Comparison of the effects of isoproterenol administered into the hippocampus, frontal cortex, or amygdala on behavior of rats maintained by differential reinforcement of low response rate

Rationale: Central administration of isoproterenol, a non-selective beta adrenergic agonist, produces behavioral changes in animal models sensitive to antidepressants. However, it is not clear which brain regions mediate these effects. Objectives: To investigate the antidepressant-like effects of site-specific administration of isoproterenol and the involvement of beta adrenergic receptor subtypes. Methods: The effects of isoproterenol, which was administered into the lateral ventricle, hippocampus, frontal cortex, or amygdala, were determined in rats under a differential-reinforcement-of-low-rate (DRL) 72-s schedule. The effects of beta adrenergic antagonists on the actions of isoproterenol also were determined. Results: When injected bilaterally into the hippocampus, isoproterenol (1-30 μg/side) decreased response rate and increased reinforcement rate in a dose-dependent manner. The minimum dose of isoproterenol required for changing DRL behavior was 6 μg (i.e., 3 μg bilaterally), compared to 10 μg for intracerebroventricular and 60 μg (30 μg bilaterally) for administration into the frontal cortex or amygdala. These effects of isoproterenol were blocked by the beta adrenergic antagonist propranolol. In addition, the effects of isoproterenol injected intrahippocampally also were antagonized dose-dependently by the beta-1 selective antagonist betaxolol and the beta-2 selective antagonist ICI 118,551. The relative potency of these antagonists for blocking the effects of isoproterenol suggested predominant mediation by beta-1 adrenergic receptors. Conclusions: The hippocampus is an important site involved in mediating the antidepressant-like effect of isoproterenol. This suggests a key, although not exclusive, role for this site in the pathophysiology of depression and its pharmacotherapy.