Nicotine Enhances Intravenous Self-administration of Cannabinoids in Adult Rats.

INTRODUCTION: Nicotine and cannabis are commonly used together, yet few studies have investigated the effects of concurrent administration. Nicotine exhibits reinforcement enhancing effects by promoting the reinforcing properties of stimuli including other drugs. As many studies of this effect used non-contingent nicotine, we implemented a dual-self-administration model where rats have simultaneous access to two drugs and choose which to self-administer throughout a session. Here, we investigated the effect of self-administered or non-contingently delivered nicotine on cannabinoid self-administration. METHODS: Adult male rats were allowed to self-administer the synthetic cannabinoid WIN 55,212-2 (WIN) intravenously, with or without subcutaneous nicotine injections before each session. A separate group of animals were allowed to self-administer WIN, nicotine, or saline using a dual-catheter procedure, where each solution was infused independently and associated with a separate operant response. A third group of male and female rats were allowed to self-administer delta-9-tetrahydrocannabinol (THC) with or without pre-session injections of nicotine. RESULTS: Nicotine injections increased self-administration of WIN and THC. During dual self-administration, nicotine availability increased saline and WIN infusions but nicotine intake was not changed by WIN or saline availability. Rats preferred nicotine over saline, but preferred nicotine and WIN equally when both were available. The effect of nicotine on cannabinoid self-administration was acute and reversible when nicotine was no longer present. CONCLUSIONS: These results expand our understanding of the ability of nicotine to enhance reinforcement of other drugs and suggest that co-use of nicotine and cannabinoids promotes cannabinoid use beyond what would be taken alone. IMPLICATIONS: This study utilizes a dual intravenous self-administration model to investigate the ability of nicotine to enhance cannabinoid intake. Our results demonstrate that the reinforcement enhancing properties of nicotine on drug use extend to include cannabinoids, but that this effect occurs specifically when nicotine is administered alongside the cannabinoid. Interestingly, cannabinoid use did not promote nicotine intake, suggesting this mechanism of reinforcement is specific to nicotine.

Nicotine Administration Normalizes Behavioral and Neurophysiological Perturbations in the MAM Rodent Model of Schizophrenia.

BACKGROUND: The present study utilized the methylazoxymethanol (MAM) neurodevelopmental rodent model of schizophrenia (SCZ) to evaluate the hypothesis that individuals with SCZ smoke in an attempt to "self-medicate" their symptoms through nicotine (NIC) intake. METHODS: To explore this question, we examined the effects of acute and chronic administration of NIC in 2 established behavioral tests known to be disrupted in the MAM model: prepulse inhibition of startle and novel object recognition. Additionally, we assessed the effects of acute and chronic NIC on 2 indices of the pathophysiology of SCZ modeled by MAM, elevated dopamine neuron population activity in the ventral tegmental area and neuronal activity in the ventral hippocampus, using in vivo electrophysiological recordings. RESULTS: Our findings demonstrated that both acute and chronic administration of NIC significantly improved deficits in prepulse inhibition of startle and novel object recognition among MAM rats and normalized elevated ventral tegmental area and ventral hippocampal neuronal activity in these animals. CONCLUSION: Together, these findings of NIC-induced improvement of deficits lend support for a "self-medication" hypothesis behind increased cigarette smoking in SCZ and illustrate the potential utility of nicotinic modulation in future pharmacotherapies for certain SCZ symptoms.

Nicotine Self-administration Is Not Increased in the Methylazoxymethanol Acetate Rodent Model of Schizophrenia.

