Role of channel activation in cognitive enhancement mediated by α7 nicotinic acetylcholine receptors

Background and purpose: Several agonists of the alpha 7 nicotinic acetylcholine receptor (nAChR) have been developed for treatment of cognitive deficits. However, agonist efficacy in vivo is difficult to reconcile with rapid alpha 7 nAChR desensitization in vitro; and furthermore, the correlation between in vitro receptor efficacy and in vivo behavioural efficacy is not well delineated. The possibility that agonists of this receptor actually function in vivo as inhibitors via desensitization has not been finally resolved. Experimental approach: Two structurally related alpha 7 nAChR agonists were characterized and used to assess the degree of efficacy required in a behavioural paradigm. Key results: NS6784 activated human and rat alpha 7 nAChR with EC(50)s of 0.72 and 0.88 mu M, and apparent efficacies of 77 and 97% respectively. NS6740, in contrast, displayed little efficacy at alpha 7 nAChR (< 2% in oocytes, < 8% in GH4C1 cells), although its agonist-like properties were revealed by adding a positive allosteric modulator of alpha 7 nAChRs or using the slowly desensitizing alpha 7V274T receptor. In mouse inhibitory avoidance (IA) memory retention, NS6784 enhanced performance as did the 60% partial agonist A-582941. In contrast, NS6740 did not enhance performance, but blocked effects of A-582941. Conclusions and implications: Collectively, these findings suggest that a degree of alpha 7 nAChR agonist efficacy is required for behavioural effects in the IA paradigm, and that such behavioural efficacy is not due to alpha 7 nAChR desensitization. Also, a partial agonist of very low efficacy for this receptor could be used as an inhibitor, in the absence of alpha 7 nAChR antagonists with favourable CNS penetration.