Acute and chronic effects of psychoactive drugs on adrenergic receptors and calmodulin.

The effects that psychoactive compounds have on those biochemical mechanisms of brain that influence the metabolism of cyclic nucleotides depend on whether the drugs are administered acutely or chronically. For example, antipsychotic agents acutely block the action of catecholamines on the adrenergic receptor-adenylate cyclase complex, thereby preventing the catecholamine-induced rise in cyclic AMP. But with long-term treatment, which might correspond more closely to the manner in which they are used clinically, the drugs appear to produce a compensatory increase in these catecholaminergic receptors. Repeated stimulation of adrenergic receptors with compounds that block the uptake of catecholamines, such as the antidepressants, produces a decrease in the number of these receptors and a concomitant subsensitivity to the effects of catecholamines on the formation of cyclic AMP. This is in contrast to their acute actions which result in a potentiation of the action of catecholamines. In addition to their effects on catecholamine receptors, clinically-effective antipsychotic drugs also bind to an endogenous calcium-dependent protein termed calmodulin, which is found in high concentrations in the CNS. This binding of antipsychotics to calmodulin can explain several of their biochemical actions and suggests that some of the pharmacological and perhaps clinical effects of these drugs may also be explained by a common mechanism. In fact, the specificity with which antipsychotic drugs bind to calmodulin suggests the possibility of searching for new and clinically more effective antipsychotic agents based on their selective binding to calmodulin.