Effect of Chronic Serotonin-2 Receptor Agonist or Antagonist Administration on Serotonin-1A Receptor Sensitivity

Abstract

We have investigated the effect of 5-HT 2 receptor agonist or antagonist administration on postsynaptic 5-HT 1A receptor sensitivity assessed by two behavioral measures, reciprocal forepaw treading or hypothermia induced by acute injection of the 5-HT 1A receptor agonist 8-OH-DPAT. The effectiveness of these drug treatments to downregulate 5-HT 2A receptors was confirmed by measuring the binding of [ 3 H]-ketanserin in cortical homogenates, because all of these drug treatments have been shown to result in the downregulation of 5-HTOf some 14 subtypes of receptor for the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) (see Hoyer et al. 1994), a tremendous amount of attention has been focused on the serotonin 1A (5-HT 1A ) receptor subtype. Drugs that act as agonists at this receptor have proved useful clinically as antidepressants (see Murphy et al. 1995) and anxiolytics (Coplan et al. 1995). The unique distribution of this serotonin receptor subtype in brain is consistent with its potential involvement in cognitive or integrative functions, as well as in emotional states. In terminal field areas of serotonergic innervation, the 5-HT 1A receptor is located postsynaptically and is present in high density in cortical and limbic structures (i.e., hippocampus, entorhinal cortex, septum, amygdala, frontal cortex) (Vergé et al. 1986;Hensler et al. 1991;Khawaja 1995). The 5-HT 1A receptor is also found in high density in serotonin cell body areas, such as the dorsal and median raphé, where it is believed to function as the somatodendritic autoreceptor modulating the activity of serotonergic neurons (see Aghajanian et al. 1990).The sensitivity of behavioral (Goodwin et al. 1987;Hensler et al. 1991;Wieland et al. 1993;Maj et al. 1996) and electrophysiological (Blier and deMontigny 1983, Received June 16, 1997; revised December 15, 1997; accepted February 16, 1998. N EUROPSYCHOPHARMACOLOGY 1998 -VOL . 19 , NO . 5 Modulation of 5-HT 1A Receptor Sensitivity 355 1985 responses mediated by the 5-HT 1A receptor is decreased after chronic administration of 5-HT 1A receptor agonists or antidepressants drugs. The desensitization of 5-HT 1A receptor-mediated responses has also been reported to occur after acute or short-term agonist administration (Kennett et al. 1987;Larsson et al. 1990). Although some investigators have reported changes in 5-HT 1A receptor number following agonist or antidepressant treatments (Welner et al. 1989;Fanelli and McMonagle-Strucko 1992), in many cases desensitization of 5-HT 1A receptor-mediated responses has not been found to be accompanied by a decrease 5-HT 1A receptor number (Larsson et al. 1990;Schecter et al. 1990;Hensler et al. 1991;Wieland et al. 1993). Changes in 5-HT 1A receptor second messenger function have not been consistently reported to follow administration of antidepressants or 5-HT 1A receptor agonists (Sleight et al. 1988;Varrault et al. 1991;Newman et al. 1992).Interactions between serotonin receptor subtypes have been observed in behavioral studies. For example, 5...

Desensitization of 5-HT1AReceptors by 5-HT2AReceptors in Neuroendocrine Neurons in Vivo

“…Our previous studies in rats indicate that a single administration of the 5-HT 2A receptor agonist DOI induces a functional desensitization of 5-HT 1A receptors that regulate the secretion of ACTH and oxytocin. Studies from other laboratories (Hensler and Truett, 1998;Valdez et al, 2002) indicate that repeated daily injections of DOI also produce a desensitization of 5-HT 1A receptor-induced hypothermia. Furthermore, repeated daily injections of DOI reduce the coupling between 5-HT 1A receptors and G proteins in the anterior cingulate cortex (Valdez et al, 2002).…”

“…Studies in cell culture and in vivo suggest that a two-way interaction exists between 5-HT 1A and 5-HT 2A receptors (Darmani et al, 1990;Pranzatelli and Pluchino, 1991;Eison et al, 1993;Eison and Mullins, 1995;Maswood et al, 1996;Hensler and Truett, 1998;Krebs-Thomson and Geyer, 1998;Valdez et al, 2002). One study indicates that 5-HT 1A and 5-HT 2A receptors are expressed by neurons in the frontal cortex (Martin-Ruiz et al, 2001).…”

Mechanisms of Ligand-Induced Desensitization of the 5-Hydroxytryptamine2AReceptor

“…The regulation of the 5-HT 2A receptor, however, does not appear to follow the pattern established for many other G protein-coupled receptors. Repeated administration of agonists (Buckholtz et al, 1988;Anji et al, 2000) as well as antagonists (Blackshear and Sanders-Bush, 1982;Gandolfi et al, 1985;Hensler and Truett, 1998) results in the desensitization and down-regulation of central 5-HT 2A receptors.Given the interest in the role of the 5-HT 2A receptor in the action of many psychoactive drugs and the apparent anomalous regulation of 5-HT 2A receptors by antagonists, including atypical neuroleptics and many antidepressant drugs (Eison et al, 1991;Kuoppamaki et al, 1995), a thorough understanding of the mechanisms that regulate 5-HT 2A receptor function is desirable. In the current study, we have examined the effect of both agonist and antagonist exposure on 5-HT 2A receptor function in C6 glioma cells.…”

“…The regulation of the 5-HT 2A receptor, however, does not appear to follow the pattern established for many other G protein-coupled receptors. Repeated administration of agonists (Buckholtz et al, 1988;Anji et al, 2000) as well as antagonists (Blackshear and Sanders-Bush, 1982;Gandolfi et al, 1985;Hensler and Truett, 1998) results in the desensitization and down-regulation of central 5-HT 2A receptors.…”

The effects of serotonin and ecdysone on primary sensory neurons in crayfish

“…Pharmacological action of agonists or antagonists binding to a receptor can regulate its functional levels (Fone et al, 1998;Kokay and Mercer, 1997;Welner et al, 1989). For example, it has been shown that 5-HT 1A receptors will be desensitized when either an agonist or antagonist is present (Hensler and Truett, 1998). In our laboratory, we have shown alterations in the physiological sensitivity to exogenous application of 5-HT at the crayfish neuromuscular junctions after altering levels of endogenous 5-HT as well as for chronic exposure of a 5-HT agonist .…”