Genome-wide association studies identified a nonsynonymous SNP (rs16969968) within the CHRNA5 gene that encodes for the ?5 nicotinic receptor (nAChR) subunit. This SNP produces a twofold higher risk for heavy smoking and increases the risk for lung cancer. Consistent with the human genetics, our preliminary studies showed that the ?5 nAChR is necessary for the expression of the nicotine withdrawal syndrome. The ?5 nAChR also regulates sensitive to nicotine-induced behaviors and controls nicotine self-administration at high doses. In these proposed studies, we will investigate ?5's mechanistic action on the midbrain dopamine (DA) systems that reinforce rewarding and addictive behaviors. We will examine the effect of the rs16969968 SNP on DA signaling from its source in the midbrain to its main targets in the striatum, including the nucleus accumbens (NAc) which is important for processing reward. Our in vivo multi-tetrode recordings show that nicotine increases the phasic burst firing of DA neurons, and our cyclic voltammetry and in vivo microdialysis data show that nicotine-induced changes in DA neuron firing are translated in a target-specific manner in areas that process reinforcement and reward, including the NAc core and shell. However, little is known about the role of the ?5 subunit or the rs16969968 SNP and about the role of the ?5-subunit in regulating the relationship between DA neuron firing and DA release in targets. Our working hypothesis is that nicotine acts via the ?5-nAChR subunit to modulate DA signaling both at the source (i.e., DA neurons in the midbrain) and at the targets (including the NAc and the dorsal striatum).
The aims examine the hypothesis that nicotine-induced changes in the DA system evolve during chronic nicotine exposure and during the withdrawal period. The significance of the study originates from the expectation that these nicotine-induced activities and changes in the DA system contribute to the transition from initial nicotine use to addiction. Tobacco use remains the leading cause of preventable death in the United States, and these studies provide a mechanistic basis for nicotine addiction and for developing therapies to aid smoking cessation.

Public Health Relevance

Nicotine addiction to tobacco is the leading cause of preventable death in the USA, causing 440,000 premature deaths annually. The ?5 nicotinic receptor has been linked to heavy smoking and lung cancer. The proposed studies will determine how the dopamine system involving ?5 mediate tobacco addiction based on the expectation that nicotine-induced changes in the dopamine system drive the addiction process.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Pollock, Jonathan D
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University of Pennsylvania
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Thomas, Alyse M; Ostroumov, Alexey; Kimmey, Blake A et al. (2018) Adolescent Nicotine Exposure Alters GABAA Receptor Signaling in the Ventral Tegmental Area and Increases Adult Ethanol Self-Administration. Cell Rep 23:68-77
Ostroumov, Alexey; Dani, John A (2018) Inhibitory Plasticity of Mesocorticolimbic Circuits in Addiction and Mental Illness. Trends Neurosci 41:898-910
Yang, Kechun; Broussard, John I; Levine, Amber T et al. (2017) Dopamine receptor activity participates in hippocampal synaptic plasticity associated with novel object recognition. Eur J Neurosci 45:138-146
Huang, Wei; Placzek, Andon N; Viana Di Prisco, Gonzalo et al. (2016) Translational control by eIF2? phosphorylation regulates vulnerability to the synaptic and behavioral effects of cocaine. Elife 5:
Ostroumov, Alexey; Thomas, Alyse M; Kimmey, Blake A et al. (2016) Stress Increases Ethanol Self-Administration via a Shift toward Excitatory GABA Signaling in the Ventral Tegmental Area. Neuron 92:493-504
Broussard, John I; Yang, Kechun; Levine, Amber T et al. (2016) Dopamine Regulates Aversive Contextual Learning and Associated In Vivo Synaptic Plasticity in the Hippocampus. Cell Rep 14:1930-9
Placzek, Andon N; Molfese, David L; Khatiwada, Sanjeev et al. (2016) Translational control of nicotine-evoked synaptic potentiation in mice and neuronal responses in human smokers by eIF2?. Elife 5:
Le, Weidong; Zhang, Lifen; Xie, Wenjie et al. (2015) Pitx3 deficiency produces decreased dopamine signaling and induces motor deficits in Pitx3(-/-) mice. Neurobiol Aging 36:3314-3320
Dani, John A; Donnelly-Roberts, Diana; Bertrand, Daniel (2015) Nicotinic acetylcholine receptors as therapeutic targets: Emerging frontiers in basic research and clinical science--Editorial Comments. Biochem Pharmacol 97:351
Dani, John A (2015) Neuronal Nicotinic Acetylcholine Receptor Structure and Function and Response to Nicotine. Int Rev Neurobiol 124:3-19

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