Nicotine-like discriminative and aversive effects of two α4β2-selective nicotine agonists, ispronicline and metanicotine

Abstract

An attempt to determine the receptor selective nature of some of nicotine's behavioral effects was undertaken through the evaluation of the ability of two nicotinic α4β2*-selective receptor agonists to produce nicotine-like effects and modify rates of responding in a discrimination assay and in an aversive stimulus assay. A group of eight rats was trained to discriminate the presence of 1 mg/kg nicotine base. Another group of 4-6 rats was trained to report the aversive effects of nicotine by selecting a lever that produced one food pellet over a second lever that produced two food pellets and an intravenous injection of nicotine. Ispronicline and metanicotine, two α4β2*selective receptor agonists, increased selection of the nicotine-appropriate lever in a dose-related manner, up to a maximum of approximately 75%. The α4β2*-selective receptor antagonist, dihydro-beta-erythroidine blocked both the discriminative stimulus effects and the ratesuppressing effects of ispronicline, metanicotine, and small, but not large doses of nicotine. The nonselective antagonist, mecamylamine, antagonized the discriminative stimulus effects of each of the three nicotine agonists as well as the rate-decreasing effects of nicotine and metanicotine. Mecamylamine did not modify the ratedecreasing effects of ispronicline. Both ispronicline and metanicotine as well as nicotine were avoided in the drug + food vs. food choice situation. The receptor-selective nature of ispronicline and metanicotine was hereby confirmed in a behavioral assay, as were earlier reports that the discriminative stimulus effects of relatively small doses of nicotine are likely mediated by activity at the α4β2* nicotine receptor.

Nicotinic aspects of the discriminative stimulus effects of arecoline

“…It is noteworthy that, in these studies, the rate-suppressing effects of large doses of ispronicline that accompanied its arecoline-like discriminative stimulus effects were not antagonized by mecamylamine but were quite effectively blocked by DHβE. An identical interaction of these antagonists with ispronicline was observed in rats trained to discriminate nicotine: mecamylamine did not block the rate-suppressing effects of ispronicline whereas DHβE was able to do so (Winger, 2021). Because mecamylamine is considered to be a nonselective, noncompetitive antagonist of all nicotine agonists (Arias et al, 2010;Rosecrans and Young, 2018), it defies conventional knowledge to specify a nicotine effect that DHβE can reverse and mecamylamine cannot.…”

“…1, bottom, closed circles). The muscarinic antagonist, L 687 306 (Freedman et al, 1992;Winger et al, 2020;Johnson et al, 2021) antagonized the discriminative stimulus effects of arecoline (Fig. 1, top, open squares) and to a lesser degree relieved the rate-suppressing effects of arecoline (Fig.…”

“…This was the case, not simply because ispronicline and metanicotine are α4β2*-selective agonists, but also because their stimulus effects in arecoline-trained rats were antagonized by an α4β2*-selective antagonist, DHβE. Interestingly, arecoline-trained rats generalized more completely to these selective agonists than did several nicotine-trained rats (Winger, 2021). This is likely because the discriminative stimulus effects of the largest dose of nicotine in this discrimination assay are mediated by effects in addition to and overriding the effects of nicotine on the α4β2* nicotinic receptor (Jutkiewicz et al, 2011); some rats may have attended more to the stimulus produced by the large, non-α4β2*-selective dose of nicotine, and hence did not report that the α4β2*-selective agonists were like those of larger doses of nicotine.…”

“…For one thing, nicotine, ispronicline and metanicotine all had aversive effects in rats, in that the animals selected an option that The effects of increasing doses of ispronicline (♦) on selection of the arecoline-appropriate lever in 6-8 rats trained to discriminate 1 mg/kg arecoline (top) and on rates of responding during the discrimination (bottom). Antagonism of the effects of ispronicline by 3. provided a lower density of food delivery when it avoided an injection of each of these drugs (Winger, 2021). This does not preclude the possibility that these receptors underlie nicotine's reinforcing effects.…”

“…The doses of the antagonists mecamylamine and DHβE were selected because they were effective in antagonizing the discriminative stimulus effects of nicotine, ispronicline and metanicotine in another study (Winger, 2021).…”