INTRODUCTION: Patients with schizophrenia (SCZ) smoke at a rate of 4-5 times higher than the general population, contributing to negative health consequences in this group. One possible explanation for this increased smoking is that individuals with SCZ find nicotine (NIC) more reinforcing. However, data supporting this possibility are limited. METHODS: The present experiments examined self-administration of NIC, alone or in combination with other reinforcers, across a range of doses in the methylazoxymethanol acetate (MAM) rodent model of SCZ. RESULTS: MAM and control animals did not differ in NIC self-administration across a range of doses and schedules of reinforcement, in both standard 1-hour self-administration sessions and 23-hour extended access sessions. However, MAM animals responded less for sucrose or reinforcing visual stimuli alone or when paired with NIC. CONCLUSIONS: To the extent that MAM-treated rats are a valid model of SCZ, these results suggest that increased NIC reinforcement does not account for increased smoking in SCZ patients. IMPLICATIONS: This study is the first to utilize nicotine self-administration, the gold standard for studying nicotine reinforcement, in the methylazoxymethanol acetate model of schizophrenia, which is arguably the most comprehensive animal model of the disease currently available. Our assessment found no evidence of increased nicotine reinforcement in methylazoxymethanol acetate animals, suggesting that increased reinforcement may not perpetuate increased smoking in schizophrenia patients.

Missing pieces of the Piezo1/Piezo2 baroreceptor hypothesis: an autonomic perspective.

Baroreceptors play a pivotal role in the regulation of blood pressure through moment to moment sensing of arterial blood pressure and providing information to the central nervous system to make autonomic adjustments to maintain appropriate tissue perfusion. A recent publication by Zeng and colleagues (Zeng WZ, Marshall KL, Min S, Daou I, Chapleau MW, Abboud FM, Liberles SD, Science 362: 464-467, 2018) suggests the mechanosensitive ion channels Piezo1 and Piezo2 represent the cellular mechanism by which baroreceptor nerve endings sense changes in arterial blood pressure. However, before Piezo1 and Piezo2 are accepted as the sensor of baroreceptors, the question must be asked of what criteria are necessary to establish this and how well the report of Zeng and colleagues (Zeng WZ, Marshall KL, Min S, Daou I, Chapleau MW, Abboud FM, Liberles SD, Science 362: 464-467, 2018) satisfies these criteria. We briefly review baroreceptor function, outline criteria that a putative neuronal sensor of blood pressure must satisfy, and discuss whether the recent findings of Zeng and colleagues suitably meet these criteria. Despite the provocative hypothesis, there are significant concerns regarding the evidence supporting a role of Piezo1/Piezo2 in arterial baroreceptor function.

Renal sensory nerves increase sympathetic nerve activity and blood pressure in 2-kidney 1-clip hypertensive mice.

Renal denervation lowers arterial blood pressure (ABP) in multiple clinical trials and some experimental models of hypertension. These antihypertensive effects have been attributed to the removal of renal afferent nerves. The purpose of the present study was to define the function, anatomy, and contribution of mouse renal sensory neurons to a renal nerve-dependent model of hypertension. First, electrical stimulation of mouse renal afferent nerves produced frequency-dependent increases in ABP that were eliminated by ganglionic blockade. Stimulus-triggered averaging revealed renal afferent stimulation significantly increased splanchnic, renal, and lumbar sympathetic nerve activity (SNA). Second, kidney injection of wheat germ agglutinin into male C57Bl6 mice (12-14 wk; Jackson Laboratories) produced ipsilateral labeling in the T11-L2 dorsal root ganglia. Next, 2-kidney 1-clip (2K1C) hypertension was produced in male C57Bl6 mice (12-14 wk; Jackson Laboratories) by placement of a 0.5-mm length of polytetrafluoroethylene tubing around the left renal artery. 2K1C mice displayed an elevated ABP measured via telemetry and a greater fall in mean ABP to ganglionic blockade at day 14 or 21 vs. day 0. Renal afferent discharge was significantly higher in 2K1C-clipped vs. 2K1C-unclipped or sham kidneys. In addition, 2K1C-clipped vs. 2K1C-unclipped or sham kidneys had lower renal mass and higher mRNA levels of several proinflammatory cytokines. Finally, both ipsilateral renal denervation (10% phenol) or selective denervation of renal afferent nerves (periaxonal application of 33 mM capsaicin) at time of clipping resulted in lower ABP of 2K1C mice at day 14 or 21. These findings suggest mouse renal sensory neurons are activated to increase SNA and ABP in 2K1C hypertension. NEW & NOTEWORTHY This study documents the function, anatomy, and contribution of mouse renal sensory nerves to neurogenic hypertension produced by renal stenosis. Activation of renal afferents increased sympathetic nerve activity and blood pressure. Renal afferent activity was elevated in hypertensive mice, and renal afferent denervation lowered blood pressure. Clinically, patients with renal stenosis have been excluded from clinical trials for renal denervation, but this study highlights the potential therapeutic efficacy to target renal nerves in these patients.

