Antidepressant and anxiolytic action on the Serotonin1A binding site

Abstract

Several lines of evidence suggest an involvement of serotonin$sb{ rm 1A}$ (5-HT$sb{ rm 1A}$ receptors in the regulation of emotions. In order to investigate the molecular basis of recent electrophysiological findings which implicated 5-HT$sb{ rm 1A}$ receptors in the mechanism of action of antidepressants and anxiolytics, radioligand binding and autoradiographic studies using tritiated 8-hydroxy-2-(di-N-propylamino)-tetralin ( ($sp3$H) -8-OH-DPAT) were done in rat brain following various treatments. These included: the tricyclic antidepressant imipramine; the reuptake blockers paroxetine and indalpine; the monoamine oxidase inhibitor clorgyline; electroconvulsive shock; lithium; the classic benzodiazepine diazepam; and the 5-HT$sb{ rm 1A}$ partial agonist gepirone. None of these treatments, nor the fluctuation in 5-HT availability provoked by the circadian cycle, gave any significant changes, with the exception of clorgyline which initially appeared to decrease the affinity of ($sp3$H) -8-OH-DPAT for its receptor. A further series of studies in vitro and in vivo ascertained the possibility that the 5-HT$sb{ rm 1A}$ receptors may display two interconvertible affinity states and that, in fact, clorgyline induces a shift of the high to the lower affinity state. The findings from this second series of experiments suggested that labile changes, which may possibly be disrupted during membrane preparation, in the coupling between the 5-HT$sb{ rm 1A}$ receptor and a guanine nucleotide binding protein (G-protein) may account for the effects that certain treatments have on 5-HT$sb{ rm 1A}$ receptor responsiveness