Antidepressant Drug-induced Changes in Brain β-Adrenergic Receptors : Subcellular Studies

Abstract

Many recent studies of neurotransmitter receptors have investigated the processes involved in receptor change and several workers have reported that when tissues become desensitized, receptors are removed from the cell plasma membrane and appear inside the cell. These internalized receptors are detectable as the “light-density vesicular fraction” when cell homogenates are centrifuged to equilibrium on continuous sucrose gradients. In the present study, we examined the effects of antidepressant drugs on the binding of a β-adrenergic antagonist to various fractions of rat brain isolated by density gradient centrifugation. Specifically, the distribution of binding of [³H] -dihydroalprenolol in sucrose gradients (0.2-2.0 M) containing rat brain cortical homogenates centrifuged to equilibrium (110, 000 × g/6 hours), was examined in controls and after various antidepressant drug treatments. There was no significant change in the number or distribution of, β-adrenergic receptors in rat brain following the acute drug treatments. However, there was a significant decrease (29%) in β-adrenergic receptor number following a chronic desipramine regimen, but no apparent alteration in the density of the receptor-containing membranes, each sample having a maximum distribution at approximately 1.1 M sucrose. Non-specific binding was maximal at 0.7 M sucrose. There were two protein peaks in the sucrose gradient, one corresponding to the non-specific and the other to the specific binding maxima; electron microscopy showed that a significant degree of non-specific binding to a myelin-containing fraction occurred and that the fraction containing most of the specific binding was composed of membrane fragments. Na⁺K⁺-ATPase activity gave a single broad peak (maximum at 1.1 M sucrose). Thus, desensitization of the β-adrenergic receptor does not occur following acute exposure to antidepressant drugs. Secondly, desensitization of the β-adrenergic receptor following chronic antidepressant administration does not apparently result in migration of receptors into the “light-density fraction” which has been reported to be present following acute exposure to agonists in vitro.