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

Abstract

Rationale: Racemic propranolol (PRO), a β-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. Materials and 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 (ED50∈=∈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 β-adrenoceptor agent pindolol, the α1-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 α1-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 α1-adrenoceptor activity. PRO might be better characterized as an adrenoceptor partial agonist. © 2008 Springer-Verlag.