| Preface | 6 |
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| Contributors | 7 |
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| Contents | 10 |
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| to 1 Nicotine, Tobacco Use, and the 55th Nebraska Symposium on Motivation | 12 |
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| to 2 Synaptic Plasticity Within Midbrain Dopamine Centers Contributes to Nicotine Addiction | 15 |
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| Introduction to the Health Problem | 15 |
| Midbrain Dopaminergic Systems | 16 |
| Action of Nicotine at Nicotinic Receptors in the Midbrain | 17 |
| Nicotine Influences Over Midbrain Synaptic Function | 19 |
| to 3 Molecular Mechanisms Underlying the Motivational Effects of Nicotine | 26 |
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| Introduction | 26 |
| Cues and Nicotine Dependence | 26 |
| Prior Chronic Nicotine Exposure Enhances Conditioned Reinforcement | 27 |
| Desensitization of nAChRs May Underlie the Ability of Nicotine to Enhance Cue Salience | 28 |
| Brain Areas Important for Nicotine's Effects on Cue Responding | 29 |
| Role of DA in Nicotine-Mediated Behaviors | 30 |
| nAChR Subtypes Involved in Modulating the DA System | 31 |
| Intracellular Signaling Downstream of nAChRs | 32 |
| Conclusions | 33 |
| to 4 Targeting Reward-Relevant Nicotinic Receptors in the Discovery of Novel Pharmacotherapeutic Agents to Treat Tobacco Dependence | 40 |
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| Introduction | 40 |
| Tobacco Alkaloids and Tobacco Use | 40 |
| Nicotinic Receptor-Mediated Dopamine Release in Nicotine Reward | 40 |
| Nicotinic Receptor Subtypes | 42 |
| nAChR Antagonists | 44 |
| Approved Smoking Cessation Pharmacotherapies | 44 |
| Novel nAChR Antagonists | 45 |
| Methods | 47 |
| Animals | 47 |
| Synthesis of Analogs | 47 |
| [ 3 H]DA Release Assay | 48 |
| Nicotine-Induced Reinstatement of Nicotine Self-Administration | 49 |
| Results and Discussion | 50 |
| [ 3 H]DA Release Assay | 50 |
| Nicotine-Induced Reinstatement of Nicotine Self-Administration | 58 |
| to 5 Multiple Motivational Forces Contribute to Nicotine Dependence | 73 |
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| Introduction | 73 |
| Rewarding Effects of Nicotine | 74 |
| Primary Rewarding Effects of Nicotine | 74 |
| Conditioned Rewarding Effects of Stimuli Associated with Nicotine Administration | 76 |
| Reward-Enhancing Effects of Nicotine | 78 |
| Primary Reward-Enhancing Effects of Nicotine | 78 |
| Conditioned Reward-Enhancing Effects of Psychomotor Stimulants | 79 |
| Nicotine Withdrawal | 81 |
| Decreased Brain Reward Function during Nicotine Withdrawal | 81 |
| The Somatic Aspects of Nicotine Withdrawal | 83 |
| Motivational Significance of Anhedonic Versus Somatic Components of Drug Withdrawal | 83 |
| Conditioned Nicotine Withdrawal | 85 |
| Cognitive-Enhancing Effects of Nicotine | 90 |
| Conclusions | 91 |
| to 6 The Role of Nicotine in Smoking: A Dual-Reinforcement Model | 98 |
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| Introduction | 98 |
| Role of Non-Nicotine Stimuli in Self-Administration and Smoking | 99 |
| Dual Reinforcing Effects of Nicotine | 102 |
| Predictions of the Dual-Reinforcement Model: Reinforcing Strength of the Nonpharmacological Stimulus | 103 |
| Predictions of the Dual-Reinforcement Model: Behavioral Dissociation | 104 |
| Predictions of the Dual-Reinforcement Model: Pharmacological Dissociation | 107 |
| Predictions of the Dual-Reinforcement Model: Role of Conditioning | 108 |
| Nature and Temporal Dynamics of Nicotine's Reinforcement-Enhancing Effects | 110 |
| Significance of the Dual-Reinforcement Model | 111 |
| Summary and Conclusions | 112 |
| to 7 Altering the Motivational Function of Nicotine through Conditioning Processes | 117 |
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| Introduction | 117 |
| Nicotine as a Reinforcer | 118 |
| Nicotine as a Discriminative Stimulus | 121 |
| Interoceptive Pavlovian Conditioning: A Historical Framework | 123 |
| Nicotine as an Interoceptive CS | 124 |
| Nicotine as an Interoceptive Occasion Setter | 128 |
| Implications for the Motivational Function of Nicotine | 130 |
| to 8 New Findings on Nicotine Addiction and Treatment | 136 |
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| Introduction | 136 |
| Pre-cessation Administration of Pharmacologic Agents | 136 |
| Pre-cessation use of Nicotine Replacement Therapy | 136 |
| Varenicline | 140 |
| Pre-cessation Mecamylamine Treatment | 141 |
| Pre-cessation Bupropion Treatment | 141 |
| Nicotine Vaccine | 141 |
| Tailoring Smoking Cessation Treatment Based on Genetics | 143 |
| Conclusion | 143 |
| Financial Disclosure | 144 |
| to 9 Sex Differences in Nicotine Reinforcement and Reward: Influences on the Persistence of Tobacco Smoking | 147 |
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| Introduction | 147 |
| Clinical Implications of Sex Differences in Factors Promoting Smoking Persistence | 148 |
| Possible Sources of Sex Differences in Smoking Reinforcement | 149 |
| Pharmacokinetic | 149 |
| Pharmacodynamic | 150 |
| Non-pharmacological | 150 |
| Gender | 151 |
| Reduced Sensitivity to Nicotine Reinforcement and Reward in Women Versus Men | 151 |
| Direct Effects of Nicotine on Self-administration Behavior and Reward
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