The primary hypothesis of this proposal is that, in addition to nicotinic acetylcholine receptors (nAChRs) on dopamine neurons, nAChRs on GABA and glutamate neurons in the ventral tegmental area (VTA) shape the response to nicotine in mouse models of addiction. We hypothesize that GABA projection neurons expressing nAChRs contribute to the ability of nicotine to alter responses to environmental cues. Further, we hypothesize that nicotine can stimulate glutamatergic cell bodies in VTA, and that this is essential for the sensitivity to dopamine-dependent behaviors and the long-term responses to nicotine. While acute effects of nicotine are mediated through nAChRs, long-lasting changes in brain circuits and behavior result from downstream effects on intracellular signaling molecules. These signaling molecules are well placed to mediate plastic changes downstream of nAChRs. We will identify the role of signaling molecules co-immunoprecipitated with nAChRs in VTA GABA and glutamate neurons.
The specific aims of this proposal are to test the hypothesis that nAChRs on VTA GABA and glutamate neurons are important for the acute and chronic effects of nicotine on circuits and behaviors related to addiction and to identify nAChR-associated signaling molecules in these cell types.

Public Health Relevance

Tobacco smoking is still the major preventable cause of death in the United States, and nicotine is widely accepted to be the primary compound in cigarette smoke responsible for tobacco consumption. Chronic smoking leads to adaptations in nicotinic receptor (nAChR)-associated signaling molecules in specific neuronal types that likely contribute to ongoing smoking and these nAChR-associated signaling pathways may represent novel targets for development of new treatments to help with smoking cessation. We will identify specific neuronal types and proteins that interact with nAChRs, and using molecular techniques, we will determine how these pathways contribute to behaviors related to nicotine addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Pollock, Jonathan D
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Yale University
Schools of Medicine
New Haven
United States
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Park, Joongkyu; Chávez, Andrés E; Mineur, Yann S et al. (2016) CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory. Neuron 92:75-83
McClure-Begley, Tristan D; Esterlis, Irina; Stone, Kathryn L et al. (2016) Evaluation of the Nicotinic Acetylcholine Receptor-Associated Proteome at Baseline and Following Nicotine Exposure in Human and Mouse Cortex. eNeuro 3:
Jung, Yonwoo; Hsieh, Lawrence S; Lee, Angela M et al. (2016) An epigenetic mechanism mediates developmental nicotine effects on neuronal structure and behavior. Nat Neurosci 19:905-14
Lewis, Alan S; Oberleitner, Lindsay M S; Morgan, Peter T et al. (2016) Association of Cigarette Smoking With Interpersonal and Self-Directed Violence in a Large Community-Based Sample. Nicotine Tob Res 18:1456-62
Picciotto, Marina R; Lewis, Alan S; van Schalkwyk, Gerrit I et al. (2015) Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states. Neuropharmacology 96:235-43
Zhou, Wen-Liang; Gao, Xiao-Bing; Picciotto, Marina R (2015) Acetylcholine Acts through Nicotinic Receptors to Enhance the Firing Rate of a Subset of Hypocretin Neurons in the Mouse Hypothalamus through Distinct Presynaptic and Postsynaptic Mechanisms(.) eNeuro 2:
Lewis, Alan S; Mineur, Yann S; Smith, Philip H et al. (2015) Modulation of aggressive behavior in mice by nicotinic receptor subtypes. Biochem Pharmacol 97:488-97
Mineur, Yann S; Einstein, Emily B; Bentham, Matthew P et al. (2015) Expression of the 5-HT1A serotonin receptor in the hippocampus is required for social stress resilience and the antidepressant-like effects induced by the nicotinic partial agonist cytisine. Neuropsychopharmacology 40:938-46
McKee, Sherry A; Potenza, Marc N; Kober, Hedy et al. (2015) A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation. J Psychopharmacol 29:300-11
Mineur, Yann S; Taylor, Seth R; Picciotto, Marina R (2014) Calcineurin downregulation in the amygdala is sufficient to induce anxiety-like and depression-like behaviors in C57BL/6J male mice. Biol Psychiatry 75:991-8

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