title: Noradrenergic modulation of the discriminative-stimulus effects of methamphetamine in rats.
abstract: BACKGROUND
  Neurochemical and clinical studies indicate involvement of noradrenergic (NE) neurotransmitter system in the actions of methamphetamine.
  
  
  OBJECTIVE
  The present study investigated NE involvement in the discriminative-stimulus effects of methamphetamine.
  
  
  METHODS
  In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine, IP, from saline under a fixed-ratio schedule of food presentation, effects of various NE agonists, antagonists and uptake inhibitors were tested.
  
  
  RESULTS
  Desipramine (3.0-18.0 mg/kg) and nisoxetine (5.6-30.0 mg/kg), two selective NE-uptake inhibitors, did not significantly generalize to methamphetamine when administered alone, but 5.6 mg/kg desipramine and 10.0 mg/kg nisoxetine significantly shifted the methamphetamine dose-response curve to the left. The beta NE agonist, isoproterenol (0.56-3.0 mg/kg), and antagonist, propranolol (1.0-18.0 mg/kg), neither generalized to methamphetamine when given alone nor altered the discriminative-stimulus effects of methamphetamine when administered in combination. The alpha- NE agonist methoxamine (1.0-5.6 mg/kg) failed to generalize to the methamphetamine training stimulus. When given in combination with methamphetamine, the alpha-1 NE antagonist, prazosin (1.0 mg/kg), shifted the methamphetamine dose-response curve somewhat to the right and partially blocked the discriminative-stimulus effects of the 1.0 mg/kg training dose of methamphetamine, but these changes were not significant or dose-related, with further increases in prazosin dose (1.8-10.0 mg/kg) either producing similar or smaller changes. The alpha-2 NE agonist, clonidine, partially generalized to methamphetamine at doses of 0.1-0.18 mg/kg and increased drug-appropriate responding at lower doses of methamphetamine, but it partially blocked the discriminative-stimulus effects of higher 0.56-1.0 mg/kg doses of methamphetamine over the same dose range. The alpha-2 NE antagonist, yohimbine, also partially generalized to methamphetamine and blocked the discriminative-stimulus effects of the 1.0 mg/kg training dose of methamphetamine at doses of 5.6-10.0 mg/kg. A lower 3.0 mg/kg dose of yohimbine increased methamphetamine-appropriate responding when given together with low 0.1-0.3 mg/kg doses of methamphetamine.
  
  
  CONCLUSIONS
  The present data suggest that the NE system plays a modulatory role in the discriminative-stimulus effects of methamphetamine. These effects appear to be mediated through NE uptake sites and alpha-2 receptors, with limited involvement of alpha- receptors and beta receptors.
authors.affiliation: Preclinical Pharmacology Laboratory, National Institutes of Health, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: P
authors.initials: P
authors.lastname: Munzar
authors.forename: S R
authors.initials: SR
authors.lastname: Goldberg
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology*; D000818:Animals; D004193:Discrimination Learning / Q000187:drug effects*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects
chemical_list: D018663:Adrenergic Agents; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D008694:Methamphetamine