Preface	6
	Contributors	7
	Contents	10
	to 1 Nicotine, Tobacco Use, and the 55th Nebraska Symposium on Motivation	12
	to 2 Synaptic Plasticity Within Midbrain Dopamine Centers Contributes to Nicotine Addiction	15
	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
	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
	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
	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
	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
	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
	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
	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 Ratings	152
	Ad Lib Self-administration of Nicotine Nasal Spray	152
	Nicotine Versus Placebo Spray Choice	153
	Reinforcing and Rewarding Effects of Nicotine Dose via Cigarettes	154
	Influence of Nicotine Pre-treatment on Subsequent Nicotine or Smoking Reinforcement	154
	Ad lib Smoking Following Nicotine Spray Pre-treatment	156
	Nicotines Spray Choice Following Nicotine Patch Pre-treatment	156
	Other Relevant Findings	157
	Sex Differences in Non-Pharmacological Influences of Smoking	157
	Sex Differences in Sensitivity to Nonverbal Drug Information (Cues)	158
	Smoking Reinforcement due to Lit Cigarette Cue	158
	Smoking Reward and Reinforcement after Blocking Smoking Cues	159
	Sex Differences in Sensitivity to Verbal Drug Information (Expectancies)	159
	Sex Differences in the Reinforcing Effects of Control over Smoking	162
	Other Relevant Findings	164
	Clinical Implications	165
	Sex Differences in NRT Efficacy	165
	Sex Differences in Response to Other Medications	167
	Sex Differences in Treatments Aimed at Non-Nicotine Influences on Smoking	167
	Conclusions and Future Directions	168
	to 10 The Functional Significance of Craving in Nicotine Dependence	174
	Introduction	174
	Conventional Craving Assumptions	175
	How Do We Study Craving?	176
	Craving Assessment	176
	Factors that Affect Cigarette Craving	177
	Cigarette Abstinence	177
	Time of Day	178
	Alcohol Intoxication	179
	Stress and Negative Affect	179
	Smoking-Related Cues	179
	Cigarette Availability and Craving	181
	Tonic -- Phasic Distinction in Cigarette Craving	183
	Craving and Drug Use	183
	Addressing the Craving-- Drug Use Conundrum	184
	If Craving and Smoking Are Not Tightly Coupled, Why Study Craving?	188
	Ubiquity of Craving Among Smokers	188
	Prominence of Craving Among Abstinent Smokers	188
	Aversive Nature of Craving	189
	Craving as a Predictor of Relapse	190
	Craving as a Core Attribute of Nicotine Dependence	190
	Future of Craving Research	192
	Final Note	194
	to 11 The Motivational Impact of Nicotine and Its Role in Tobacco Use: Final Comments and Priorities	201
	Some Final Comments	201
	Future Priorities: The NIH Perspective	203
	Long-Term Surveys of Tobacco Use	203
	Genetics/Epigenetics	204
	Nicotine Vaccine	204
	Drug Exposure and Development	204
	Co-morbidity	205
	Neurobiological Substrates of Behavior	205
	National Cooperative Drug Discovery Group (NCDDG)	205
	Index	1