Ethanol-induced reinforcement (i.e., elicitation of a pleasurable response to ingestion of ethanol), and the generation of craving for ethanol after chronic ingestion of ethanol, have been considered as phenomena which involve the neuronal systems projecting to an area of brain identified as the nucleus accumbens. The dopaminergic systems projecting to the nucleus accumbens and the post-receptor signal transduction systems (i.e., G proteins, adenylyl cyclases, protein kinase A) of cells receiving this dopaminergic input have been implicated in the reinforcing and craving phenomena associated with intake of cocaine, amphetamine and opiates. The data regarding ethanol's actions are more sparse. We will, therefore, identify with in situ hybridization techniques which adenylyl cyclases are expressed in the nucleus accumbens of rats. We will characterize the activity of these enzyme(s) in the presence and absence of ethanol in vitro and we will then detail the effects of chronic ethanol intake on the various components of the dopamine receptor-modulated cAMP signaling cascade in the nucleus accumbens. D1 and D2 dopamine receptors will be quantified by use of autoradiographic and membrane binding techniques, G protein alpha and beta gamma subunits will be examined with immunohistochemistry and quantitative Western blotting techniques, mRNA for specific adenylyl cyclases will be examined using RNAse protection assays and adenylyl cyclase proteins and their distribution will be measured with immunohistochemical and Western blotting techniques. The activity of adenylyl cyclase(s) under various stimulatory and inhibitory conditions and the activity of PKA will be examined in nucleus accumbens tissue obtained from control and ethanol-treated animals. Finally, to provide further insights into the relationship of the cAMP signalling cascade and inherent levels of ethanol consumption by animals, we will perform a phenotypic and genetic correlation analysis of the adenylyl cyclase systems in the nucleus accumbens and the alcohol preferences of HAD (alcohol preferring) and LAD (alcohol non-preferring) rats and their F1, F2 and backcross offspring. These later studies will be guided by our initial work with control and ethanol treated animals with regard to the optimal parameters of the adenylyl cyclase systems to be examined in the HAD and LAD rats and their offspring. Our studies, in total, should shed light on important components of ethanol's actions which may be intimately related to the addictive properties of ethanol as well as other drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA009014-09
Application #
2894033
Study Section
Special Emphasis Panel (ZRG4-ALTX-3)
Project Start
1991-08-01
Project End
2001-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
9
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Bhave, Sanjiv V; Hoffman, Paula L (2004) Phosphatidylinositol 3'-OH kinase and protein kinase A pathways mediate the anti-apoptotic effect of pituitary adenylyl cyclase-activating polypeptide in cultured cerebellar granule neurons: modulation by ethanol. J Neurochem 88:359-69
Nelson, Eric J; Hellevuo, Kaisa; Yoshimura, Masami et al. (2003) Ethanol-induced phosphorylation and potentiation of the activity of type 7 adenylyl cyclase. Involvement of protein kinase C delta. J Biol Chem 278:4552-60
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Kirstein, S L; Tabakoff, B (2001) Genetic correlations between initial sensitivity to Ethanol and brain cAMP signaling in inbred and selectively bred mice. Alcohol Clin Exp Res 25:791-9
Tabakoff, B; Nelson, E; Yoshimura, M et al. (2001) Phosphorylation cascades control the actions of ethanol on cell cAMP signalling. J Biomed Sci 8:44-51
Yoshimura, M; Wu, P H; Hoffman, P L et al. (2000) Overexpression of type 7 adenylyl cyclase in the mouse brain enhances acute and chronic actions of morphine. Mol Pharmacol 58:1011-6
Bhave, S V; Snell, L D; Tabakoff, B et al. (1999) Ethanol sensitivity of NMDA receptor function in developing cerebellar granule neurons. Eur J Pharmacol 369:247-59
Yoshimura, M; Tabakoff, B (1999) Ethanol's actions on cAMP-mediated signaling in cells transfected with type VII adenylyl cyclase. Alcohol Clin Exp Res 23:1457-61
Rabbani, M; Nelson, E J; Hoffman, P L et al. (1999) Role of protein kinase C in ethanol-induced activation of adenylyl cyclase. Alcohol Clin Exp Res 23:77-86

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