Neuropharmacological Profile of Novel and Selective 5-HT6 Receptor Agonists: WAY-181187 and WAY-208466

Abstract

One of the most recently identified serotonin (5-hydroxytryptamine (5-HT)) receptor subtypes is the 5-HT 6 receptor. Although in-depth localization studies reveal an exclusive distribution of 5-HT 6 mRNA in the central nervous system, the precise biological role of this receptor still remains unknown. In the present series of experiments, we report the pharmacological and neurochemical characterization of two novel and selective 5-HT 6 receptor agonists. WAY-181187 and WAY-208466 possess high affinity binding (2.2 and 4.8 nM, respectively) at the human 5-HT 6 receptor and profile as full receptor agonists (WAY-181187: EC 50 ¼ 6.6 nM, E max ¼ 93%; WAY-208466: EC 50 ¼ 7.3 nM; E max ¼ 100%). In the rat frontal cortex, acute administration of WAY-181187 (3-30 mg/kg, subcutaneous (s.c.)) significantly increased extracellular GABA concentrations without altering the levels of glutamate or norepinephrine. Additionally, WAY-181187 (30 mg/kg, s.c.) produced modest yet significant decreases in cortical dopamine and 5-HT levels. Subsequent studies showed that the neurochemical effects of WAY-181187 in the frontal cortex could be blocked by pretreatment with the 5-HT 6 antagonist, SB-271046 (10 mg/kg, s.c.), implicating 5-HT 6 receptor mechanisms in mediating these responses. Moreover, the effects of WAY-181187 on catecholamines were attenuated by an intracortical infusion of the GABA A receptor antagonist, bicuculline (10 mM), confirming a local relationship between 5-HT 6 receptors and GABAergic systems in the frontal cortex. In the dorsal hippocampus, striatum, and amygdala, WAY-181187 (10-30 mg/kg, s.c.) elicited robust elevations in extracellular levels of GABA without producing similar effects on concentrations of norepinephrine, serotonin, dopamine, or glutamate. In contrast to these brain regions, WAY-181187 had no effect on the extracellular levels of GABA in the nucleus accumbens or thalamus. Additional studies showed that WAY-208466 (10 mg/kg, s.c.) preferentially elevated cortical GABA levels following both acute and chronic (14 day) administration, indicating that neurochemical tolerance does not develop following repeated 5-HT 6 receptor stimulation. In hippocampal slice preparations (in vitro), 5-HT 6 receptor agonism attenuated stimulated glutamate levels elicited by sodium azide and high KCl treatment. Furthermore, in the rat schedule-induced polydipsia model of obsessive compulsive disorder (OCD), acute administration of WAY-181187 (56-178 mg/kg, po) decreased adjunctive drinking behavior in a dose-dependent manner. In summary, WAY-181187 and WAY-208466 are novel, selective, and potent 5-HT 6 receptor agonists displaying a unique neurochemical signature in vivo. Moreover, these data highlight a previously undescribed role for 5-HT 6 receptors to modulate basal GABA and stimulated glutamate transmission, as well as reveal a potential therapeutic role for this receptor in the treatment of some types of anxiety-related disorders (eg OCD).

The 5-HT6 receptor agonist EMD 386088 produces antidepressant and anxiolytic effects in rats after intrahippocampal administration

“…Literature data suggest that the gamma-aminobutyric acid (GABA) system is involved in the modulation of anxiety-like behavior by 5-HT6 receptor agonists. Consistent with the localization of 5-HT6 receptors on GABAergic interneurons (Woolley et al 2004), the activation of 5-HT6 receptors enhanced GABA transmission in the hippocampus as revealed by in vivo microdialysis (Schechter et al 2008) and electrophysiological (West et al 2009) techniques. Since positive modulators of GABA receptors as well as agents enhancing GABAergic tone have been widely used to exert anxiolytic effects, it is possible that an elevated GABA release underlies the anti-anxiety action of 5-HT6 receptor agonists.…”

“…In fact, the blockade of 5-HT6 receptor counteracted the increase in extracellular GABA concentration induced by 5-HT6 agonists (Schechter et al 2008) and increased glutamate levels in the frontal cortex and dorsal hippocampus (Dawson et al 2001). Though the 5-HT6 blockade-induced increase in acetylcholine release has been previously suggested to participate in anxiolytic-like effects , the precise mechanism of the 5-HT6 antagonist anti-anxiety action remains unknown.…”

“…Since positive modulators of GABA receptors as well as agents enhancing GABAergic tone have been widely used to exert anxiolytic effects, it is possible that an elevated GABA release underlies the anti-anxiety action of 5-HT6 receptor agonists. In addition to facilitation of GABAmediated inhibitory transmission, a 5-HT6 agonist also decreased stimulated glutamate release (Schechter et al 2008). This effect may also contribute to the effectiveness of 5-HT6 agonists especially in the stress-related conditions associated with enhanced excitatory glutamatergic transmission.…”

Schedule-induced polydipsia as a model of compulsive behavior: neuropharmacological and neuroendocrine bases

“…Because of its characteristics of "excessiveness" and "persistence," growing evidence points to schedule-induced polydipsia (SIP) as a candidate model for the study of neuropsychiatric disorders presenting with compulsive behavior such as OCD, schizophrenia (Hawken et al 2011;Rosenzweig-Lipson et al 2007;Schechter et al 2008;Woods-Kettelberger et al 1997; for review, see Platt et al 2008), and alcohol abuse (Gilpin et al 2008;Mittleman et al 2003Mittleman et al , 2011Wayner 2002). The SIP model is characterized by the development of an adjunctive behavior of excessive drinking in food-deprived animals exposed to intermittent food-reinforcement schedules (Falk 1961(Falk , 1971.…”

Transporters

“…Selective agonists (pKi) DOI (7.2-8.6), Ro600175 (7.7-8.2) WAY163909 (8.0, Locaserin (7.8, Thomsen et al, 2008) Selective antagonists (pKi) -ketanserin (8.1-9.7), MDL100907 (9.4) RS127445 (9.0), EGIS-7625 (9.0) SB242084 (8.2 -9.0), RS102221 (8.3-8.4) FR260010 (8.9, Harada et al, 2006) Probes (KD) [ Malgouris et al,1993), [ Selective agonists (pKi) BIMU8 (7.3), ML10302 (7.9-9.0), RS67506 (8.8-guinea-pig, Eglen et al, 1995) --WAY181187 (8.7, Schechter et al, 2008) E6801 (partial agonist, 8.7, Holenz et al, 2005) Selective antagonists (pKi) GR113808 (9.3-10.3), SB204070 (9.8 -10.4), RS100235 (8.7-12.2) SB699551 (8.2) -SB399886 (9.4, Hirst et al, 2006) SB271046 (8.9), SB357134 (8.5, Bromidge et al, 2001), Probes (KD) [ Other names 5-HT1-like, 5-HT1Y, orphan…”