Determination of the precise mechanisms of ethanol's actions on CNS neurotransmitter function has been the focus of much ongoing investigative effort. Use of an animal model of genetic differences in initial CNS sensitivity to ethanol (LS and SS mice) has provided evidence that certain of the behavioral actions of ethanol may be mediated by this agent's differential effects on monoaminergic neuronal systems in specific brain regions and the adrenal gland. It has also been determined that LS and SS mice differ substantially in the extent of the analeptic response to thyrotropin-releasing hormone (TRH) following ethanol administration. Although controversy exists as to the exact sites and mechanism of TRH's analeptic action it is believed to involve activation of central cholinergic and/or monoaminergic neurons. A thorough examination of TRH effects on monoamine function in LS and SS mice in the presence and absence of ethanol should provide further insight into the neurochemical mechanisms mediating both the CNS depression by ethanol and its antagonism by TRH. Similar experiments will be conducted with pentobarbital, a CNS depressant to which LS and SS mice do not differ in initial CNS sensitivity, and the results compared to those obtained with ethanol. Initial studies will include a comparison of the effects of TRH with various TRH analogs (possessing improved pharmacokinetic and non-endocrine profiles) on behavioral actions of ethanol or pentobarbital, i.e., narcosis and hypothermia. Subsequently, the effects of TRH and TRH analogs on these behavioral measures of ethanol and pentobarbital intoxication will be correlated with their effects on ethanol-induced alterations of monoamine neurochemistry. Aspects of monoamine function to be evaluated in brain regions and adrenal gland include: (1) monoamine synthesis by performing in vitro kinetic analysis of the enzymes tyrosine and tryptophan hydroxylase as well as in vivo estimates of enzyme activity by measuring the accumulation of dopa and 5-hydroxytryptophan, respectively, following treatment with a decarboxylase inhibitor, (2) levels of the enzyme substrates, tyrosine and tryptophan, (3) availability of the enzyme cofactor by measuring biopterin levels and the activity of its synthetic enzyme, GTP-cyclohydrolase, and (4) monoamine release (overflow) in vivo in specific brain regions by employing both electrochemical and microdialysis techniques. Finally, in order to assess the possible contribution of the pituitary-thyroid axis to the analeptic and thermogenic actions of acute TRH and TRH analog administration, we will evaluate their effects on thyroid function, including serum thyrotropin (TSH) triiodothyronine (T3), and thyroxine (T4) levels, % hormone uptake, and free hormone index, in the presence and absence of ethanol and pentobarbital.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
2P50AA003527-21
Application #
2778001
Study Section
Project Start
Project End
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
21
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Bennett, B; Carosone-Link, P; Beeson, M et al. (2008) Genetic dissection of quantitative trait locus for ethanol sensitivity in long- and short-sleep mice. Genes Brain Behav 7:659-68
Vasiliou, Vasilis; Ziegler, Thomas L; Bludeau, Pequita et al. (2006) CYP2E1 and catalase influence ethanol sensitivity in the central nervous system. Pharmacogenet Genomics 16:51-8
Bowers, Barbara J; Miyamoto-Ditmon, Jill; Wehner, Jeanne M (2006) Regulation of 5-HT2A/C receptors and DOI-induced behaviors by protein kinase Cgamma. Pharmacol Biochem Behav 85:441-7
Zimatkin, Sergey M; Pronko, Sergey P; Vasiliou, Vasilis et al. (2006) Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol Clin Exp Res 30:1500-5
Radcliffe, Richard A; Bludeau, Pequita; Asperi, William et al. (2006) Confirmation of quantitative trait loci for ethanol sensitivity and neurotensin receptor density in crosses derived from the inbred high and low alcohol sensitive selectively bred rat lines. Psychopharmacology (Berl) 188:343-54
Smith, Amy M; Bowers, Barbara J; Radcliffe, Richard A et al. (2006) Microarray analysis of the effects of a gamma-protein kinase C null mutation on gene expression in striatum: a role for transthyretin in mutant phenotypes. Behav Genet 36:869-81
Bowers, Barbara J; Radcliffe, Richard A; Smith, Amy M et al. (2006) Microarray analysis identifies cerebellar genes sensitive to chronic ethanol treatment in PKCgamma mice. Alcohol 40:19-33
Haughey, Heather M; Kaiser, Alan L; Johnson, Thomas E et al. (2005) Norepinephrine transporter: a candidate gene for initial ethanol sensitivity in inbred long-sleep and short-sleep mice. Alcohol Clin Exp Res 29:1759-68
Wu, Peter H; Poelchen, Wolfgang; Proctor, William R (2005) Differential GABAB Receptor Modulation of Ethanol Effects on GABA(A) synaptic activity in hippocampal CA1 neurons. J Pharmacol Exp Ther 312:1082-9
Quertemont, Etienne; Eriksson, C J Peter; Zimatkin, Sergey M et al. (2005) Is ethanol a pro-drug? Acetaldehyde contribution to brain ethanol effects. Alcohol Clin Exp Res 29:1514-21

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