In the United States, tobacco use causes 400,000 deaths a year, making it the leading cause of premature death. Although multiple psychopharmacological effects contribute to tobacco abuse, nicotine is accepted as the primary component that reinforces the habit. Nicotine binds to nicotinic acetylcholine receptors (nAChRs). The rate of nicotine delivery and the time of exposure dictates how the populations of nAChRs distributes among functional states that are closed, ion conducting, desensitized, or long term inactivated. Smokers take in a small pulse of nicotine with each cigarette. These peaks of nicotine ride on a maintained low level of nicotine that increases with repeated cigarettes during the day. The research will test the following hypothesis: The pulse of nicotine could activate nAChRs that evoke dopamine release and produce """"""""rewarding"""""""" effects mediated mainly via the mesolimbic dopaminergic system. The sustained low levels of nicotine, however, could cause significant desensitization or longer-term inactivation of nAChRs that may underlie tolerance or aspects of withdrawal symptoms mediated by non-reward pathways. Patch-clamp electrophysiology, calcium measurements, and immunocytochemistry will be used to investigate the hypothesis. Microexplants of ventral tegmental area (VTA) neurons synapsing onto low density cultures of nucleus accumbens neurons will be examined to determine how nicotine evokes dopamine release. VTA brain slices and tissue cultures of VTA and habenula neurons will be used to understand the time scales and effects of nAChR desensitization and long-term inactivation as well as recovery from those states. Nicotinic AChR activation, leading to DA release by mesolimbic neurons, may provide the reinforcing reward that initiates tobacco abuse. A further drive to smoke may arise because smokers are medicating themselves with nicotine on longer time scales to control the degree to nAChR desensitization and inactivation that may underlie aspects of tolerance and withdrawal symptoms.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009411-04
Application #
6125019
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Sorensen, Roger
Project Start
1997-01-15
Project End
2001-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
4
Fiscal Year
2000
Total Cost
$166,695
Indirect Cost
Name
Baylor College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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
Placzek, Andon N; Prisco, Gonzalo Viana Di; Khatiwada, Sanjeev et al. (2016) eIF2?-mediated translational control regulates the persistence of cocaine-induced LTP in midbrain dopamine neurons. Elife 5:
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
Thompson-Lake, Daisy G Y; Cooper, Kim N; Mahoney 3rd, James J et al. (2015) Withdrawal Symptoms and Nicotine Dependence Severity Predict Virtual Reality Craving in Cigarette-Deprived Smokers. Nicotine Tob Res 17:796-802

Showing the most recent 10 out of 61 publications