Regulation of central 5-HT2A receptors: a review of in vivo studies.

Numerous investigations have studied in vivo regulation of central 5-HT2A receptors. The majority of pharmacological studies point to non-classical regulation of this site. Serotonergic denervation does not modify 5-HT2A receptor density or second messenger responses (phosphoinositide hydrolysis). 5-HT2A receptor downregulation is produced by the chronic administration of 5-HT2A receptor agonists and uniquely among monoamine receptors by antagonists. Several classes of psychotherapeutic agents also downregulate 5-HT2A receptors with chronic administration including classical antidepressants and antipsychotics. 5-HT2A receptor downregulation produced by 5-HT2A antagonists and antidepressants occurs after presynaptic 5-HT denervation, suggesting that 5-HT2A receptors are postsynaptically localized and emphasizing that they are regulated differently than traditional monoaminergic receptors. Interestingly, the behavioral and biochemical effects of 5-HT2A receptor activation are modulated by activity at other 5-HT receptor subtypes (5-HT1A), as well as by stimulation of receptors for other neurotransmitters and hormones such as norepinephrine (beta-adrenergic) and melatonin. It is suggested that these diverse modulatory influences on 5-HT2A receptor regulation and function may meaningfully impact the therapeutic actions of drugs, including pharmacologically distinct antidepressants.