Nicotine has been indicated as a prevalent drug for substance abuse comorbidities in mental illness. Tobacco use is elevated in those suffering from psychiatric disorders, most notably in schizophrenia (SZ), where a three-to-five fold increase in usage compared to the general population is observed. Our laboratory has established a rodent model of psychosis. In this model, male and female rats are neonatally treated with quinpirole (NQ), a dopamine (DA) D2-like agonist for 21 days postpartum, resulting in lifelong supersensitization of the DAD2 receptor. Increases in dopamine D2 receptor sensitivity is a hallmark of psychosis. Interestingly, the dopamine D2 receptor forms a triple mutual inhibitor heteromer in the dorsal striatum with the adenosine A(2A) and metabotropic glutamate receptor type 5 (mGlu5), such that stimulation of the A(2A) or mGlu5 receptor results in decreased dopamine D2 signaling. The present study was designed to analyze the role of the mGlu5 receptor in a behavioral task involved in testing the associative aspects of rewarding drugs known as conditioned place preference (CPP). CPP is a behavioral task in which animals are conditioned with a reinforcing drug to prefer a particular environmental context. Male and female rats were neonatally treated with saline (NS) or quinpirole from postnatal day (P) 1 to 21. From P41-51, which is mid-adolescence in a rat, all rats were behaviorally tested on CPP. Results revealed that compared to NS rats, NQ animals administered nicotine demonstrated enhanced CPP, replicating our past work. Groups receiving a positive allosteric modulator to mGlu5, which results in stimulation of the mGlu5 receptor, reduced the enhanced rewarding effects of nicotine in CPP for NQ treated rats equal to control levels. Brain tissue was analyzed for brain-derived neurotropic factor (BDNF), a neurotrophin involved in cell growth, as well cell adhesion molecule cadherin-13 in the ventral tegmental area (VTA), which is a brain area rich in dopamine cell bodies. Results revealed elevations of BDNF in NQ-treated rats given nicotine compared to all other groups, and a sex difference in the increase in cadherin-13, with female NQ rats given nicotine demonstrating increases compared to all other groups. These effects were blocked by the mGlu5 receptor positive allosteric modulator. In addition, we analyzed phospho-p70S6 kinase in the nucleus accumbens (NAcc), which is the dopamine neuronal terminal region in the VTA mitigating drug reward. The NQ group given nicotine demonstrated significant increases in NAcc P70S6 kinase compared to all other groups, suggesting increased synaptic growth, which was also blocked by the positive allosteric modulator to mGlu5. Taken together, these results elucidate mGlu5 as a drug target for reducing the rewarding effects of nicotine via CDPPB administration in a model of substance abuse in psychosis.

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Two approaches to smoking cessation were evaluated. One approach, the standard condition, utilized a nicotine fading procedure, group support, and an attendance contingent monetary contract. The other approach, the maintenance condition, utilized nicotine fading, group support, and a smoking-contingent monetary contract. The maintenance condition also received two additional post-cessation sessions and additional instructions for cessation. Both conditions significantly improved over the course of the study. The maintenance condition achieved significantly better outcome on the reported average cigarettes per day, cessation rates, and CO levels for the follow-up periods. The maintenance condition also had significantly lower SCN levels at the three month follow-up. The maintenance condition also had significantly lower diastolic and systolic blood pressure at the six month follow-up when compared to the standard condition. However, few other significant health differences emerged when smoking subjects were compared with reduced smoking or nonsmoking subjects for this study. The maintenance condition was shown to be more cost effective than the standard condition. The results were interpreted as indicating the promise of nicotine fading and behavioral contracting procedures. Limitations of the wide-scale application of these methods was noted, however. In particular, group smoking cessation projects reach limited subjects, successful projects still have only moderate success rates, and the wide-spread application of these methods would strain available resources. It is recommended that further research and clinical efforts continue with nicotine fading, behavioral contracting and rapid smoking cessation programs. In addition, efforts at applying behavioral contracting principles without therapeutic support was suggested. Finally, more research on the functional determinants of tobacco smoking was recommended. / Ph. D.

