The long-range goals of this project are to elucidate mechanisms involved in the CNS rewarding actions of ethanol, and the contribution of these rewarding effects toward maintaining high alcohol drinking. The overall hypothesis to be tested is that responsiveness of the limbic system to the reinforcing, stimulating effects of ethanol (EtOH) contributes toward the initiation of alcohol drinking and development of high alcohol drinking. The intra-cranial self-administration (ICSA) technique will be used to examine the reinforcing effects of EtOH and certain receptor agents within discrete regions. The micro-injection/micro-dialysis procedure will be use to assess the response of the meso-limbic dopamine (DA) system to the stimulating actions of EtOH and selected receptor agents.
Aim 1 will test the hypothesis that the reinforcing effects of EtOH within the nucleus accumbens (ACB) shell are mediated by serotonin-3 (5-HT3), and/or 5-HT2A receptors.
Aim will determine the involvement of the caudal ventral pallidum (VP) and/or the dorsal medial prefrontal cortex (mPFC) in mediating the reinforcing actions of EtOH.
Aim 3 will examine neuronal mechanisms within the posterior ventral tegmental area (pVTA) that underlie the increased sensitivity and responsiveness of this region to the reinforcing effects of EtOH following chronic alcohol drinking.
Aim 4 will test the hypothesis that alterations in the 5-HT3 receptor and D2 auto-receptor contribute to the development of sensitization to the stimulating effects of EtOH within the pVTA. To assess possible genetic influences on the rewarding, stimulating effects of EtOH within the limbic system, selected experiments will be conducted with alcohol-preferring (P) rats and stock Wistar rats. The results of this project will provide important information on (a) CNS sites and receptors mediating the reinforcing effects of EtOH, (b) neuronal mechanisms underlying the increased responsiveness of the pVTA to the stimulating, reinforcing effects of EtOH produced by chronic or repeated EtOH exposure, and (c) genetic influences on the reinforcing responses to EtOH. A better understanding of the complex basic brain mechanisms that contribute to high alcohol drinking behavior is critical for the development of treatment strategies for alcohol abuse.

Public Health Relevance

Alcohol abuse and alcoholism present serious health, social and economic problems. In order to develop appropriate treatment strategies, it is important to understand the complex neuronal mechanisms that regulating the rewarding actions of alcohol that contribute to alcohol addiction. The objectives of this proposal are to determine neuronal mechanisms underlying the CNS reinforcing actions of alcohol that contribute to high alcohol drinking behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA012262-10A1
Application #
8257996
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Grakalic, Ivana
Project Start
2000-04-01
Project End
2017-01-31
Budget Start
2012-02-10
Budget End
2013-01-31
Support Year
10
Fiscal Year
2012
Total Cost
$346,500
Indirect Cost
$121,500
Name
Indiana University-Purdue University at Indianapolis
Department
Psychiatry
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Ding, Zheng-Ming; Ingraham, Cynthia M; Rodd, Zachary A et al. (2016) Alcohol drinking increases the dopamine-stimulating effects of ethanol and reduces D2 auto-receptor and group II metabotropic glutamate receptor function within the posterior ventral tegmental area of alcohol preferring (P) rats. Neuropharmacology 109:41-8
Deehan Jr, Gerald A; Hauser, Sheketha R; Waeiss, R Aaron et al. (2015) Co-administration of ethanol and nicotine: the enduring alterations in the rewarding properties of nicotine and glutamate activity within the mesocorticolimbic system of female alcohol-preferring (P) rats. Psychopharmacology (Berl) 232:4293-302
Ding, Zheng-Ming; Ingraham, Cynthia M; Rodd, Zachary A et al. (2015) The reinforcing effects of ethanol within the nucleus accumbens shell involve activation of local GABA and serotonin receptors. J Psychopharmacol 29:725-33
Toalston, Jamie E; Deehan Jr, Gerald A; Hauser, Sheketha R et al. (2015) The reinforcing properties of ethanol are quantitatively enhanced in adulthood by peri-adolescent ethanol, but not saccharin, consumption in female alcohol-preferring (P) rats. Alcohol 49:513-8
Ding, Zheng-Ming; Ingraham, Cynthia M; Rodd, Zachary A et al. (2015) The reinforcing effects of ethanol within the posterior ventral tegmental area depend on dopamine neurotransmission to forebrain cortico-limbic systems. Addict Biol 20:458-68
McBride, William J; Rodd, Zachary A; Bell, Richard L et al. (2014) The alcohol-preferring (P) and high-alcohol-drinking (HAD) rats--animal models of alcoholism. Alcohol 48:209-15
Wilden, Jessica A; Qing, Kurt Y; Hauser, Sheketha R et al. (2014) Reduced ethanol consumption by alcohol-preferring (P) rats following pharmacological silencing and deep brain stimulation of the nucleus accumbens shell. J Neurosurg 120:997-1005
Toalston, Jamie E; Deehan Jr, Gerald A; Hauser, Sheketha R et al. (2014) Reinforcing properties and neurochemical response of ethanol within the posterior ventral tegmental area are enhanced in adulthood by periadolescent ethanol consumption. J Pharmacol Exp Ther 351:317-26
Hauser, Sheketha R; Deehan Jr, Gerald A; Toalston, Jamie E et al. (2014) Enhanced alcohol-seeking behavior by nicotine in the posterior ventral tegmental area of female alcohol-preferring (P) rats: modulation by serotonin-3 and nicotinic cholinergic receptors. Psychopharmacology (Berl) 231:3745-55
Ding, Zheng-Ming; Rodd, Zachary A; Engleman, Eric A et al. (2013) Alcohol drinking and deprivation alter basal extracellular glutamate concentrations and clearance in the mesolimbic system of alcohol-preferring (P) rats. Addict Biol 18:297-306

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