Rick A. Bevins

Pavlovian conditioning plays a crucial role in promoting well-being and supporting healthy behaviors but also contributes to the development of diseases and psychopathologies. Much of the basic and applied research on these conditioning processes has focused on external or exteroceptive cues (tone, spider, context, and brewery) as the conditioned stimulus (CS) or occasion setter. Considerably less empirical effort has been devoted to studying Pavlovian conditioning involving internal or interoceptive stimuli, such as indigestion, low blood sugar, back pain, or drug intoxication function as the CS or occasion setter. In this targeted review, we focus on our research on the interoceptive stimulus effects of nicotine. We summarize methods employing discriminated goal-tracking that have been refined over the years to investigate how the function of the nicotine stimulus changes with excitatory or inhibitory conditioning protocols. That research provides substantive evidence indicating that what is known about Pavlovian conditioning with exteroceptive stimuli generally holds for the nicotine stimulus-extinction, CS salience, generalization, overshadowing, blocking, conditioned inhibition, devaluation, and overexpectation. Extension of the interoceptive conditioning methodology to include intravenous nicotine as a stimulus found that the nicotine stimulus acquires additional reinforcing value when previously paired with an appetitive outcome. In closing this review, we highlight notable gaps in the literature and discuss potential directions for research and conceptual development. Ultimately, we hope to encourage others to consider the intersection of interoception and Pavlovian conditioning in their area of scientific inquiry. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Tobacco use is the leading cause of death globally and in the United States. After decades of decline, driven by decreases in combusted tobacco use, nicotine product use has increased due to electronic nicotine delivery systems, also known as e‐cigarettes or vapes. Preclinical models of nicotine self‐administration can serve as important lodestars in the search for effective intervention and prevention tactics. Current variants of the preclinical models have substantial limitations, however. Therefore, we created the rodent electronic nicotine delivery system (RENDS), a novel low‐cost nonproprietary nose‐only preclinical model of nicotine aerosol self‐administration. We confirmed that RENDS sequesters nicotine aerosol in the nose port by measuring fine particulate matter (PM <2.5 microns) generated by e‐cigarettes. We also showed that rats robustly self‐administer flavored nicotine aerosol, resulting in high blood levels of cotinine (the major nicotine metabolite) and spontaneous somatic withdrawal symptoms. Thus, we provide validation of the operation and function of the RENDS, opening the door to an open‐source preclinical aerosol model of nicotine self‐administration that is relatively low in cost. Four existing operant chambers can be retrofitted with the RENDS for less than $325/chamber. All RENDS diagrams and plans for custom‐designed components are on Open Science Framework ( https://osf.io/x2pqf/?view_only=775b55435b8e428f98e6da384ef7889d ).

We have previously demonstrated that the interoceptive stimulus effects of intravenous nicotine (0.03 mg/kg/inf) can acquire conditioned reinforcing value through appetitive Pavlovian conditioning. In this report, we replicate and extend that work by examining the dose- and sex-generality of this effect. 240 male and female Sprague-Dawley rats were divided into groups defined by infusion dose (0, 0.003, 0.01, or 0.03 mg/kg nicotine). These were further divided into rats who received Paired or Unpaired appetitive conditioning between infusions and sucrose presentations. Interoceptive conditioning took place over 24 daily sessions. The Paired group received 10 trials of response-independent infusions of their assigned nicotine dose followed 30 s afterwards by 4-s access to sucrose. The Unpaired group also received 10 infusions and 10 deliveries of sucrose but spaced 4–8 min apart. Thereafter, the chambers were refitted with nosepokes and all groups could self-administer infusions of their assigned solution according to a progressive ratio schedule. Paired conditioning history enhanced the later self-administration of 0.01 and 0.03 mg/kg/inf nicotine in females. Males self-administered 0.03 mg/kg/inf nicotine—regardless of conditioning history. These data demonstrate that appetitive learning involving the stimulus effects of nicotine can substantially alter the reinforcing effects of nicotine in later self-administration, which effect is both dose- and sex-dependent.

Tobacco use is the leading cause of death globally and in the U.S. After decades of decline, driven by decreases in combusted tobacco use, nicotine product use has increased due to Electronic Nicotine Delivery Systems, also known as e-cigarettes or vapes. Preclinical models of nicotine self-administration can serve as important lodestars in the search for effective intervention and prevention tactics. Current variants of the task have substantial limitations, however. Therefore, we created the Rodent Electronic Nicotine Delivery System, a novel low-cost non-proprietary nose-only preclinical model of nicotine aerosol self-administration. We confirmed that RENDS sequesters nicotine aerosol in the nose port by measuring fine particulate matter (PM < 2.5 microns) generated by e-cigarettes. We also showed that rats robustly self-administer flavored nicotine aerosol, resulting in high blood levels of cotinine (the major nicotine metabolite) and spontaneous somatic withdrawal symptoms. Thus, we provide strong validation of the operation and function of the RENDS, opening the door to an open-source preclinical aerosol model of nicotine self-administration that is relatively low cost. Four existing operant chambers can be retrofitted with the RENDS for less than $325/chamber. All RENDS diagrams and plans for custom designed components are on Open Science Framework ( https://osf.io/x2pqf/?view_only=775b55435b8e428f98e6da384ef7889d ).

Varenicline (Chantix) is an FDA-approved smoking cessation aid that is pharmacologically similar to nicotine, the primary addictive component found within tobacco. In support of this similarity, previous drug discrimination research in rats has reported that the internal or interoceptive stimulus effects of nicotine and varenicline share stimulus elements. Those shared elements appear to be mediated, in part, by overlapping action at alpha4beta2–containing nicotinic acetylcholine receptors (nAChRs). The research supporting this conclusion, however, has only used nicotine, and not varenicline, as the training drug. Accordingly, we used the discriminated goal tracking (DGT) task in which 1 mg/kg varenicline signaled intermittent access to sucrose. On separate intermixed saline days, sucrose was not available. Rats acquired the discrimination as measured by a differential increase in dipper entries (goal tracking) evoked by varenicline. These rats then received a series of tests with several doses of varenicline, nicotine, nornicotine (a metabolite of nicotine and tobacco alkaloid), sazetidine-A (a partial alpha4beta2 agonist), PHA-543613 (an alpha7 agonist), and bupropion (a norepinephrine and dopamine reuptake inhibitor). Control of goal tracking by varenicline was dose-dependent. Nicotine and nornicotine evoked responding comparable to the varenicline training dose indicating full substitution. Sazetidine-A partially substituted for the varenicline stimulus, whereas bupropion and PHA-543613 evoked little to no varenicline-like responding. These findings indicate that varenicline can serve as the training stimulus in the DGT task. Further, stimulus control of varenicline in the DGT task is driven by its partial agonist activity at alpha4beta2–containing nAChRs. The use of this approach could lead to a better understanding of the pharmacological action of varenicline and help guide treatment geared towards tobacco cessation through a more targeted development of novel synthetically designed, subunit-specific pharmacological interventions.