Neuroendocrine Evidence That (S)-2-(Chloro-5-fluoro-indol- l-yl)-1-methylethylamine Fumarate (Ro 60-0175) Is Not a Selective 5-Hydroxytryptamine_2C Receptor Agonist

Abstract

The 5-hydroxytryptamine 2A and 2C (5-HT 2A and 5-HT 2C ) receptors are so closely related that selective agonists have not been developed until recently with the advent of (S)-2-(chloro-5-fluoro-indol-l-yl)-1-methylethylamine fumarate (Ro 60-0175), a putatively selective 5-HT 2C receptor agonist. In the present study, Ro 60-0175 was used to analyze the importance of 5-HT 2C receptors in hormone secretion. Injection of Ro 60-0175 (5 mg/kg s.c.) produced a maximum increase in plasma levels of adrenocorticotrophic hormone, oxytocin, and prolactin at 15 min postinjection and a maximum increase in plasma corticosterone levels at 60 min postinjection. Ro 60-0175-mediated increases in plasma hormone levels were dose-dependent (corticosterone ED 50 ϭ 2.43 mg/kg; oxytocin ED 50 ϭ 4.19 mg/kg; and prolactin ED 50 ϭ 4.03 mg/kg). To assess the role of 5-Hydroxytryptamine 2 (5-HT 2A and/or 5-HT 2C ) receptors play important roles in depression, obsessive compulsive disorder, eating disorders, and schizophrenia (Blier and de Montigny, 1999;Aghajanian and Marek, 2000). Both 5-HT 2A and 5-HT 2C receptors are G protein-linked receptors that couple to phospholipase C as a second messenger and thereby increase diacylglycerol, inositol trisphosphate, and intracellular Ca 2ϩ levels (for review, see Barnes and Sharp, 1999). The lack of selective agonists for each 5-HT 2 receptor subtype has hindered a precise differentiation between 5-HT 2A and 5-HT 2C receptor-mediated effects.The involvement of the 5-HT 2C and/or 5-HT 2A receptors in the regulation of hormone secretion has been examined with a variety of 5-HT 2 receptor agonists, the most common being (Ϯ)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI). DOI increases the plasma levels of adrenocorticotrophic hormone (ACTH), corticosterone, oxytocin, prolactin, and renin (Rittenhouse et al., , 1994Van de Kar et al., 2001). DOI was shown to stimulate the secretion of ACTH, corticosterone, oxytocin, prolactin, and renin by specifically activating the 5-HT 2A receptor as the increase in plasma levels of all these hormones was blocked by very low doses of the 5-HT 2A receptor antagonist MDL 100,907 (Van de Kar et al., 2001). Moreover, evidence suggests that 5-HT 2A receptors mediate hormone responses to other 5-HT 2C/2A agonists, such as mchlorophenylpiperazine (m-CPP), MK-212, and quipazine. The increase in plasma corticosterone levels after injection of MK-212, m-CPP, and quipazine are blocked by MDL 100,907. On the other hand, SB 242084 and SB 200646A, 5-HT 2C receptor antagonists, do not inhibit the m-CPP-, MK-212-, and quipazine-mediated increases in plasma corticosterone levels (Hemrick-Luecke and Fuller, 1996;Hemrick-Luecke and Evans, 2002). Both studies provide evidence for the importance of the 5-HT 2A receptor subtype in the regulation of neuroendocrine responses. However, there is no direct evidence to evaluate the role of the 5-HT 2C receptor subtype in

Implication of 5-HT2 receptor subtypes in the mechanism of action of antidepressants in the four plates test

“…RO 60-0175 at 1 mg/kg may occupy 5-HT 2B receptors, as it has been recently revealed to possess potent affinity for this receptor (pK i =9.3) and has now been suggested to act as a non-selective agonist for the 5-HT 2C receptor (Damjanoska et al 2003). This activation in conjunction with the lower dose of paroxetine may lead to an increase of synaptic 5-HT, resulting in the observed anti-punishment effects.…”

Strain‐dependent serotonin neuron feedback control: role of serotonin2C receptors

“…Accordingly, a dose of Ro60‐0175 (0.3 mg/kg) selectively targeting 5‐HT 2C receptors maximally suppressed 5‐HT release and increased GABA in the DR of DBA/2 mice but had no effect in C57BL/6 mice. Although at higher doses Ro60‐0175 loses selectivity for 5‐HT 2C receptors (Figure S3; see also Damjanoska et al. 2003), its effect on extracellular 5‐HT remained significantly greater in DBA/2 mice.…”

Support for 5-HT2C receptor functional selectivity in vivo utilizing structurally diverse, selective 5-HT2C receptor ligands and the 2,5-dimethoxy-4-iodoamphetamine elicited head-twitch response model

“…Also, in a pilot experiment measuring human 5-HT2A receptor-mediated PLC signaling in vitro , we observed Ro 60-0175 to be a potent agonist with an EC50 value and efficacy nearly equivalent to 5-HT (data not shown). Finally, in vivo , Ro 60-0175 is known to possess activity at receptors other than 5-HT2C (Damjanoska et al, 2003). Thus, suppression of the DOI-elicited-HTR by selective 5-HT2C agonists may not be mediated solely by activation of 5-HT2C receptors, but may also involve activation of 5-HT2A and/or 5-HT2B receptors.…”