Nicotine is the main addictive component of tobacco that motivates continued use despite the harmful effects. In developed countries, tobacco use is estimated to be the largest single cause of premature death, causing approximately 440,000 deaths and more than $75 billion in direct medical costs annually in the USA. Although many areas of the brain participate, the midbrain dopamine (DA) systems serve a vital role in the acquisition of behaviors that are inappropriately reinforced by psychostimulant drugs, including nicotine. The proposed studies examine the following broad hypothesis: during the progression from casual tobacco (nicotine) use to addiction the DA systems change, contributing to the transition to nicotine abuse. The studies specifically examine the physiological changes in the DA systems that evolve as the nicotine exposure continues through time. The changes within the DA systems often use the mechanisms of synaptic plasticity that normally underlie learning and memory. Thus, an ancillary hypothesis is that nicotine induces synaptic changes of the kind that underlie drug-linked memory. Recent advances indicate that addiction shares many commonalities with the synaptic plasticity normally attributed to learning and memory. Drugs subvert normal memory mechanisms, leading to long-lasting changes in behavior that accrue with the ongoing progression of addiction. Subsequently, environmental cues that elicit memories linked to addictive behaviors motivate cravings and relapse. The three aims examine the physiological changes induced by nicotine exposure that progresses from an acute single administration to a short-term chronic exposure and, finally, to a long-term chronic exposure. In each of the three specific aims, we will use in vivo unit recordings to examine nicotine-influences over DA neuron firing patterns and to examine the relationship between DA neurons and the neighboring circuitry. The firing patterns of the DA neurons measured in vivo will guide detailed studies of nicotine modulation of DA release measured using microdialysis and fast cyclic voltammetry. In addition, for each nicotine exposure we will follow the time-course for nicotine-induced synaptic potentiation of the glutamatergic afferents onto DA neurons of the ventral tegmental area. The time course of the synaptic plasticity suggests a window of vulnerability during which DA signaling is altered by drug-associated memory. Our strategy is to investigate DA signaling in vivo, which preserves the overall intact biological systems. Then, we sacrifice some of the pertinence provided by the in vivo studies to pursue greater experimental control and greater detail using in vitro brain slices. A novel combination of physiological studies applied at multiple levels of neuronal integration will provide complementary data sets that are presently lacking within the field of nicotine addiction.

Public Health Relevance

Addiction to nicotine motivates tobacco use, which causes approximately 440,000 deaths and more than $75 billion in direct medical costs annually in the USA. This study will determine the nicotine induced short-term and long-term neuronal changes that underlie 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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Sorensen, Roger
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Baylor College of Medicine
Schools of Medicine
United States
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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
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:
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
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

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