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

Abstract

Stimulation of central beta(2) adrenergic receptors produces antidepressant-like effects on behavior. At present, it is not known what brain sites are involved in mediating such effects, although some recent evidence suggests the importance of the dorsal hippocampus. Experiments were carried out to determine whether central administration of beta-adrenergic antagonists blocks antidepressant-like effects produced by peripheral administration of the beta(2)-adrenergic agonist clenbuterol. The following were determined: 1) the ability of ICV or intrahippocampal administration of the non-selective beta adrenergic antagonists propranolol and CGP-12177, which are lipophilic and hydrophilic, respectively, to antagonize the effects of peripherally administered clenbuterol on differential-reinforcement-of-low-rate (DRL) behavior; 2) the effects of clenbuterol, administered bilaterally into the dorsal hippocampus, on DRL behavior. The antidepressant-like effects of clenbuterol, i.e. reduced response rate and increased reinforcement rate under the DRL schedule, were antagonized by either ICV or bilateral intrahippocampal infusions of propranolol or CGP-12177; CGP-12177 was approximately 8-fold more potent than propranolol. Direct infusion of clenbuterol into the bilateral dorsal hippocampus also produced antidepressant-like effects. Central beta-adrenergic receptors, in particular those in the dorsal hippocampus, are involved in the mediation of the antidepressant-like effect of clenbuterol. Probably resulting from its enhanced access to the sites of action, the hydrophilic antagonist CGP-12177 was more potent than the lipophilic antagonist propranolol, even though they exhibit similar potency in vitro.