Tobacco use remains a major public health concern in the United States and abroad where it is a major factor in the initiation of illnesses leading to preventable death. Yet, despite such adverse consequences, the number of smokers continues to increase worldwide. Although considerable progress has been made in elucidating the neuronal mechanisms underlying several of the effects of nicotine, the active component of tobacco, the knowledge accumulated to date falls short of what is necessary to intervene successfully to reduce tobacco use. The experiments proposed in this program project will use a multi-disciplinary approach to assess the impact of repeated exposure to nicotine on nicotinic acetylcholine receptors (nAChRs), neuronal excitability and behavior. They have in common the goal of ultimately understanding how nicotine acts to initiate self-administration behaviors and how repeated exposure to nicotine produces changes that promote the continued expression of these behaviors. Nicotine produces its effects on motivated behavior by activating brain nAChRs. The ability of nicotine to up regulate these receptors can thus have a substantial impact on the ability of this drug to initiate such behaviors in animals subsequently re-exposed to it. Project 1 will aim to identify the molecular mechanisms underlying nicotine-induced up regulation of nAChRs and characterize this phenomenon in different brain regions of nicotine-exposed rats. As with other drugs of abuse, nicotine use relies in large part on its ability to increase midbrain dopamine transmission. Project 2 will characterize the effect of previous exposure to nicotine on the functional properties of nAChRs with access to these dopamine systems and assess their contribution to long-term potentiation of synapses onto dopamine cells. Repeated exposure to nicotine is known to lead to locomotor sensitization, yet little is known about how this effect is produced. Project 3 will identify the brain nAChR fields involved, characterize their role in the induction of sensitization of dopamine neuron reactivity and determine whether their repeated activation leads to increased motivation to self-administer nicotine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA019695-04
Application #
7812223
Study Section
Special Emphasis Panel (ZDA1-RXL-E (03))
Program Officer
Frankenheim, Jerry
Project Start
2007-05-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$907,666
Indirect Cost
Name
University of Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
McDaid, John; Abburi, Chandrika; Wolfman, Shannon L et al. (2016) Ethanol-Induced Motor Impairment Mediated by Inhibition of α7 Nicotinic Receptors. J Neurosci 36:7768-78
Neugebauer, Nichole M; Cortright, James J; Sampedro, Georgia R et al. (2014) Exposure to nicotine enhances its subsequent self-administration: contribution of nicotine-associated contextual stimuli. Behav Brain Res 260:155-61
Augustin, Shana M; Beeler, Jeff A; McGehee, Daniel S et al. (2014) Cyclic AMP and afferent activity govern bidirectional synaptic plasticity in striatopallidal neurons. J Neurosci 34:6692-9
Umana, Iboro C; Daniele, Claire A; McGehee, Daniel S (2013) Neuronal nicotinic receptors as analgesic targets: it's a winding road. Biochem Pharmacol 86:1208-14
Lin, Eric I; Jeyifous, Okunola; Green, William N (2013) CASK regulates SAP97 conformation and its interactions with AMPA and NMDA receptors. J Neurosci 33:12067-76
Baker, Lorinda K; Mao, Danyan; Chi, Henry et al. (2013) Intermittent nicotine exposure upregulates nAChRs in VTA dopamine neurons and sensitises locomotor responding to the drug. Eur J Neurosci 37:1004-11
Antinone, Sarah E; Ghadge, Ghanashyam D; Lam, Tukiet T et al. (2013) Palmitoylation of superoxide dismutase 1 (SOD1) is increased for familial amyotrophic lateral sclerosis-linked SOD1 mutants. J Biol Chem 288:21606-17
Govind, Anitha P; Walsh, Heather; Green, William N (2012) Nicotine-induced upregulation of native neuronal nicotinic receptors is caused by multiple mechanisms. J Neurosci 32:2227-38
Cortright, James J; Sampedro, Georgia R; Neugebauer, Nichole M et al. (2012) Previous exposure to nicotine enhances the incentive motivational effects of amphetamine via nicotine-associated contextual stimuli. Neuropsychopharmacology 37:2277-84
Singaraja, Roshni R; Huang, Kun; Sanders, Shaun S et al. (2011) Altered palmitoylation and neuropathological deficits in mice lacking HIP14. Hum Mol Genet 20:3899-909

Showing the most recent 10 out of 26 publications