Receptor Adaptation & Receptor Cross-Talk
The actions mediated by psychotropic drugs on receptors occur rapidly. These actions do not explain the therapeutic effect that is generally delayed for weeks after initiation of treatment. This discrepancy in the time course, particularly evident with antidepressants, has led to studies on the effect of anti-depressants on more slowly developing receptor-mediated adaptive processes in brain. These studies have revealed that chronic antidepressant treatment (ie, using MAO inhibitors, tricyclic antidepressants, and electroconvulsive therapy) causes a desensitization of the ß-adrenoceptor-coupled adenylate cyclase system in brain, usually associated with downregulation of the density of ß-adrenoceptors. These findings have shifted the focus of research onto the mode of action of antidepressants and the pathophysiology of affective disorders, from acute presynaptic to delayed postsynaptic adaptive processes in the cascade of signal transduction. Besides causing adaptations at the ß-adrenoceptor, chronic administration of antidepressants alters the density of various subtypes of 5-HT receptors (eg, 5-HT2A, 5-HT1A, and 5-HT1B).
Persistent blockade of dopamine D2 receptors by antipsychotic drugs causes an upregulation of the density of this subtype of dopamine receptors. Upregulation of D2 receptors has often been associated with the development of tardive dyskinesia (hypersensitivity to dopamine in the striatum). Clozapine, a weak D2 blocker, does not cause upregulation of D2 receptors and is less likely to produce tardive dyskinesia. Research into the action of antipsychotic drugs has focused on excitatory amino acids, particularly the interaction of dopamine systems with glutamate systems. After chronic (but not acute) administration, antipsychotic drugs alter the levels of expression of specific glutamate receptor subunits and extracellular levels of glutamate in specific areas of the brain. Dopamine-glutamate interactions have been implicated in the regulation of conditional, emotional, and motivational aspects of motor function in the mammalian CNS.
