Nicotine effects on time perception in rats

Abstract

a7PAMspreserve spatio-temporal patternsofnAChRactivationand unlike AChE inhibitors, activate only the a7 nAChR subtype, which should provide a better side effect profile. We have performed detailed characterization of BNC375, a Type I positive allosteric modulatorofa7nAChR.ActionofBNC375ona7nAChRs invitrowas examined in GH4C1 cells stably, expressing rat a7 nAChR. Manual patch-clamp recordings were made with a fast-application add-on (Dynaflow Resolve, Cellectricon, Sweden). A concentration– response curve of a7 nAChR potentiation by BNC375 yielded an EC50 1.9mM, nH 1.62, Emax 1572% for peak current and 1.3mM, 1.60, 2616% for areaunder curve (AUC), respectively. In the presence of 2mM ( EC50) BNC375 the concentration–response of acetylcholine exhibited 10 fold leftward shift (EC50 14.5mM vs. 127.7mM, nH 1.66 vs. 1.76) as well as 246% potentiation of a saturating ACh concentration. BNC375 had a minimal effect on the kinetics of potentiated currents and in contrast to a classical Type II a7 PAM PNU-120596, was not able to re-activate a7 nAChRs after desensitization with 0.5–1 mM ACh. The cognition-enhancing properties of BNC375 were evaluated using reversal of scopolamine-induced memory deficits in the mouse T-maze Continuous Alternation Task (T-CAT) and the rat novel object recognitionmodel (NOR). In the T-CAT, BNC375 at doses from 0.003 to 3 mg/kg p.o. dose-dependently reversed the memory-impairing effect of scopolamine from0.03 mg/kg. In the NOR all three doses (0.1, 0.3, 1 mg/kg p.o.) showed a significant reversal of scopolamine-induced deficits. In summary, we show that BNC375 potently enhances a7 nAChRmediated currents in vitro and has a favourable PAM Type I-like kinetic profile. The compound is efficacious in a broad range of agonist concentrations – from subthreshold to saturating. BNC375 demonstrates cognition-enhancing properties in two different in vivo animal models of episodic and working memory with a broad therapeutic window (100 fold).