1. ¹Discovery Neuroscience, Wyeth Research, Princeton, NJ, USA
2. ²Chemical and Screening Sciences, Wyeth Research, Princeton, NJ, USA

Correspondence: Dr LE Schechter, Depression and Anxiety, Discovery Neuroscience, Wyeth Discovery, CN-8000, Princeton, NJ 08543-8000, USA. Tel: +1 732 274 4060; Fax: +1 732 274 4020; E-mail: schechl@wyeth.com

Received 6 February 2007; Revised 31 May 2007; Accepted 6 June 2007; Published online 11 July 2007.

Abstract

One of the most recently identified serotonin (5-hydroxytryptamine (5-HT)) receptor subtypes is the 5-HT₆ receptor. Although in-depth localization studies reveal an exclusive distribution of 5-HT₆ 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-HT₆ receptor agonists. WAY-181187 and WAY-208466 possess high affinity binding (2.2 and 4.8 nM, respectively) at the human 5-HT₆ receptor and profile as full receptor agonists (WAY-181187: EC₅₀=6.6 nM, E_max=93%; WAY-208466: EC₅₀=7.3 nM; E_max=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-HT₆ antagonist, SB-271046 (10 mg/kg, s.c.), implicating 5-HT₆ 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 M), confirming a local relationship between 5-HT₆ 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-HT₆ receptor stimulation. In hippocampal slice preparations (in vitro), 5-HT₆ 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-HT₆ receptor agonists displaying a unique neurochemical signature in vivo. Moreover, these data highlight a previously undescribed role for 5-HT₆ 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).