Dopaminergic (DA) neurons in the ventral tegmental area (VTA) provide the DA innervation of the nucleus accumbens;this mesolimbic DA pathway is important for the rewarding properties of ethanol. Ethanol directly excites acutely dissociated DA VTA neurons, in the absence of input from surrounding cells. Ethanol excitation of DA VTA neurons is associated with a reduction in the action potential afterhyperpolarization (AHP) suggesting that it is due to a decrease in a potassium (K) current which contributes to the AHP. Ethanol excitation is completely blocked by quinidine, but not by the other K channel blockers apamin, tetraethylammonium, barium or cesium. In whole cell voltage clamp experiments, ethanol reduced the sustained outward current evoked by depolarizing voltage steps from aholding potential of-40 mV (to inactivate A-current). These data suggest that ethanol excites DA VTA neurons by reducing a non- or slowly inactivating, quinidine-sensitive, K current of the delayed rectifier type.
The specific aims of the present application are two-fold. 1) Electrophysiological and pharmacological characterization of this ethanol- sensitive K current in DA VTA neurons, and determination of the cutoff for ethanol excitation and for reduction of the ethanol-sensitive K current by longer chain length alcohols. 2) Molecular biological studies to try to identify the native ethanol-sensitive K current in terms of cloned K channels of known structure. Candidate channels have been selected according to their electrophysiological and pharmacological similarityto the native channel. RT-PCR on pooled neurons and single cell RT-PCR will be used to determine which candidate channel mRNAs are expressed in DA VTA neurons. Then immunohistochemistrywill be used to see which channel proteins are actually present on the soma and dendrites of DA VTA neurons. Finally, the most likely candidate channels will be expressed in Xenopus oocytes and the electrophysiological properties and cutoff for longer chain alcohols will be determined for these K currents and compared to the properties of the native ethanol-sensitive K current in DA VTA neurons. These data should give important information on the mechanism by which ethanol directly excites DA VTA reward neurons. Taken together, the electrophysiological and molecular biological data should help to identify the ethanol-sensitive native channel on DA VTA reward neurons and therefore point to a gene responsible for its expression. Such a discovery could have major implications for understanding genetic differences in ethanol effects on the mesolimbic reward pathway and how changes in the response of DA VTA neurons during chronic ethanol consumption leads to alcohol craving and addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA005846-24
Application #
7826913
Study Section
Special Emphasis Panel (NSS)
Program Officer
Liu, Qi-Ying
Project Start
1983-04-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
24
Fiscal Year
2010
Total Cost
$417,206
Indirect Cost
Name
University of Illinois at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Nimitvilai, Sudarat; You, Chang; Arora, Devinder S et al. (2016) Differential Effects of Toluene and Ethanol on Dopaminergic Neurons of the Ventral Tegmental Area. Front Neurosci 10:434
Nimitvilai, Sudarat; Herman, Melissa; You, Chang et al. (2014) Dopamine D2 receptor desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release. Neuropharmacology 82:28-40
Arora, Devinder S; Nimitvilai, Sudarat; Teppen, Tara L et al. (2013) Hyposensitivity to gamma-aminobutyric acid in the ventral tegmental area during alcohol withdrawal: reversal by histone deacetylase inhibitors. Neuropsychopharmacology 38:1674-84
Nimitvilai, Sudarat; McElvain, Maureen A; Brodie, Mark S (2013) Reversal of dopamine D2 agonist-induced inhibition of ventral tegmental area neurons by Gq-linked neurotransmitters is dependent on protein kinase C, G protein-coupled receptor kinase, and dynamin. J Pharmacol Exp Ther 344:253-63
Nimitvilai, Sudarat; Arora, Devinder S; McElvain, Maureen A et al. (2012) Ethanol blocks the reversal of prolonged dopamine inhibition of dopaminergic neurons of the ventral tegmental area. Alcohol Clin Exp Res 36:1913-21
Nimitvilai, S; Arora, D S; McElvain, M A et al. (2012) Reversal of inhibition of putative dopaminergic neurons of the ventral tegmental area: interaction of GABA(B) and D2 receptors. Neuroscience 226:29-39
Nimitvilai, Sudarat; McElvain, Maureen A; Arora, Devinder S et al. (2012) Reversal of quinpirole inhibition of ventral tegmental area neurons is linked to the phosphatidylinositol system and is induced by agonists linked to G(q). J Neurophysiol 108:263-74
Nimitvilai, Sudarat; Arora, Devinder S; Brodie, Mark S (2012) Reversal of dopamine inhibition of dopaminergic neurons of the ventral tegmental area is mediated by protein kinase C. Neuropsychopharmacology 37:543-56
Nimitvilai, Sudarat; Brodie, Mark S (2010) Reversal of prolonged dopamine inhibition of dopaminergic neurons of the ventral tegmental area. J Pharmacol Exp Ther 333:555-63
Melis, Miriam; Diana, Marco; Enrico, Paolo et al. (2009) Ethanol and acetaldehyde action on central dopamine systems: mechanisms, modulation, and relationship to stress. Alcohol 43:531-9

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