Discriminative Stimulus Properties of S(−)-Nicotine: “A Drug for All Seasons”

Abstract

S(-)-Nicotine is the major pharmacologically active substance in tobacco and can function as an effective discriminative stimulus in both experimental animals and humans. In this model, subjects must detect and communicate the nicotine drug state versus the non-drug state. This review describes the usefulness of the procedure to study nicotine, presents a general overview of the model, and provides some relevant methodological details for the establishment of this drug as a stimulus. Once established, the (-)-nicotine stimulus can be characterized for dose response and time course effects. Moreover, tests can be conducted to determine the similarity of effects produced by test drugs to those produced by the training dose of nicotine. Such tests have shown that the stimulus effects of nicotine are stereoselective [S(-)-nicotine >R(+)-nicotine] and that other "natural" tobacco alkaloids and (-)-nicotine metabolites can produce (-)-nicotine-like effects, but these drugs are much less potent than (-)-nicotine. Stimulus antagonism tests with mecamylamine and DHβE (dihydro-β-erythroidine) indicate that the (-)-nicotine stimulus is mediated via α4β2 nicotinic acetylcholine receptors (nAChRs) in brain; dopamine systems also are likely involved. Individuals who try to cease their use of nicotine-based products are often unsuccessful. Bupropion (Zyban) and varenicline (Chantix) may be somewhat effective as anti-smoking medications because they probably produce stimulus effects that serve as suitable substitutes for (-)-nicotine in the individual who is motivated to quit smoking. Finally, it is proposed that future drug discrimination studies should apply the model to the issue of maintenance of abstinence from (-)-nicotine-based products.

Nicotinic aspects of the discriminative stimulus effects of arecoline

“…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. In the Discussion in Winger (in press) of this peculiar finding of insensitivity of the rate-suppressing effects of ispronicline to mecamylamine in nicotine-trained rats, the finding of Bondarenko et al .…”

From cis-Lobeline to trans-Lobeline: Study on the Pharmacodynamics and Isomerization Factors

“…Despite extensive studies, a comprehensive analysis of the pharmacological activities and the influencing factors of the isomerization of trans -lobeline is missing. The presence of cis and trans isomers in lobeline is well known, and many studies on the relationship between the structure and pharmacological activity of lobeline and its analogs have been reported [ 18 , 19 , 20 ]. However, the differences in pharmacological activities and the influencing factors of isomerization between the two isomers have not been reported.…”