The major purpose of this study was to test the effectiveness of a relapse prevention program which was designed to help smokers anticipate and avoid relapse. To do this, twenty-three male and thirty-seven female smokers who volunteered for an experimental stop smoking clinic were randomly assigned to one of four treatments: (NF) a nicotine fading treatment in which smokers were required to gradually reduce the nicotine content of their brand prior to quitting; (ACS) an abbreviated American Cancer Society Stop Smoking Program; (NFACS) a treatment which combined the nicotine fading program with the American Cancer Society program; (NFRPT) a treatment which combined nicotine fading with a relapse prevention training program designed from the suggestions of Marlatt and Gordon (1978). A pre-test, post-test factorial design was used in which daily smoking rate, tar and nicotine levels, alveolar carbon monoxide levels, smoking topography measures, feelings of self-efficacy regarding quitting smoking, and attitude regarding health were assessed at baseline, end of treatment, 2-month follow-up, 3-month follow-up and 6-month follow-up. Contrary to expectations, the NFRPT group failed to exhibit superior outcome over controls on any dependent variable measuring smoking consumption. Further, the NFRPT group exhibited the poorest 6-month abstinence rate and had significantly higher 6-month daily smoking rates than the NF and ACS controls. As such, these findings fail to support the recent arguments of Marlatt and Gordon (1978) and others regarding the efficacy of relapse prevention training as a means of improving treatment outcome in smoking cessation programs. These results are also consistent with other recent studies which have failed to demonstrate the unique effectiveness of maintenance procedures. A secondary purpose of this study was to replicate the findings of Foxx and Brown (1979) and Prue, Krapfl, and Martin (1981) regarding the effectiveness of nicotine fading as an easy to administer, nonaversive smoking cessation treatment. As expected, the NF group exhibited significant decreases from baseline in daily cigarette rate and total nicotine intake at the 6-month follow-up. However, only moderate abstinence rates and carbon monoxide reductions were achieved. Compared to the data presented by Foxx and Brown (1979), the NF group of the present study achieved superior decreases in daily cigarette rate and tar and nicotine intake but poorer overall abstinence rates. Further, the present NF group did not exhibit superiority of the ACS control group. As such, these results are encouraging but only partially replicate the findings of Foxx and Brown (1979). / Ph. D.

no abstract provided by author / Master of Science

Tobacco dependence is the leading cause of preventable death in the United States. Despite currently available smoking cessation therapies, there is a high rate of relapse in smoking among those attempting to quit. While the somatic signs of nicotine withdrawal (insomnia, increased appetite, weight gain) contribute to the continuation of smoking behavior, it has been hypothesized that the affective signs (depression, anxiety, craving, irritability) are greater motivators of relapse and continued tobacco use. There are few studies that assess the molecular and receptor-mediated mechanisms of nicotine withdrawal; therefore, our studies focus on identifying the nicotinic acetylcholine receptor (nAChR) subtypes and post-receptor calcium-dependent mechanisms involved in nicotine withdrawal behaviors. Using precipitated, spontaneous, and conditioned place aversion (CPA) models, we measured physical and affective signs of nicotine withdrawal in mice. Our data show that major nAChR subtypes have differential roles in nicotine withdrawal. Additionally, our results suggest a behavioral relevance for L-type calcium channels in physical nicotine withdrawal signs, while calcium/calmodulin dependent protein kinase II (CaMKII) appears to be involved in both physical and affective withdrawal behaviors. Additionally, we conducted biochemical studies in the ventral tegmental area (VTA) and nucleus accumbens (NAc) to examine the relationship between altered withdrawal behavioral responses and calcium-dependent molecular mechanisms that contribute to nicotine withdrawal behaviors. Our results suggest an important role for β2-containing nAChRs in nicotine-withdrawal induced decreases in CaMKII and synapsin I function in the NAc. Overall, our studies implicate a critical role for the α4α6β2* nAChR subtype in the behavioral and molecular aspects of nicotine withdrawal, thus aiding in the elucidation of nAChR subunits and mechanisms that contribute to nicotine withdrawal behaviors. The current studies are imperative for generating more successful smoking cessation therapies.

Electronic cigarettes (ECIGs) aerosolize an often nicotine-containing solution for user inhalation. ECIG nicotine delivery may depend on liquid nicotine concentration and user puffing behavior (topography). This study examined the relationship among liquid nicotine concentration, puff topography, and plasma nicotine concentration. Thirty-three ECIG-experienced and 31 ECIG-naïve individuals completed four laboratory sessions that differed by ECIG liquid nicotine concentration (0, 8, 18, or 36 mg/ml). A 3.3 volt “eGo” ECIG battery attached to a 1.5 Ohm dual coil “cartomizer” filled with 1 ml of 70% propylene glycol/30% vegetable glycerin nicotine liquid was used in two ECIG-bouts (10 puffs; 30 s IPI). Plasma nicotine concentration, puff topography, and HR were evaluated. Some ECIG/liquid combinations can deliver physiologically active doses of nicotine to users, and nicotine delivery depends on liquid nicotine concentration and user puffing behavior. Liquid contents, device characteristics, and user behavior should be considered when regulating ECIGs.