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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA014241-11A1
Application #
8776161
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Pollock, Jonathan D
Project Start
1996-09-01
Project End
2019-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
Lewis, Alan S; van Schalkwyk, Gerrit Ian; Lopez, Mayra Ortiz et al. (2018) An Exploratory Trial of Transdermal Nicotine for Aggression and Irritability in Adults with Autism Spectrum Disorder. J Autism Dev Disord 48:2748-2757
Calarco, Cali A; Li, Zhiying; Taylor, Seth R et al. (2018) Molecular and cellular characterization of nicotinic acetylcholine receptor subtypes in the arcuate nucleus of the mouse hypothalamus. Eur J Neurosci :
Li, Daniel; Musante, Veronica; Zhou, Wenliang et al. (2018) Striatin-1 is a B subunit of protein phosphatase PP2A that regulates dendritic arborization and spine development in striatal neurons. J Biol Chem 293:11179-11194
Jung, Yonwoo; Lee, Angela M; McKee, Sherry A et al. (2017) Maternal smoking and autism spectrum disorder: meta-analysis with population smoking metrics as moderators. Sci Rep 7:4315
Roberts, Walter; Verplaetse, Terril L; Moore, Kelly et al. (2017) Effects of varenicline on alcohol self-administration and craving in drinkers with depressive symptoms. J Psychopharmacol 31:906-914
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
Esterlis, Irina; Hillmer, Ansel T; Bois, Frederic et al. (2016) CHRNA4 and ANKK1 Polymorphisms Influence Smoking-Induced Nicotinic Acetylcholine Receptor Upregulation. Nicotine Tob Res 18:1845-52
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:
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
Park, Joongkyu; Chávez, Andrés E; Mineur, Yann S et al. (2016) CaMKII Phosphorylation of TARP?-8 Is a Mediator of LTP and Learning and Memory. Neuron 92:75-83

Showing the most recent 10 out of 77 publications