The effects of PRX-07034, a novel 5-HT₆ antagonist, on cognitive flexibility and working memory in rats

Rationale Accumulating evidence indicates that schizophrenia and autism spectrum disorder patients are marked by cognitive deficits in working memory and strategy switching. There is accumulating evidence that 5-hydroxytryptamine (5-HT)₆ receptors may serve as a useful target to improve cognitive functioning. Objectives In the present experiments, the novel 5-HT₆ antagonist, PRX-07034, was examined for its selectivity of the 5-HT₆ receptor, as well as its effect on delayed spontaneous alternation and strategy switching. Methods The binding affinity of PRX-07034 to the 5-HT₆ receptor, other 5-HT receptors, as well as other G-protein coupled receptors, ion channels, and transporters was transfected HEK-293 cells. In separate behavioral experiments, rats received different doses of PRX-07034 (0.1, 1, or 3 mg/kg, i.p.) 30 min prior to delayed spontaneous alternation testing or prior to the acquisition and switch phases in a place-response switch test. Results The results indicated that PRX-07034 is both a potent (Ki=4-8 nM) and highly selective 5-HT₆ receptor antagonist (≥100-fold selectivity for the 5-HT₆ receptor compared to 68 other GPCRs, ion channels, and transporters, except D₃ (Ki=71 nM) and 5-HT_1B (Ki=260 nM) receptors. For cyclic AMP quantification, PRX-07034 demonstrated antagonist activity (IC₅₀=19 nM) without an effect on basal levels and did not show any agonist activity up to 10 μM. PRX-07034 at 1 and 3 mg/kg (but not 0.1 mg/kg) significantly enhanced delayed spontaneous alternation. The drug at 1 and 3 mg/kg also enhanced switching between a place and response strategy, but did not affect initial learning of either a place or response discrimination. Conclusions These findings demonstrate that PRX-07034 is a selective 5-HT ₆ receptor antagonist that may represent a novel treatment for enhancing working memory and cognitive flexibility.