TRANSGENIC MOUSE MODELS TO STUDY THE ROLE OF NEUROTENSIN RECEPTOR

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DESCRIPTION: The goal of this pilot project is to understand the role of the neurotensin receptor (NTR) gene in alcohol sensitivity. It has become increasingly clear that individual differences in alcohol sensitivity are genetically determined, and may translate into components of a genetic predisposition for alcoholism. Several lines of evidence suggest polygenic control of the behavioral and pharmacologic responses to ethanol. Specific candidate genes have been identified for the increased or decreased sensitivity to alcohol. Among these genes is the NTR, known to modulate central dopaminergic function. Pharmacological effects of neurotensin include hypothermia, altered locomotor activity, analgesia, muscle relaxation and neuroendocrine effects. It has been shown that neurotensin potentiates ethanol-induced sleep time and hypothermia implicating the NTR as a mediator in some of the actions of ethanol. Endogenous NTR levels are higher in various areas of the brain of LS than SS mice. Moreover recent studies show a significant positive correlation between NTR density and hypnotic sensitivity to ethanol using LSXSS RI strains. Consistently, HAS rats have higher NTR densities compared to the LAS further indicating the positive genetic correlation between the hypnotic sensitivity to ethanol and the NTR densities. NTR cDNAs have been cloned and sequenced in rat and human. We are in the process of sequencing the mouse NTR cDNA. Here we propose to test the hypothesis that NTR gene plays a critical role in the sensitivity to alcohol, by using an LSXSS RI (with low levels of NTR) transgenic mouse line having overexpression of the NTR. LAS further indicating the positive genetic correlation between the hypnotic sensitivity to ethanol and the NTR densities. NTR cDNAs have been cloned and sequenced in rat and human. We are in the process of sequencing the mouse NTR cDNA. For the 2-year period of this grant application, we therefore propose to: 1. Complete the sequence of the mouse NTR cDNA. 2. Use the mouse NTR cDNA to develop a NTR(u/u) (ultra-expression) transgenic mouse line. 3. Use the RI LSXSS and the NTR(u/u) mouse lines to investigate the role of NTR in ethanol sensitivity by means of initial sensitivity, hypnotic sensitivity and locomotor activity. These studies will greatly enhance our understanding about the role of NTR as a genetic factor associated with alcohol sensitivity. Because of high conservation between human and mouse genome studies with these intact mice should help to elucidate the mechanisms surrounding genetic differences in alcoholism.