The long range goals of this project are to identify CNS sites, receptors and neurotransmitter systems involved in mediating the rewarding properties of alcohol. The overall hypotheses to be tested in the present proposal are that the posterior ventral tegmental area (VTA) dopamine (DA) neuronal system plays a major role in mediating ethanol (E) reinforcement and there is a relationship between the reinforcing properties of E in the posterior VTA and innate high alcohol drinking behavior. In support of these hypotheses, initial data indicate that Wistar rats will self-administer E directly into the posterior VTA and that self-infusion of E into the VTA is significantly different between lines of rats selectively bred for disparate alcohol drinking behaviors. However, E reinforcement in the VTA has not been fully characterized and it is not known if DA neurons may be mediating E reinforcement within the posterior VTA nor what receptors may be involved. The objectives of this proposal are to 1) characterize the reinforcing properties of E within the VTA of selectively-bred alcohol preferring P, alcohol non-preferring NP, high alcohol-drinking HAD and low alcohol drinking LAD lines of rats, and Wistar rats; 2) establish the involvement of VTA DA neurons and GABA A and 5HT3 receptors in mediating E reinforcement within the posterior VTA; and 3) examine the influence of alcohol drinking on the reinforcing effects of E within the posterior VTA. The technique of intra-cranial self- administration (ICSA) will be used to assess E reinforcement within the VTA. Microdialysis procedures will be used to measure changes in the extracellular levels of DA in the n. accumbens (ACB) as an index of VTA neuronal activity. Pharmacological studies will be undertaken to determine the effects of co-infusing D2, GABAA and 5HT3 receptor agents with alcohol in the posterior VTA on ICSA behavior. The results will establish a relationship between alcohol drinking and the reinforcing effects of E in the posterior VTA and will provide important information on neurotransmitter systems and receptors mediating the reinforcing actions of alcohol, which could be valuable in developing pharmacological strategies for the treatment of alcoholism and alcohol abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA012262-05
Application #
6727461
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Egli, Mark
Project Start
2000-04-01
Project End
2006-08-31
Budget Start
2004-04-01
Budget End
2006-08-31
Support Year
5
Fiscal Year
2004
Total Cost
$260,750
Indirect Cost
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; Hauser, Sheketha R et al. (2017) Reduced Levels of mGlu2 Receptors within the Prelimbic Cortex Are Not Associated with Elevated Glutamate Transmission or High Alcohol Drinking. Alcohol Clin Exp Res 41:1896-1906
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 109:41-48
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
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 nucleus accumbens shell involve activation of local GABA and serotonin receptors. J Psychopharmacol 29:725-33
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
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
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
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

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