Multiple serotonin receptors and their physiological significance

Identification of multiple receptors for neurotransmitters has had important theoretical and practical therapeutic relevance. With the advent of receptor-binding techniques, the ability to detect heterogeneity of receptors has been greatly enhanced. There appear to be multiple serotonin (5-HT) receptors in the central nervous system. At least two distinct 5-HT receptors can be differentiated by binding techniques. 5-HT₁ sites are labeled preferentially by [³H]5-HT, whereas [³H]spiroperidol selectively labels 5-HT₂ receptors. 5-HT and other agonists display 50-1000 times greater affinity for 5-HT₁ than 5-HT₂ sites, whereas most known 5-HT antagonists have 100-1000 times greater affinity for 5-HT₂ than 5-HT₁ receptors. Ergot-related drugs, such as LSD and lisuride, have similar affinities for 5-HT₁ and 5-HT₂ receptors. Drug potencies in blocking 5-HT behavioral effects in rodents and in antagonizing vascular effects of 5-HT in several blood vessel systems correlate best with influences on 5-HT₂ receptors. In some adenylate cyclase systems drug effects on the 5-HT response of adenylate cyclase correlate with 5-HT₁ receptor affinity. Chronic treatment with antidepressants lowers the numbers of 5-HT₂ but not 5-HT₁ receptors. With most antidepressants the reduction of 5-HT₂ receptor site number is greater than the reduction in β-adrenergic receptors. Thus, influences of antidepressants on 5-HT₂ receptors may provide a useful predictive test for antidepressant drug action.