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, Emax=93%; WAY-208466: EC50=7.3 nM; Emax=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 microM), 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-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-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).