Nicotine in tobacco smoke is the principle psychoactive chemical responsible for maintaining tobacco consumption (Benowitz, 2008, Stolerman and Jarvis, 1995; USDHHS, 2010). However, tobacco smoke also contains more than 7000 different constituents that may exhibit nicotine-like pharmacological properties (Jacob et al., 1999). Surprisingly, limited information is available on the psychopharmacological and adverse actions of these non-nicotinic chemical constituents in humans (Hoffman and Evans, 2013). Preclinical studies in laboratory rodents and nonhuman primates (NHP) have found that some minor tobacco alkaloids produce nicotine-like pharmacological actions (e.g., Goldberg et al., 1989a; Brennan et al., 2014; Hoffman and Evans, 2013; Caine et al., 2014, Smith et al., 2015; Desai et al., 2016a, Desai et al., 2016b). For example, some minor tobacco alkaloids (e.g., nornicotine, anabasine, anatabine) engender nicotine-like discriminative stimulus effects in mice, rats, and monkeys (Caine et al., 2014, Desai et al., 2016a) and fully mimic nicotine-like intracranial self-stimulation (Harris et al., 2015). Moreover, studies have reported that rats will self-administer intravenous (IV) injections of nornicotine, but not other minor tobacco alkaloids like anabasine or anatabine under simple fixed-ratio schedules conditions (Caine et al., 2014, Bardo et al., 1999). Along these lines, Desai et al. (2016b) reported that squirrel monkeys reliably self-administered IV nicotine and to a much lesser extent IV anatabine under more complex second-order fixed interval schedule conditions that have previously been used to study nicotine’s reinforcing effects in NHPs (e.g., Spealman and Goldberg, 1982; Goldberg et al., 1981b). Taken together, these findings highlight the importance of experimental conditions under which the effects of nicotine and minor tobacco alkaloids are studied in laboratory animals and suggest that minor tobacco alkaloids that display nicotine-like behavioral effects may contribute to maintaining consumption of tobacco and tobacco-related products.

Despite significant research effort, robust reinforcing effects of IV nicotine across a wide range of schedule parameters and conditions can be difficult to document (Le Foll et al., 2007, Le Foll and Goldberg, 2009, Goodwin et al., 2015, Desai et al., 2016b) possibly due to the limited reinforcing strength of nicotine (Koffarnus and Winger 2015) and/or the adverse effects (e.g., emesis, tremor) of accumulated nicotine injections under simple fixed-ratio or progressive-ratio schedules of reinforcement (e.g., Spealman et al., 1981; Goldberg et al., 1981a, b, 1983; Le Foll and Goldberg, 2009). In fact, it is well known that at high doses nicotine and other nicotinic drugs can produce acute adverse effects in humans, like emesis/vomiting and retching. In laboratory animals, however, examination of such acute adverse observable effects of nicotinic drugs are limited because many commonly used animal models (e.g., mice, rats, guinea pigs, rabbits) cannot produce an emetic response precluding their evaluation. As such, other behaviors, like conditioned taste aversion (Garcia et al., 1974), conditioned gaping (Parker, 2014), and intracranial self-stimulation threshold-increases (Harris et al., 2015) have been used in rodents to indirectly study behaviors associated with emesis or aversive effects of nicotinic drugs; however, these assays lack translational value. Given that NHPs have an emetic reflex like that of humans, it is surprising that the acute adverse behavioral effects of nicotinic drugs that induce emesis are not studied more frequently in monkeys. In this regard, earlier studies from our laboratory showed that select doses of nicotine and other nicotinic agonists can produce a variety of observable adverse effects in squirrel monkeys (e.g., hypersalivation, emesis, tremors, and loss of posture) without interfering with their discriminative-stimulus effects (Desai and Bergman, 2014, Desai et al., 2016a, Wooldridge and Kangas, 2019, Wooldridge et al., 2020). Although nicotine and nicotinic drugs been shown to induce emesis at high doses, few studies have fully characterized the adverse behavioral effects of minor tobacco alkaloids alone in NHPs and whether such adverse effects are likely to interfere with IV self-administration behavior or contribute to the adverse effects that can be induced by tobacco smoke.

Although some studies in rodents have suggested that minor tobacco alkaloids in combination with nicotine do not alter rates of self-administration behavior more than nicotine alone (e.g., Smith et al., 2015), there is a strong likelihood that nicotine and minor tobacco alkaloids interact with one another to produce psychopharmacological effects and maintain smoking behavior. Given the lack of information available on the behavioral pharmacology of minor tobacco alkaloids alone in a primate species, as a first step we sought to test several prominent minor tobacco alkaloids individually to better understand their reinforcing/adverse effects in NHPs. Thus, in the present study, we used a second-order fixed-interval schedule of reinforcement to compare the reinforcing effects of nicotine and three minor tobacco alkaloids nornicotine, anatabine, and myosmine that are commonly found in tobacco products (Jacob et al., 1999). In addition, observational studies were conducted in a separate group of squirrel monkeys to determine the presence or absence of adverse emetic effects, including hypersalivation and retching which are thought to be a prodromal sign related to emesis (Horn, 2008).