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

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 microg 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 microg). 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.