Effects of Antidepressants in Rats Trained to Discriminate Centrally Administered Isoproterenol

Abstract

Previous work has shown that the discriminative stimulus effects of centrally administered isoproterenol are mediated primarily via ␤1-adrenergic receptors. In the present study, this model was used to investigate the ability of antidepressant drugs displaying various pharmacological profiles to stimulate ␤1-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 g 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-Larginine 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 ␤1-adrenergic receptors. The present results indicate that drugs with noradrenergic activity generalize to isoproterenol's discriminative stimulus. Although this suggests a role for central ␤1-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.Substantial research has implicated ␤-adrenergic receptors in the mechanism of action of antidepressant drugs. Stimulation of either ␤1-or ␤2-adrenergic receptors is sufficient to produce antidepressant-like effects on behavior in animal models such as learned helplessness, the forced-swim test, and differential-reinforcement-of-low rate (DRL) behavior (Martin et al., 1986;Finnegan et al

Antagonism of the antidepressant-like effects of clenbuterol by central administration of ?-adrenergic antagonists in rats

“…Consistent with this, it has been shown that antidepressant drugs do not substitute for the discriminative stimulus effects of clenbuterol (Makhay and O'Donnell 1999), which suggests that administration of these drugs does not result in increased stimulation of central b 2 -adrenergic receptors. By contrast, antidepressants with noradrenergic activity, such as desipramine, substitute for the discriminative stimulus effects of centrally administered isoproterenol (Crissman and O'Donnell 2002). Since this effect is mediated by b 1 -adrenergic receptors (Crissman et al 2001), it appears that administration of such antidepressants results in increased stimulation of b 1 -adrenergic receptors in vivo.…”

Interaction between the antidepressant-like behavioral effects of beta adrenergic agonists and the cyclic AMP PDE inhibitor rolipram in rats

“…The discriminative stimulus effect of isoproterenol, which is primarily mediated by beta-1 adrenergic receptors (Crissman et al 2001), generalizes to a number of antidepressant drugs (Crissman and O'Donnell 2002), indicating that noradrenergic antidepressants like desipramine indirectly stimulate central beta-1 adrenergic receptors in vivo at behaviorally relevant doses. In rats trained to discriminate the type 4 phosphodiesterase (PDE4) inhibitor rolipram from its vehicle, clenbuterol completely and dobutamine partially substitute .…”

Postsynaptic α-2 Adrenergic Receptors are Critical for the Antidepressant-Like Effects of Desipramine on Behavior

“…Activation of either β-1 or β-2 adrenergic receptors produces antidepressant-like effects on DRL behavior (O’Donnell et al , 1994; Zhang et al , 2001, 2005; Zhang et al , 2003). In addition, desipramine and other NE reuptake inhibitors substitute for the β-adrenergic agonist isoproterenol in a drug discrimination task, indicating that β-adrenergic receptors play a role in mediating the effects of desipramine, as well as other NE reuptake inhibitors (Crissman et al , 2001; Crissman and O’Donnell, 2002). Further, repeated treatment with desipramine downregulates β-1, but not β-2, adrenergic receptors in the brain (Paetsch and Greenshaw, 1993).…”