Exploring the Neurochemical Impact of 5-HT6 Receptor Agonists WAY-181187 and WAY-208466

The 5-HT6 receptor is a relatively newly discovered subtype of serotonin receptor, with its mRNA predominantly found in the central nervous system. Despite its identification, the specific biological function of the 5-HT6 receptor remains unclear. This study presents the characterization of two new and selective 5-HT6 receptor agonists, WAY-181187 and WAY-208466, which exhibit high affinity for the human 5-HT6 receptor and act as full agonists.

WAY-181187, when administered subcutaneously in rats, significantly increased extracellular GABA levels in the frontal cortex without affecting glutamate or norepinephrine levels. It also induced a decrease in cortical dopamine and serotonin levels. These neurochemical effects were blocked by pretreatment with the 5-HT6 antagonist SB-271046, indicating the involvement of 5-HT6 receptors. The impact on catecholamines was further confirmed to have a local relationship with GABAergic systems in the frontal cortex through the use of the GABA A receptor antagonist bicuculline.

In various brain regions, including the dorsal hippocampus, striatum, and amygdala, WAY-181187 increased extracellular GABA levels without affecting norepinephrine, serotonin, dopamine, or glutamate. However, it did not influence GABA levels in the nucleus accumbens or thalamus. WAY-208466 was found to elevate cortical GABA levels both after acute and chronic administration, suggesting no neurochemical tolerance develops with repeated 5-HT6 receptor activation.

In vitro, 5-HT6 receptor agonism reduced stimulated glutamate levels in hippocampal slice preparations. Furthermore, in a rat model of obsessive compulsive disorder (OCD), WAY-181187 decreased adjunctive drinking behavior in a dose-dependent manner.

In conclusion, WAY-181187 and WAY-208466 are potent and selective 5-HT6 receptor agonists with distinct neurochemical effects in vivo. The study suggests a role for 5-HT6 receptors in modulating GABA and stimulated glutamate transmission and hints at a potential therapeutic role for 5-HT6 receptor agonists in treating anxiety-related disorders, such as OCD.