Journal Article

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

Dawson, Lee A, Robichaud, Albert, Beyer, Chad E, Bernotas, Ron, Schechter, Lee E, Brandt, Michael R, Platt, Brian, Lin, Qian, Rosenzweig-Lipson, Sharon, Shan, Qin, Smith, Deborah L, Zhang, Guoming, Cole, Derek

2008

Overview

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 =6.6 nM, E max =93%; WAY-208466: EC 50 =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-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 μM), 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).

• Publisher: Springer International Publishing,Nature Publishing Group
• Subject: Amino Acids - metabolism / Analysis of Variance / Animals / Behavioral Sciences / Biological Psychology / Brain - anatomy & histology / Brain - drug effects / Brain - metabolism / Brain Chemistry - drug effects / Chromatography, High Pressure Liquid - methods / Disease Models, Animal / Dopamine / Dose-Response Relationship, Drug / Drinking Behavior - drug effects / Drug Interactions / Humans / Ischemia - chemically induced / Ischemia - drug therapy / Male / Medicine / Medicine & Public Health / Microdialysis - methods / Nervous system / Neuropharmacology / Neurosciences / Obsessive compulsive disorder / original-article / Pharmacotherapy / Potassium Chloride / Protein Binding - drug effects / Proteins / Psychiatry / Rats / Rats, Sprague-Dawley / Receptors, Serotonin - metabolism / Serotonin / Serotonin Receptor Agonists - pharmacology / Sodium Azide