Effects of antidepressants in rats trained to discriminate centrally administered isoproterenol

Previous work has shown that the discriminative stimulus effects of centrally administered isoproterenol are mediated primarily via beta1-adrenergic receptors. In the present study, this model was used to investigate the ability of antidepressant drugs displaying various pharmacological profiles to stimulate beta1-adrenergic receptors in vivo; this was assessed by determining whether they substituted for the discriminative stimulus effects of isoproterenol. Rats were trained to discriminate centrally administered isoproterenol (10 microg i.c.v.) from artificial cerebral spinal fluid using a water-reinforced, two-lever operant task (fixed ratio 10 schedule). After acquisition of the discrimination, drugs were tested for substitution (i.p.). The tricyclic antidepressants protriptyline and desipramine, the norepinephrine uptake inhibitor nisoxetine, the monoamine oxidase inhibitor phenelzine, and the atypical antidepressants bupropion, mirtazapine, and venlafaxine all produced greater than 90% isoproterenol-appropriate responding. The serotonin uptake inhibitor fluoxetine, the atypical antidepressants buspirone and trazodone, and the novel, putative antidepressants N(G)-nitro-L-arginine and N-acetyl-L-tryptophan 3,5-bis benzyl ester failed to substitute for isoproterenol at the dose ranges tested. Antagonism studies carried out with betaxolol for those drugs that fully generalized to isoproterenol's cue verified mediation by beta1-adrenergic receptors. The present results indicate that drugs with noradrenergic activity generalize to isoproterenol's discriminative stimulus. Although this suggests a role for central beta1-adrenergic receptors in the mechanism of action of certain antidepressant drugs, it does not seem that stimulation of these receptors is an effect shared by antidepressants from all pharmacological classes.