The prevailing view is that enhancement of dopamine (DA) transmission in the mesocorticolimbic system underlies the rewarding properties of alcohol and nicotine (NIC). The mesolimbic DA system consists of DA neurons in the midbrain ventral tegmental area (VTA) that innervate the nucleus accumbens (NAc). Dopamine neurotransmission is regulated by inhibitory VTA GABA neurons, whose excitability is a net effect of glutamate (GLU) and GABA neurotransmission that are modulated by NIC cholinergic receptors (nAChRs) on afferent terminals. We have shown that these neurons are excited by low-dose ethanol (Steffensen et al., 2009), but inhibited by moderate to high-dose ethanol (Gallegos et al., 1999; Ludlow et al., 2009; Steffensen et al., 2009; Stobbs et al., 2004; Yang et al., 2010), and adapt to chronic ethanol (Gallegos et al., 1999), evincing marked hyperexcitability during withdrawal. Based on our previous studies and data presented here, we propose that VTA GABA neurons are a common substrate for the acute actions of ethanol and NIC. The core thesis underlying this proposal is that alpha6*-nAChRs on GABA terminals mediate acute ethanol inhibition of VTA GABA neurons and DA release in the NAc. In addition, VTA GABA neuron hyperexcitability during withdrawal from chronic ethanol results from adaptations in presynaptic alpha6*-nAChRs and postsynaptic GABA(A)R-mediated inhibitory synaptic transmission to these neurons, which contributes to the dysregulation of mesolimbic DA homeostasis that accompanies dependence on ethanol and co-dependence on NIC. We will study of the role of alpha6*-nAChRs in acute and chronic effects of ethanol on VTA GABA neurons and on DA release. Our proposed studies constitute a focused investigation into the role of alpha6*-nAChRs in mediating acute ethanol effects on these neurons and their adaptation with alcohol dependence. Our studies will test the following specific hypotheses: 1) Acute ethanol inhibition of VTA GABA neuron activity and phasic DA release results from enhancement of GABA release via alpha6*-nAChRs on GABA terminals; 2) Lack of alpha6*-nAChRs results in disrupted ethanol consumption and reward; and 3) Hyperexcitability of VTA GABA neurons during withdrawal from chronic ethanol results from adaptation of alpha6*-nAChRs and subsequent reduction of DA release at terminals in the NAc. To test these hypotheses, we propose three Specific Aims, which involve electrophysiological, behavioral, neurochemical and molecular experiments with acute and chronic ethanol exposure in GAD GFP knock-in mice, and in wild type (WT) and alpha6*-nAChR KO mice: 1) Define the role of alpha6*-nAChRs in acute ethanol actions on VTA neurons and dopamine release in the NAc; 2) Define the role of alpha6*-nAChRs in mediating ethanol consumption and reward; and 3) Define the role of alpha6-nAChRs in mediating the hyperexcitability of VTA GABA neurons and lowered dopamine release in the NAc during withdrawal from chronic ethanol. We will show preliminary evidence that alpha6*-nAChRs mediate ethanol enhancement of NIC currents in recombinant nAChRs expression systems, that ethanol enhancement of GABA inhibition to VTA GABA neurons and ethanol reduction in DA release in the NAc, and compromised ethanol reward in alpha6*- nAChR KO mice. The proposed studies constitute a thorough and systematic investigation into the role of VTA GABA neurons in mediating the acute effects of ethanol and NIC and the role of alpha6*-nAChR in modulating GABA neurotransmission to these neurons that critically regulate DA neurotransmission in the mesolimbic system implicated in alcohol reward and dependence. Results from this study could provide a preclinical pharmacologic rationale for considering drugs that act selectively on alpha6*-nAChR as putative therapeutic agents for the treatment of alcohol dependence and alcohol and NIC co-dependence.

Public Health Relevance

Alcoholism and nicotine addiction are chronic relapsing disorders that have enormous impact on society. A major goal of research on addiction is to characterize the critical neural substrates that are most sensitive to the drug, adapt in association with chronic abuse and drive subsequent drug-seeking behavior. Currently, there are no evidence-based, clinically useful, pharmacotherapeutic interventions that might reverse the neuroadaptive effects of alcohol or nicotine dependence. Alcohol and NIC are the most commonly abused drugs, and a large body of evidence indicates that there is a positive correlation between their consumption. Today, smoking NIC-containing tobacco products is recognized as one of the greatest risk factors in the development of alcoholism. A major goal of addiction research is to characterize the critical neural substrates that are most sensitive to these drugs, adapt in association with chronic consumption and drive subsequent drug-seeking behavior. Alcohol and nicotine addiction share much in common, including co-dependence. The long-term objective of our research program is to advance our understanding of the neural basis of drug reward and dependence. The rationale for this proposal is predicated on the belief that advancement in the understanding the brain mechanisms underlying the recreational use and abuse potential of alcohol and nicotine will pave the way for more effective treatment strategies that could reverse dependence on these drugs and save lives and resources throughout the world.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA035958-03
Application #
9068857
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Sorensen, Roger
Project Start
2014-06-01
Project End
2019-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Brigham Young University
Department
Psychology
Type
Other Specialized Schools
DUNS #
009094012
City
Provo
State
UT
Country
United States
Zip Code
84602
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Mitchell, Ulrike H; Obray, J Daniel; Hunsaker, Erik et al. (2018) Peripheral Dopamine in Restless Legs Syndrome. Front Neurol 9:155
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Jang, Eun Young; Ryu, Yeon-Hee; Lee, Bong Hyo et al. (2015) Involvement of reactive oxygen species in cocaine-taking behaviors in rats. Addict Biol 20:663-75
Vargas-Perez, Hector; Bahi, Amine; Bufalino, Mary Rose et al. (2014) BDNF signaling in the VTA links the drug-dependent state to drug withdrawal aversions. J Neurosci 34:7899-909

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