The effects of antidepressant drugs on adenylyl cyclase linked beta adrenergic binding sites on mouse astrocytes in primary cultures

Abstract

1. 1) It has been widely reported that the chronic administration of antidepressant drugs induces a down regulation of beta receptors in the brains of experimental animals with a time course that parallels the therapeutic improvement seen in depressed patients given these drugs. It has been tacitly assumed that these beta receptors are located on neurons. 2. 2) All classes of antidepressant drugs tested, various monoamine uptake inhibitors, a monoamine oxidase inhibitor, or novel drugs lacking either of these actions, reduced the retention of dihydroalprenolol by intact astrocytes in primary cultures. The drug concentrations altering this retention by astrocytes (K i) are in the same range as those reported by other investigators using homogenates of glioma cells or whole brain. 3. 3) The isoproterenol-induced stimulation of cyclic AMP formation by astrocytes in primary cultures is reduced acutely by the antidepressants amitriptyline, tranylcypromine and doxepin. Following washout of the antidepressant drug, isoproterenol stimulation of adenylyl cyclase is reduced in astrocytes exposed in culture to amitriptyline or tranylcypromine for 12–14 days or longer but is not altered in astrocytes exposed to the antidepressants for only 5 days. 4. 4) This indicates that the chronic exposure of astrocytes in culture to antidepressant drugs, down regulates astrocyte beta receptors with a time course that parallels the beta down regulation seen in vivo in animal brain homogenates and the therapeutic improvement seen in depressed patients. The possible functional aspects of drug astrocyte interactions must be considered in any hypothesis concerning drug-brain interactions.