Animal Research on Nicotine Reduction: Current Evidence and Research Gaps.

A mandated reduction in the nicotine content of cigarettes may improve public health by reducing the prevalence of smoking. Animal self-administration research is an important complement to clinical research on nicotine reduction. It can fill research gaps that may be difficult to address with clinical research, guide clinical researchers about variables that are likely to be important in their own research, and provide policy makers with converging evidence between clinical and preclinical studies about the potential impact of a nicotine reduction policy. Convergence between clinical and preclinical research is important, given the ease with which clinical trial participants can access nonstudy tobacco products in the current marketplace. Herein, we review contributions of preclinical animal research, with a focus on rodent self-administration, to the science of nicotine reduction. Throughout this review, we highlight areas where clinical and preclinical research converge and areas where the two differ. Preclinical research has provided data on many important topics such as the threshold for nicotine reinforcement, the likelihood of compensation, moderators of the impact of nicotine reduction, the impact of environmental stimuli on nicotine reduction, the impact of nonnicotine cigarette smoke constituents on nicotine reduction, and the impact of nicotine reduction on vulnerable populations. Special attention is paid to current research gaps including the dramatic rise in alternative tobacco products, including electronic nicotine delivery systems (ie, e-cigarettes). The evidence reviewed here will be critical for policy makers as well as clinical researchers interested in nicotine reduction. IMPLICATIONS: This review will provide policy makers and clinical researchers interested in nicotine reduction with an overview of the preclinical animal research conducted on nicotine reduction and the regulatory implications of that research. The review also highlights the utility of preclinical research for research questions related to nicotine reduction.

Reducing nicotine exposure results in weight gain in smokers randomised to very low nicotine content cigarettes.

BACKGROUND: The Food and Drug Administration can reduce the nicotine content in cigarettes to very low levels. This potential regulatory action is hypothesised to improve public health by reducing smoking, but may have unintended consequences related to weight gain. METHODS: Weight gain was evaluated from a double-blind, parallel, randomised clinical trial of 839 participants assigned to smoke 1 of 6 investigational cigarettes with nicotine content ranging from 0.4 to 15.8 mg/g or their own usual brand for 6 weeks. Additional analyses evaluated weight gain in the lowest nicotine content cigarette groups (0.4 and 0.4 mg/g, high tar) to examine the effect of study product in compliant participants as assessed by urinary biomarkers. Differences in outcomes due to gender were also explored. FINDINGS: There were no significant differences in weight gain when comparing the reduced nicotine conditions with the 15.8 mg/g control group across all treatment groups and weeks. However, weight gain at week 6 was negatively correlated with nicotine exposure in the 2 lowest nicotine content cigarette conditions. Within the 2 lowest nicotine content cigarette conditions, male and female smokers biochemically verified to be compliant on study product gained significantly more weight than non-compliant smokers and control groups. CONCLUSIONS: The effect of random assignment to investigational cigarettes with reduced nicotine on weight gain was likely obscured by non-compliance with study product. Men and women who were compliant in the lowest nicotine content cigarette conditions gained 1.2 kg over 6 weeks, indicating weight gain is a likely consequence of reduced exposure to nicotine. TRIAL REGISTRATION NUMBER: NCT01681875, Post-results.

Self-Administered Nicotine Suppresses Body Weight Gain Independent of Food Intake in Male Rats.

