Influence of adrenocorticotropin hormone and yohimbine on antidepressant-induced declines in rat brain neurotransmitter receptor binding and function

Chronic (1-3 weeks), but not acute, administration of antidepressants leads to a reduction in beta adrenergic and serotonin₂ receptor binding in rat brain frontal cortex. This effect is thought to be secondary to the antidepressant-induced enhancement in monoaminergic transmission inasmuch as administration of yohimbine, an alpha-2 adrenergic receptor antagonist, in combination with some tricyclic drugs shortens the amount of time necessary to observe the decline in beta receptor binding. There have also been reports that hormones, such as adrenocorticotropin (ACTH), can influence the neurotransmitter receptor responses to these drugs. The aim of the present study was to characterize these interactions further in an attempt to better understand the mechanisms involved. Thus, it was found that yohimbine or ACTH can modify the receptor changes brought on by only certain antidepressants and that yohimbine causes a more rapid (3 days) decline in serotonin₂ as well as beta adrenergic receptor binding in rat brain frontal cortex. In those cases in which ACTH accelerated the beta receptor response to antidepressants, the receptor decline is no greater than that observed after long-term (>1 week) treatment with the drug alone and the ACTH effect is not readily reversible. Experiments with ACTH_4-10 reveal that the peptide modifies the receptor sites by a direct action in brain, rather than through release of adrenal hormones. The rapid decrease in beta receptor binding observed after these treatments appears to have functional significance because there is a concomitant decline in the potency of norepinephrine to stimulate cyclic AMP accumulation in this brain area. Moreover, by itself, ACTH reduces brain beta receptor activity without altering recognition site binding. The results suggest that these agents alter neurotransmitter receptor number and function by different mechanisms, and support the contention that drug response may be dependent, in part, on the hormonal state of the subject.