Abstract

The effects of administering the antidepressant drugs desmethylimipramine and nialamide on the beta-adrenergic receptor-adenylate cyclase system of rat pineal gland were studied. The maximal elevation of cyclic AMP in response to varying concentrations of norepinephrine added in vitro to whole pineal glands was reduced following repeated but not acute administration of desmethylimipramine. Repeated administration of desmethylimipramine also reduced the norepinephrine-induced stimulation of adenylate cyclase activity in pineal gland homogenates. Neither acute nor repeated doses of desmethylimipramine had any significant effect on cyclic AMP phosphodiesterase activity of pineal gland. The loss of norepinephrine sensitivity of the adenylate cyclase system following repeated doses of desmethylimipramine was accompanied by a decreased density of beta-adrenergic receptors, as measured by the specific binding of [³H]dihydroalprenolol. This loss of adrenergic receptors may be related to the action of this drug in blocking the reuptake of norepinephrine into the adrenergic nerve terminals, since the effects of desmethylimipramine were prevented in animals whose pineal glands had been sympathetically denervated by ganglionectomy. Repeated but not acute doses of the monoamine oxidase inhibitor, nialamide, also decreased the binding of [³H]dihydroalprenolol in pineal glands and decreased the accumulation of cyclic AMP in response to intraperitoneal administration of isoproterenol. These findings provide further evidence that excessive noradrenergic input produces a compensatory reduction in the number of postsynaptic beta-adrenergic receptors, which, in turn, causes a decreased sensitivity of the norepinephrine-stimulated adenylate cyclase system. They suggest further that the mechanism by which antidepressant drugs exert their clinical effects should be re-evaluated, since following repeated administration they produce a reduced, rather than enhanced, responsiveness to noradrenergic stimuli.