INTRODUCTION: The action of nicotine to suppress body weight is often cited as a factor impacting smoking initiation and the failure to quit. Despite the weight-suppressant effects of nicotine, smokers and nonsmokers report equal daily caloric intake. The weight-suppressive effects of nicotine in animal models of smoking are poorly understood. Furthermore, the Food and Drug Administration has authority to implement a policy markedly reducing nicotine levels in cigarettes; such a reduction could reduce smoking behavior, but have detrimental effects on body weight. The aim of this investigation was to examine the effects of self-administered nicotine on body weight and food intake in rats. METHODS: In Experiment 1, rats with ad libitum access to chow responded for intravenous infusions of nicotine (60 µg/kg/infusion) or saline in daily 1-hour sessions; body weight and 24-hour food intake were measured. Experiment 2 tested the effects of subcutaneous injections of nicotine on food intake. In Experiment 3, rats were food restricted and self-administered nicotine across a range of doses (3.75-60 µg/kg/infusion) while body weight was measured. In Experiment 4, rats self-administered 60 µg/kg/infusion nicotine before reduction to one of several doses (1.875-15 µg/kg/infusion) for 50 days. RESULTS: Self-administered nicotine suppressed weight gain independent of food intake. In food restricted rats, self-administered nicotine dose-dependently suppressed body weight gain. In rats self-administering 60 µg/kg/infusion nicotine, dose reduction increased body weight. CONCLUSIONS: Self-administered nicotine, even at low doses, suppressed body independent of food intake; this may have important implications for nicotine reduction policy. IMPLICATIONS: The results of the present studies demonstrate that self-administered nicotine suppresses body weight independent of food intake in rats. Further, the present studies establish that self-administered nicotine suppresses body weight even at very low doses and that reduction of nicotine dose results in weight gain. These results have important implications for nicotine reduction policy.

Nicotine Enhances Footshock- and Lithium Chloride-Conditioned Place Avoidance in Male Rats.

INTRODUCTION: Numerous studies have shown that nicotine (NIC) can enhance the reinforcing effects of non-NIC stimuli through a nonassociative mechanism. To date, it is unclear whether NIC reinforcement enhancement serves to increase behaviors motivated by rewarding stimuli only, or whether NIC potentiates behavior motivated by all stimuli, regardless of valence. METHODS: The current study used a place conditioning procedure to examine whether acute NIC injection modulates avoidance of an environment previously associated with an aversive stimulus. Separate groups of rats underwent place conditioning using either lithium chloride (125mg/kg/ml, i.p.) or footshock (0.75 mA) as the aversive stimulus. Other rats served as nonconditioned controls. The magnitude of place avoidance was assessed after acute NIC (0.1 or 0.4mg/kg/ml, s.c.) or saline. RESULTS: Rats avoided chambers previously paired with either lithium chloride or footshock, and conditioned place avoidance was significantly enhanced by NIC pre-treatment. CONCLUSIONS: These results demonstrate that the ability of NIC to enhance motivated behavior extends to behaviors elicited by aversive stimuli, evidence that NIC affects behavior motivated by a broader range of stimuli than previously appreciated. IMPLICATIONS: The current study examined whether the reinforcement enhancement properties of NIC apply to aversive stimuli by testing NIC enhancement of conditioned place avoidance in rats. The results demonstrate that NIC enhances the motivational impact of these distinct aversive stimuli, providing novel evidence that NIC affects behavior motivated by a broader range of stimuli than has previously been demonstrated.

Adolescent Rats Self-Administer Less Nicotine Than Adults at Low Doses.

INTRODUCTION: Although nearly 90% of current smokers initiated tobacco use during adolescence, little is known about reinforcement by nicotine in adolescents. Researchers are currently investigating whether a potential public health policy setting a tobacco product standard with very low nicotine levels would improve public health, and it is essential to understand whether data generated in adults translates to adolescents, particularly as it relates to the threshold dose of nicotine required to support smoking. The present study compared self-administration of low doses of nicotine between adolescent and adult rats. METHODS: Adolescent (postnatal day [P] 30) and adult (P90) male and female rats were allowed to nosepoke to receive intravenous infusions of nicotine (3-100 µg/kg/infusion) during 16 daily 1-hour sessions. RESULTS: At 10 µg/kg/infusion nicotine, adolescent rats earned significantly fewer infusions than adults. When responding for 30 µg/kg/infusion nicotine, rats of both ages earned a similar number of infusions; however, there were subtle differences in the distribution of infusions across the 1-hour session. No sex differences were apparent in either age group at any dose. CONCLUSIONS: These results demonstrate that adolescent rats are less sensitive than adults to the primary reinforcing effects of nicotine. However, at nicotine doses that support self-administration in both age groups, adolescent and adult rats do not differ in acquisition or number of infusions earned. These results suggest that reducing nicotine levels in cigarettes to a level that does not support smoking in adults may be sufficient to reduce the acquisition of smoking in adolescents. IMPLICATIONS: The results of the present studies demonstrate that adolescent rats are less sensitive than adults to the primary reinforcing effects of nicotine. These results suggest that reducing nicotine levels in cigarettes to a level that does not support smoking in adults will be sufficient to reduce the acquisition of smoking in adolescents.

