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

Abstract.

Rationale: Centrally active beta-1 and beta-2 adrenergic agonists produce antidepressant-like effects in several behavioral tests, suggesting that these receptors may be involved in the mediation of the effects of antidepressant drugs. Objectives: This study aimed to evaluate the ability of intra-cerebral ventricular (ICV) isoproterenol to produce discriminative stimulus effects 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 isoproterenol (10 µg ICV) from artificial cerebral spinal fluid (aCSF) using a water-reinforced two-lever operant task [fixed ratio-10 schedule of reinforcement (FR10)]. For substitution and antagonism tests, drugs were administered IP. Results: Following acquisition of the discrimination, ICV isoproterenol produced dose-related increases in drug-appropriate responding (ED₅₀=1.14 µg). The beta-1 selective adrenergic agonist dobutamine fully substituted 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% isoproterenol-appropriate responding when administered at doses up to 0.1 mg/kg. The beta adrenergic antagonist propranolol fully antagonized the isoproterenol cue at a dose of 0.03 mg/kg (ID₅₀=0.013 mg/kg). The beta-1 selective antagonist 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 effects of isoproterenol are mediated primarily via beta-1 adrenergic receptors. This provides a functional model for activation of central beta-1 adrenergic receptors, permitting further characterization of the role of this receptor subtype in the mechanism of action of antidepressant drugs.