Co-modulation of an allosteric modulator of nicotinic receptor-cholinesterase inhibitor (galantamine) and a 5-HT4 receptor agonist (RS-67333): effect on scopolamine-induced memory deficit in the mouse.

AIM: It is widely assumed that the upcoming therapeutics for Alzheimer's disease will require to act on more than one target to be effective. We investigated here whether a combination of the nicotinic receptor allosteric modulator/cholinesterase inhibitor galantamine can act synergistically with the type 4 serotonin receptor (5-HT4R) partial agonist, RS-67333, to counterbalance deficits in short- and long-term memory. To select sub-efficacious doses of both drugs, dose-response studies were first performed on the scopolamine-induced deficits of spontaneous alternation in the Y-maze task and of acquisition and retrieval processes in a passive avoidance task. RESULT: For spontaneous alternation behavior, combination of 1 mg/kg galantamine and 0.5 mg/kg RS-67333 fully reversed the deficit. In the passive avoidance task, no sub-efficacious doses could be found in the retention paradigm, but a beneficial effect of the association has been demonstrated in the acquisition paradigm. CONCLUSION: Mnesic effects of galantamine can be thus potentiated by activation of 5-HT4R. Such a combination treatment might (1) strengthen symptomatic relief, (2) attenuate adverse effects given the lower doses of each compound required, and (3) afford a disease-modifying effect given the known action of 5-HT4R on amyloidogenesis cascade.