Nikiforuk_2016_Behav.Brain.Res_313_214

The combination of memantine and acetylcholinesterase inhibitors (AChEIs) is used as a therapeutic strategy to improve cognition in Alzheimer's disease. Among AChEIs, galantamine, which is also a positive allosteric modulator (PAM) of nicotinic acetylcholine receptors (nAChRs), including alpha7-nAChRs, may be particularly beneficial. The alpha7-nAChR is involved in interactions between the cholinergic and glutamatergic systems. In the present study, we investigated the potential role of alpha7-nAChRs in the pro-cognitive effects of this drug combination. To this aim, cognitive performance in rats was assessed using the attentional set shifting task (ASST) and novel object recognition task (NORT). Co-administration of inactive doses of memantine with galantamine facilitated the rats' set-shifting performance and reversed delay-induced deficits in object recognition. These effects were blocked by the alpha7-nAChR antagonist methyllycaconitine, suggesting that the observed cognitive enhancement is alpha7-nAChR dependent. Moreover, combined administration of memantine with inactive doses of selective alpha7-nAChRs PAMs, CCMI and PNU-120596, also improved ASST and NORT performance in a methyllycaconitine-dependent manner. Stimulation of alpha7-nAChRs may underlie the pro-cognitive effects of combining memantine and galantamine. Our results suggest that memantine, when given with enhancers of alpha7-nAChRs, may represent an effective strategy for cognitive improvement.