Effects of Nicotine in Combination with Positive Allosteric Modulators of nAChRs

Allosteric nicotinic acetylcholine receptor (nAChR) modulators are a potential strategy for modifying treatments for cholinergic-based diseases such as cognitive decline and tobacco dependence. Desformylflustrabromine (dFBr), PNU-120596 and LY 2087101 are positive allosteric modulators of nAChRs in vitro; however, in vivo effects have not been firmly established. The modulators were administered alone and in combination with nicotine in two separate groups of male C57BL/6J mice: hypothermic effects were measured in one group and the discriminative stimulus effects of nicotine (1 mg/kg) were measured in the other. Nicotine decreased rectal temperature from 37°C (control) to 29.8°C (1 mg/kg); this effect was antagonized by both mecamylamine and the b2-selective nAChR antagonist DHbE, but not by the a7-selective nAChR antagonist MLA. Both dFBr and PNU-120596, up to 100 mg/kg, produced a maximum decrease in temperature to 30.8°C and 34.5°C, respectively; effects in combination with nicotine were additive. However, mecamylamine did not antagonize the hypothermic effects of dFBr or PNU-120596. LY 2087101 did not modify rectal temperature when administered alone and did not modify nicotine-induced hypothermia. Up to doses that disrupted discrimination performance, dFBr, PNU-120596 and LY 2087101 produced no more than 23% nicotine-appropriate responding when administered alone. Neither PNU-120596 nor LY 2087101 modified the discriminative stimulus effects of nicotine, whereas dFBr (3.2 mg/kg) produced a 2-fold leftward shift in the nicotine dose-response function. These results suggest that dFBr, but not PNU-120596 or LY 2087101, might have effects in vivo consistent with positive nAChR allosteric modulation.