Effects of Nicotine in Combination with Positive Allosteric Modulators of nAChRs

Saturday, February 13, 2016
Megan Moerke, University of Texas Health Science Center, San Antonio, TX
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.