The overall specific aims of this project are to understand the action of ethanol on brain pathways that mediate reward. The dopaminergic neurons of the ventral tegmental area (DA-VTA neurons) are important for the mediation of the reinforcing properties of ethanol, and the firing rate of these neurons is increased by ethanol. We have shown that serotonin potentiates ethanol excitation of DA-VTA neurons. Our subsequent studies have investigated ionic currents in the membrane of DA-VTA neurons to elucidate the ionic mechanism of this potentiation. In the previous project period, we focused on two membrane currents that may underlie the serotonin potentiation, the calcium-dependent potassium current SK, and the mixed cationic current lh. SK can be reduced by drugs like apamin or by depletion of intracellular calcium. We found that serotonin reduces Ih, and produces changes in the spike afterhyperpolarization similar to those produced by apamin. In our preliminary studies, we found that concurrent reduction of both of these currents produces profound potentiation of ethanol excitation. We have developed a model to explain this observation. In the proposed studies, five specific aims will seek to explore the relationship between ethanol excitation and potentiation of that excitation by serotonin.
Specific Aim #1 will establish the concentration-response curve for very low concentrations of ethanol during blockade of SK and Ih.
Specific Aim #2 will ascertain whether serotonin potentiation of ethanol excitation is mediated by concurrent reduction of SK and Ih.
Specific Aims #3 and #4 will determine how blockade of SK and Ih alter specific membrane properties of DA-VTA neurons, and how ethanol effects on specific membrane properties are altered by SK and Ih blockade.
Specific Aim #5 will use imaging of intracellular free calcium to determine whether prolonged administration of serotonin depletes intracellular stores of calcium. These studies directly build on our interesting initial observations of ethanol potentiation by blockade of SK and Ih, and will provide important information on how sensitivity to ethanol excitation may be modulated by neurotransmitter effects on ionic currents in DA-VTA neurons. Ultimately, information generated by this project may help in the development of pharmacotherapies for the amelioration of alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA009125-10
Application #
7253460
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Twombly, Dennis
Project Start
1992-08-01
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2010-06-30
Support Year
10
Fiscal Year
2007
Total Cost
$293,936
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
Dutton 3rd, John W; Chen, Hu; You, Chang et al. (2017) Anaplastic lymphoma kinase regulates binge-like drinking and dopamine receptor sensitivity in the ventral tegmental area. Addict Biol 22:665-678
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
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
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, 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; 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
McDaid, John; McElvain, Maureen A; Brodie, Mark S (2008) Ethanol effects on dopaminergic ventral tegmental area neurons during block of Ih: involvement of barium-sensitive potassium currents. J Neurophysiol 100:1202-10
Koyama, Susumu; Brodie, Mark S; Appel, Sarah B (2007) Ethanol inhibition of m-current and ethanol-induced direct excitation of ventral tegmental area dopamine neurons. J Neurophysiol 97:1977-85

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