We have identified a homogeneous population of y-aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA) that undergo adaptation in association with ethanol dependence. We have recently reported that VTA GABA neurons form part of a larger electrical network of ventral brain GABA neurons linked by connexin-36 gap junctions whose electrical coupling is enhanced by dopamine via D2 receptor-mediated activation of adenylate cyclase, and sensitive to low-dose ethanol. We hypothesize that VTA GABA neurons, and the electrical network they form, may act as unique integrators of convergent information from sensory, cortical and limbic areas subserving ethanol addiction. The overall objective of this application is to extend our evaluation of the role of this specific class of mesocorticolimbic GABA neurons in mediating the intoxicating and rewarding properties of ethanol. The core thesis underlying this proposal is that VTA GABA neurons underlie ethanol self-administration and that adaptive changes in VTA GABA neuron excitability and electrical synaptic transmission result from repeated exposure to contingent and/or non-contingent ethanol and contribute to the dysregulation of mesolimbic homeostasis that accompanies alcohol addiction. Our proposed in vivo and in vitro studies are designed to test four major hypotheses: 1) That VTA GABA neuron activity correlates with ethanol self-administration; 2) That lesioning VTA GABA neurons disrupts ethanol self-administration; 3) That gap junction transmission between VTA GABA neurons, or glutamate (GLU), GABA, or DA synaptic modulation of VTA GABA neuron gap junctions, is sensitive to ethanol; and 4) That persistent alterations in the gene expression of NMD A, non-NMDA, GABA, DA receptors, or connexin-36 gap junction proteins parallels the plasticity in synaptic adaptation that underlies the physiological manifestations of alcohol reward and dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA013666-07
Application #
7478554
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Liu, Qi-Ying
Project Start
2001-09-13
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
7
Fiscal Year
2008
Total Cost
$291,300
Indirect Cost
Name
Brigham Young University
Department
Psychology
Type
Other Domestic Higher Education
DUNS #
009094012
City
Provo
State
UT
Country
United States
Zip Code
84602
Steffensen, Scott C; Shin, Samuel I; Nelson, Ashley C et al. (2017) ?6 subunit-containing nicotinic receptors mediate low-dose ethanol effects on ventral tegmental area neurons and ethanol reward. Addict Biol :
Yorgason, Jordan T; Ferris, Mark J; Steffensen, Scott C et al. (2014) Frequency-dependent effects of ethanol on dopamine release in the nucleus accumbens. Alcohol Clin Exp Res 38:438-47
Allison, David W; Wilcox, Rebecca S; Ellefsen, Kyle L et al. (2011) Mefloquine effects on ventral tegmental area dopamine and GABA neuron inhibition: a physiologic role for connexin-36 GAP junctions. Synapse 65:804-13
Steffensen, Scott C; Bradley, Katie D; Hansen, David M et al. (2011) The role of connexin-36 gap junctions in alcohol intoxication and consumption. Synapse 65:695-707
Steffensen, Scott C; Bradley, Katie D; Hansen, David M et al. (2010) The role of connexin-36 gap junctions in alcohol intoxication and consumption. Synapse :
Yang, Chae Ha; Yoon, Seong Shoon; Hansen, David M et al. (2010) Acupuncture inhibits GABA neuron activity in the ventral tegmental area and reduces ethanol self-administration. Alcohol Clin Exp Res 34:2137-46
Vargas-Perez, Hector; Ting-A Kee, Ryan; Walton, Christine H et al. (2009) Ventral tegmental area BDNF induces an opiate-dependent-like reward state in naive rats. Science 324:1732-4
Ludlow, Kimberly H; Bradley, Katie D; Allison, David W et al. (2009) Acute and chronic ethanol modulate dopamine D2-subtype receptor responses in ventral tegmental area GABA neurons. Alcohol Clin Exp Res 33:804-11
Steffensen, Scott C; Walton, Christine H; Hansen, David M et al. (2009) Contingent and non-contingent effects of low-dose ethanol on GABA neuron activity in the ventral tegmental area. Pharmacol Biochem Behav 92:68-75
Steffensen, Scott C; Taylor, Seth R; Horton, Malia L et al. (2008) Cocaine disinhibits dopamine neurons in the ventral tegmental area via use-dependent blockade of GABA neuron voltage-sensitive sodium channels. Eur J Neurosci 28:2028-40

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