title: S(-)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats.
abstract: BACKGROUND
  Racemic propranolol (PRO), a beta-adrenoceptor antagonist, has been evaluated as a test agent but not as a discriminative stimulus. Its S(-) stereoisomer is thought to subserve the effects of (+/-)PRO.
  
  
  METHODS
  Rats were trained to discriminate S(-)PRO (5 mg/kg) from saline in a two-lever food-reinforced operant conditioning task.
  
  
  RESULTS
  The S(-)PRO stimulus was shown to be centrally mediated, dose-related, time dependent, and stereoselective: S(-)PRO (ED(50) = 2.2 mg/kg) was twice as potent as (+/-)PRO and approximately four times as potent as R(+)PRO. The S(-)PRO stimulus generalized fully to the beta-adrenoceptor agent pindolol, the alpha(1)-adrenoceptor agonist methoxamine, cocaine, and the serotonergic agents TFMPP and RU 24969; partial generalization occurred to (-)ephedrine and nisoxetine but not to fenfluramine or 5-OMe DMT. The S(-)PRO stimulus was blocked completely (and competitively) when prazosin, an alpha(1)-adrenoceptor antagonist, was given in combination with the training dose of S(-)PRO. Moreover, prazosin exerted antagonism of the S(-)PRO-like effect of (+/-)PRO or R(+)PRO but produced only partial antagonism of the S(-)PRO-like effect of cocaine. In a second study, rats were trained to discriminate 8 mg/kg of cocaine from saline. The cocaine stimulus generalized to S(-)PRO, (+/-)PRO, and R(+)PRO. Prazosin partially attenuated the stimulus effect of cocaine (8 mg/kg) but completely blocked the cocaine-like effects of (+/-), S(-), and R(+)PRO.
  
  
  CONCLUSIONS
  PRO and cocaine exhibited cross-substitution, but their stimulus effects were antagonized differentially by prazosin. PRO (and its optical isomers) can exert a stimulus effect that is based, at least in part, on increased alpha(1)-adrenoceptor activity. PRO might be better characterized as an adrenoceptor partial agonist.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia Campus, Virginia Commonwealth University, 410 North 12th St., P. O. Box 980540, Richmond, VA 23298-0540, USA. ryoung@vcu.edu
authors.forename: Richard
authors.initials: R
authors.lastname: Young
authors.forename: Richard A
authors.initials: RA
authors.lastname: Glennon
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D011433:Propranolol / Q000737:chemistry / Q000494:pharmacology*; D011600:Psychopharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
chemical_list: D000316:Adrenergic alpha-Agonists; D000319:Adrenergic beta-Antagonists; D011433:Propranolol; D003042:Cocaine
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