Mechanisms of action of antidepressant drugs: Presynaptic and postreceptor mechanisms.

Abstract

The etiology of clinical depression is unknown, but thought to be related to an impairment in brain transmission of monoamines. Depression is treated with antidepressant drugs which, regardless of classification, ultimately result in increased efficacy of aminergic transmission. Tricyclic antidepressants are known to inhibit the presynaptic uptake of amines. [3H]Imipramine, the prototype tricyclic antidepressant and a potential biological marker in depression, binds to both high- and a low-affinity sites in the brain. The high-affinity binding of [3H]imipramine to its binding site on the serotonin (5-HT) neuronal transporter has been shown to be a sodium-dependent process. However, that of [3H]paroxetine, a novel and selective 5-HT uptake inhibitor, has not yet been investigated. Because of a discrepancy between the onset of uptake-blocking effect and alleviation of depressive symptoms, the blockage of uptake is probably not the only pharmacological action of antidepressants underlying their clinical effect. Recent studies have reported decreases in beta-adrenoceptor and 5-HT2 receptor numbers following long-term treatment with antidepressants, and suggested that an adaptive change in amine receptors may be more relevent for the clinical effect. However, not all 5-HT uptake inhibitors elicit this downregulation. Recent research has thus centred on elucidating changes in the signal transduction apparatus of aminergic neurons. The 5-HT2 receptor in the brain is coupled to the phosphoinositide turnover cascade and protein kinase C (PKC) activity. The subcellular distribution of PKC following chronic antidepressant treatment has not yet been investigated. This study was undertaken (1) To compare the sodium dependence of [3H]paroxetine binding and [3H]5-HT uptake in rat diencephalon in order to confirm whether paroxetine binds to the 5-HT recognition site on the transporter, and (2) to investigate the effects of both acute and chronic antidepressant treatment on PKC location and activity (both basal and 5-HT2 receptor agonist (DOI)-challenged) in rat cortex and hippocampus. Results indicate that, antidepressant drugs induce differing but significant effects on PKC activity in the subcellular fractions of neurons both after acute and chronic treatment. These changes in PKC activity may alter transduction of cellular signals evoked by the binding of 5-HT to receptors. (Abstract shortened by UMI.)