Recently we have demonstrated that a homogeneous population of gamma-aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA) undergo adaptation in association with ethanol dependence. The overall objective of this proposal is to evaluate the role, whether contributory or reflective, of VTA GABA neurons in mediating the reinforcing properties of ethanol, under non-dependent and dependent conditions. The core thesis underlying this proposal is that adaptive changes in VTA GABA neuron excitability result from repeated exposure to acute intoxicating levels of ethanol and contribute to the dysregulation of mesolimbic dopamine homeostasis that accompanies ethanol reinforcement. Our proposed studies are designed to test three major hypotheses: 1) That persistent alterations in VTA GABA neuron excitability, N-methyl-D-aspartate (NMDA) and/or GABA receptor-mediated neurotransmission occur in association with ethanol dependence; 2) That enhancement of VTA GABA neuron excitability, NMDA and/or GABA neurotransmission anticipates ethanol self-administration (SA); and 3) That adaptation of VTA GABA neuron excitability, NMDA and/or GABA neurotransmission parallels the continuum of ethanol intoxication, aversion, reinforcement and dependence. We will employ electrophysiological methods to determine if VTA GABA neuron firing rate, axonal excitability and/or NMDA and GABA receptor- mediated synaptic input undergo adaptation to chronic ethanol. We will evaluate VTA GABA neuron firing rate, axonal excitability and response to afferent synaptic input during ethanol self- administration and in the ethanol operant runway paradigms. These studies will determine if VTA GABA neurons or their corticolimbic inputs undergo plasticity during ethanol reinforcement. VTA GABA neurons may act as unique integrators of convergent information from sensory, cortical and limbic areas subserving ethanol addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA013666-02
Application #
6532409
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Twombly, Dennis
Project Start
2001-09-13
Project End
2005-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
2
Fiscal Year
2002
Total Cost
$318,290
Indirect Cost
Name
Brigham Young University
Department
Psychology
Type
Other Domestic Higher Education
DUNS #
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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