Behavioral studies of serotonin receptor agonists as antidepressant drugs

Recent developments in the pharmacology of antidepressant drugs have focused on compounds that enhance the neurotransmission of serotonin (5-hydroxytryptamine; 5-HT), such as 5-HT uptake inhibitors. In addition, the 5-HT1A receptor partial agonist buspirone and other similarly structured compounds termed azapirones are also candidates for antidepressant therapy. The author reviews results from clinical and preclinical studies that support the efficacy of 5-HT1A receptor agonists as antidepressants. Initial clinical trials and animal behavior studies that predict clinical activity of antidepressant drugs have reported evidence favoring the antidepressant-like activity of 5-HT1A receptor partial agonists. Animal behavior studies have also examined the potential neurochemical mechanisms underlying the antidepressant effects of buspirone and related compounds. Evidence is reviewed that the antidepressant activity may be due to the activation of postsynaptic 5-HT1A receptors, although 5-HT1A receptor agonists also activate somatodendritic autoreceptors which diminish the release of 5-HT. Evidence does not support the involvement of a common metabolite 1-PP in the antidepressant activity of 5-HT1A receptor-selective azapirones. Few studies have examined the effects of chronic administration of 5-HT1A receptor agonists and their potential interaction with other receptors, such as 5-HT2 receptors.