Selective C1 Lesioning Slightly Decreases Angiotensin II Type I Receptor Expression in the Rat Rostral Ventrolateral Medulla (RVLM).

Cardiovascular homeostasis is regulated in large part by the rostral ventrolateral medulla (RVLM) in mammals. Projections from the RVLM to the intermediolateral column of the thoracolumbar spinal cord innervate preganglionic neurons of the sympathetic nervous system causing elevation of blood pressure and heart rate. A large proportion, but not all, of the neurons in the RVLM contain the enzymes necessary for the production of epinephrine and are identified as the C1 cell group. Angiotensin II (Ang II) activates the RVLM acting upon AT1 receptors. To assess the proportion of AT1 receptors that are located on C1 neurons in the rat RVLM this study employed an antibody to dopamine-beta-hydroxylase conjugated to saporin, to selectively destroy C1 neurons in the RVLM. Expression of tyrosine hydroxylase immunoreactive neurons in the RVLM was reduced by 57 % in the toxin injected RVLM compared to the contralateral RVLM. In contrast, densitometric analysis of autoradiographic images of (125)I-sarcosine(1), isoleucine(8) Ang II binding to AT1 receptors of the injected side RVLM revealed a small (10 %) reduction in AT1-receptor expression compared to the contralateral RVLM. These results suggest that the majority of AT1 receptors in the rat RVLM are located on non-C1 neurons or glia.

Obese Smokers as a Potential Subpopulation of Risk in Tobacco Reduction Policy.

Smoking and obesity represent the largest challenges to public health. There is an established inverse relationship between body mass index (BMI) and smoking, but this relationship becomes more complicated among obese smokers. Smokers with higher BMI consume more cigarettes per day and may be more nicotine-dependent than lean smokers. Rates of obesity are lower among smokers than non-smokers, indicating that chronic exposure to tobacco smoke may prevent excess weight gain in people who would otherwise become obese. Furthermore, obese smokers may be more sensitive to the weight-suppressive and reinforcing effects of nicotine. Consequently, obese smokers may respond differently to reduction in the nicotine content of cigarettes, a tobacco control policy being considered both in the Unites States and abroad. Here, we review the interrelationship between nicotine and obesity in the context of a potential nicotine reduction policy. We discuss the implications of nicotine-induced body weight suppression in obese smokers, as well as the possibility that obesity might increase susceptibility to smoking and nicotine dependence.

Nicotine reduction as an increase in the unit price of cigarettes: a behavioral economics approach.

Urgent action is needed to reduce the harm caused by smoking. Product standards that reduce the addictiveness of cigarettes are now possible both in the U.S. and in countries party to the Framework Convention on Tobacco Control. Specifically, standards that required substantially reduced nicotine content in cigarettes could enable cessation in smokers and prevent future smoking among current non-smokers. Behavioral economics uses principles from the field of microeconomics to characterize how consumption of a reinforcer changes as a function of the unit price of that reinforcer (unit price=cost/reinforcer magnitude). A nicotine reduction policy might be considered an increase in the unit price of nicotine because smokers are paying more per unit of nicotine. This perspective allows principles from behavioral economics to be applied to nicotine reduction research questions, including how nicotine consumption, smoking behavior, use of other tobacco products, and use of other drugs of abuse are likely to be affected. This paper reviews the utility of this approach and evaluates the notion that a reduction in nicotine content is equivalent to a reduction in the reinforcement value of smoking-an assumption made by the unit price approach.

