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

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. 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. 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 evaluated. Cyclic AMP production was measured from 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. The results indicated that PRX-07034 is both a potent (Ki = 4-8 nM) and highly selective 5-HT6 receptor antagonist (a parts per thousand yen100-fold selectivity for the 5-HT6 receptor compared to 68 other GPCRs, ion channels, and transporters, except D-3 (Ki = 71 nM) and 5-HT1B (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 mu M. 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. These findings demonstrate that PRX-07034 is a selective 5-HT6 receptor antagonist that may represent a novel treatment for enhancing working memory and cognitive flexibility.