S(−)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats

Abstract

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. Rats were trained to discriminate S(-)PRO (5 mg/kg) from saline in a two-lever food-reinforced operant conditioning task. 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. 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.