Reduced nicotine product standards for combustible tobacco: building an empirical basis for effective regulation.

INTRODUCTION: Both the Tobacco Control Act in the U.S. and Article 9 of the Framework Convention on Tobacco Control enable governments to directly address the addictiveness of combustible tobacco by reducing nicotine through product standards. Although nicotine may have some harmful effects, the detrimental health effects of smoked tobacco are primarily due to non-nicotine constituents. Hence, the health effects of nicotine reduction would likely be determined by changes in behavior that result in changes in smoke exposure. METHODS: Herein, we review the current evidence on nicotine reduction and discuss some of the challenges in establishing the empirical basis for regulatory decisions. RESULTS: To date, research suggests that very low nicotine content cigarettes produce a desirable set of outcomes, including reduced exposure to nicotine, reduced smoking, and reduced dependence, without significant safety concerns. However, much is still unknown, including the effects of gradual versus abrupt changes in nicotine content, effects in vulnerable populations, and impact on youth. DISCUSSION: A coordinated effort must be made to provide the best possible scientific basis for regulatory decisions. The outcome of this effort may provide the foundation for a novel approach to tobacco control that dramatically reduces the devastating health consequences of smoked tobacco.

Microdissection of neural networks by conditional reporter expression from a Brainbow herpesvirus.

Transneuronal transport of neurotropic viruses is widely used to define the organization of neural circuitry in the mature and developing nervous system. However, interconnectivity within complex circuits limits the ability of viral tracing to define connections specifically linked to a subpopulation of neurons within a network. Here we demonstrate a unique viral tracing technology that highlights connections to defined populations of neurons within a larger labeled network. This technology was accomplished by constructing a replication-competent strain of pseudorabies virus (PRV-263) that changes the profile of fluorescent reporter expression in the presence of Cre recombinase (Cre). The viral genome carries a Brainbow cassette that expresses a default red reporter in infected cells. However, in the presence of Cre, the red reporter gene is excised from the genome and expression of yellow or cyan reporters is enabled. We used PRV-263 in combination with a unique lentivirus vector that produces Cre expression in catecholamine neurons. Projection-specific infection of central circuits containing these Cre-expressing catecholamine neurons with PRV-263 resulted in Cre-mediated recombination of the PRV-263 genome and conditional expression of cyan/yellow reporters. Replication and transneuronal transport of recombined virus produced conditional reporter expression in neurons synaptically linked to the Cre-expressing catecholamine neurons. This unique technology highlights connections specific to phenotypically defined neurons within larger networks infected by retrograde transneuronal transport of virus from a defined projection target. The availability of other technologies that restrict Cre expression to defined populations of neurons indicates that this approach can be widely applied across functionally defined systems.

Physiological Mechanisms of Dietary Salt Sensing in the Brain, Kidney, and Gastrointestinal Tract.

Excess dietary salt (NaCl) intake is strongly correlated with cardiovascular disease and is a major contributing factor to the pathogenesis of hypertension. NaCl-sensitive hypertension is a multisystem disorder that involves renal dysfunction, vascular abnormalities, and neurogenically-mediated increases in peripheral resistance. Despite a major research focus on organ systems and these effector mechanisms causing NaCl-induced increases in arterial blood pressure, relatively less research has been directed at elucidating how NaCl is sensed by various tissues to elicit these downstream effects. The purpose of this review is to discuss how the brain, kidney, and gastrointestinal tract sense NaCl including key cell types, the role of NaCl versus osmolality, and the underlying molecular and electrochemical mechanisms.

Gradual and immediate nicotine reduction result in similar low-dose nicotine self-administration.

