated. Metyrapone pre-treated subjects with PVCs had lower HVA and MHPG concentrations.
  
  
  CONCLUSIONS
  Raising cortisol concentration and blocking cortisol synthesis did not produce opposite effects, perhaps because of metyrapone's effect on the hypothalamic-pituitary-adrenal axis, its stress-like effects, and its effects on neurosteroids.
authors.affiliation: Department of Psychiatry and Tri-State Tobacco and Alcohol Research Center, University of Cincinnati and Cincinnati VA Medical Center, Cincinnati, OH 45220, USA. debra.harris4@va.gov
authors.forename: D S
authors.initials: DS
authors.lastname: Harris
authors.forename: V I
authors.initials: VI
authors.lastname: Reus
authors.forename: O
authors.initials: O
authors.lastname: Wolkowitz
authors.forename: P
authors.initials: P
authors.lastname: Jacob
authors.forename: E T
authors.initials: ET
authors.lastname: Everhart
authors.forename: M
authors.initials: M
authors.lastname: Wilson
authors.forename: J E
authors.initials: JE
authors.lastname: Mendelson
authors.forename: R T
authors.initials: RT
authors.lastname: Jones
mesh_terms: D000328:Adult; D001143:Arousal / Q000187:drug effects*; D018592:Cross-Over Studies; D003913:Dextroamphetamine / Q000494:pharmacology*; D004311:Double-Blind Method; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D006719:Homovanillic Acid / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000037:antagonists & inhibitors / Q000097:blood* / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000097:blood; D008797:Metyrapone / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000187:drug effects; D011292:Premedication; D012201:Reward
chemical_list: D008734:Methoxyhydroxyphenylglycol; D003913:Dextroamphetamine; D006854:Hydrocortisone; D006719:Homovanillic Acid; D008797:Metyrapone