Discriminative stimulus effects of centrally administered isoproterenol inrats: mediation by beta-1 adrenergic receptors

Rationale. Centrally active beta-1 and beta-2 adrenergic agonists produce a ntidepressant-like effects in several behavioral tests, suggesting that the se receptors may be involved in the mediation of the effects of antidepress ant drugs. Objectives: This study aimed to evaluate the ability of intra-ce rebral ventricular (ICV) isoproterenol to produce discriminative stimulus e ffects mediated by beta adrenergic receptors, establishing a reliable model of in vivo activation of central beta adrenergic receptors. Methods: Rats were trained to discriminate the non-selective beta adrenergic agonist isop roterenol (10 mug ICV) from artificial cerebral spinal fluid (aCSF) using a water-reinforced two-lever operant task [fixed ratio-10 schedule of reinfo rcement (FR10)]. For substitution and antagonism tests, drugs were administ ered IF. Results: Following acquisition of the discrimination, ICV isoprote renol produced dose-related increases in drug-appropriate responding (ED50= 1.14 mug) The beta-1 selective adrenergic agonist dobutamine fully substitu ted for isoproterenol at a dose of 0.3 mg/kg (ED50=0.15 mg/kg). By contrast , the beta-2 selective adrenergic agonist clenbuterol produced 20% isoprote renol-appropriate responding when administered at doses up to 0.1 mg/kg. Th e beta adrenergic antagonist propranolol fully antagonized the isoprotereno l cue at a dose of 0.03 mg/kg (ID50=0.013 mg/kg). The beta-1 selective anta gonist betaxolol (ID50=0.03 mg/kg) more potently antagonized isoproterenol' s cue than did the beta-2 selective antagonist ICI 118,551 (ID50=0.41 mg/kg ). The antidepressant desipramine (1.0 mg/kg) substituted for isoproterenol . Conclusions: These results demonstrate that the discriminative stimulus e ffects of isoproterenol are mediated primarily via beta-1 adrenergic recept ors. This provides a functional model for activation of central beta-1 adre nergic receptors, permitting further characterization of the role of this r eceptor subtype in the mechanism of action of antidepressant drugs.