INTRODUCTION: Food and Drug Administration-mandated product standards that drastically reduce nicotine content in cigarettes aim to decrease smoking and thus improve health outcomes for millions of U.S. smokers. Researchers have suggested that nicotine reduction should be implemented gradually, but a gradual nicotine reduction may shift the minimum level of nicotine required to reinforce behavior or may result in different levels of compensatory smoking behavior. METHOD: Rats were given the opportunity to acquire nicotine self-administration at 60 µg/kg/infusion nicotine with a cocktail of other tobacco constituents included as the vehicle. Rats were subsequently assigned to one of six immediate dose reductions (30, 15, 7.5, 3.75, 1.875, or 0.0 µg/kg/infusion) for 10 sessions (n = 9-15). Rats in the 30 µg/kg/infusion reduction group continued to have their nicotine dose reduced by half after at least 10 sessions at each dose until reaching 1.875 µg/kg/infusion (i.e., gradual reduction). RESULTS: For both methods of reduction, reduction to 3.75 µg/kg/infusion resulted in significant decreases in behavior. Reduction to doses above 3.75 µg/kg/infusion resulted in only limited compensation. The largest compensation was temporary. There was no compensation following reduction to 3.75 µg/kg/infusion or below. CONCLUSION: This study suggests that reduction to the same nicotine dose will result in similar reductions in behavior for both gradual and immediate reductions, and both methods result in similar compensation. Future studies using humans should investigate differences in other outcomes such as withdrawal and craving.

Elucidating the reinforcing effects of nicotine: a tribute to Nadia Chaudhri.

Nadia Chaudhri worked with us as a graduate student in the Center for Neuroscience at the University of Pittsburgh from 1999 until she earned her PhD in 2005, a time that coincided with the discovery in our lab of the dual reinforcing actions of nicotine, a concept that she played an important role in shaping. The research that was described in her doctoral thesis is among the foundational pillars of the now well-accepted notion that nicotine acts as both a primary reinforcer and an amplifier of other reinforcer stimuli. This reinforcement-enhancing action of nicotine is robust and likely to be a powerful driver of nicotine use. Below, we discuss the evidence that these two actions of nicotine - primary reinforcement and reinforcement enhancement - are distinct and dissociable, a finding that Nadia was closely associated with. We go on to address two other topics that greatly interested Nadia during that time, the generalizability of the reinforcement-enhancing action of nicotine to multiple classes of reinforcing stimuli and potential sex differences in the dual reinforcing actions of nicotine. The research has greatly expanded since Nadia's involvement, but the core ideas that she helped to develop remain central to the concept of the dual reinforcing actions of nicotine and its importance for understanding the drivers of nicotine use.

Precipitated withdrawal from nicotine reduces reinforcing effects of a visual stimulus for rats.

INTRODUCTION: Research has identified at least two positive reinforcement-related effects of nicotine: (a) primary reinforcement and (b) enhancement of reinforcement from concurrently available stimuli. Prior examples of the reinforcement-enhancing effects with rats showed that repeated, intermittent nicotine exposure increased responding for non-nicotine reinforcers, and this effect remained robust over several weeks. However, the effects of continuous nicotine exposure on responding for a non-nicotine reinforcer are unknown, as are the effects of abruptly withdrawing continuous nicotine on behavior maintained by the same reinforcer. METHODS: Lever pressing for a visual reinforcer under a fixed ratio schedule was assessed while rats were maintained on a chronic, continuous infusion of nicotine (3.16 mg/kg/day; osmotic minipump). The effects of precipitated withdrawal on responding, following 16 days of continuous nicotine exposure, were assessed by pre-session subcutaneous injections of mecamylamine (1.0 mg/kg). RESULTS: Continuous nicotine initially increased active responding for the visual reinforcer; however, continued exposure resulted in an attenuation of this effect. Precipitated withdrawal from nicotine resulted in a significant decline in active responding. CONCLUSIONS: The initial increase in responding for the visual reinforcer with chronic nicotine exposure is consistent with prior research showing that intermittent exposure to nicotine acts as a reinforcement enhancer. However, the attenuation of this enhancement following prolonged nicotine exposure is in contrast with the persistent effects previously reported. Finally, the decrease in visual reinforcers below control levels (nicotine-naive animals) following nicotine withdrawal highlights a potential for affective withdrawal, which may serve as a motive for continued nicotine use.