Synergistic effect of 5-HT₄ receptor activation and phosphodiesterase type 7 inhibition on object recognition and...

Low-dose multitarget pharmacological strategies are viewed as promising approaches for managing cognitive impairment in aging. Here, we assessed the preclinical efficacy of co-modulating the 5-HT₄ receptor-dependent cAMP pathway to improve memory.

The individual and combined effects of RS67333, a partial 5-HT₄ receptor agonist, and BRL50481, a phosphodiesterase 7 inhibitor, were investigated on recognition and working memory performances in adult mice. Behavioral assessments included the novel object recognition test and the spontaneous alternation test under conditions of spontaneous forgetting and scopolamine-induced amnesia.

Dose-response studies revealed that RS67333 (0.5 and/or 1 mg/kg) and BRL50481 (2.5 and 5 mg/kg) significantly prolonged recognition memory trace and reversed scopolamine-induced deficits in both recognition and working memory, whereas lower doses were ineffective. Consistent with our hypothesis, co-administration of subactive doses of each compound (RS67333 at 0.37 mg/kg and BRL50481 at 1.75 mg/kg) produced a synergistic pro-memory effect in the novel object recognition test. Furthermore, anti-amnestic effects of the combined treatment were observed: BRL50481 at 1 mg/kg attenuated object recognition memory deficits when combined with RS67333 at 0.5 mg/kg, and reduced working memory deficits when combined with RS67333 at 0.25 mg/kg. These effects were observed in the absence of changes in locomotion or motivation.

These findings demonstrate that co-modulation of 5-HT₄ receptors and PDE7 enzymes enhances memory performance through a synergistic mechanism, likely though convergent activation of the cAMP/PKA/CREB signaling cascade. This study provides compelling preclinical proof of concept supporting the development of multi-target pharmacological strategies for cognitive decline.