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John C CrabbeMice that Drink Too Much: New Genetic Animal Models .

Abstract :


Many animal models have targeted alcohol abuse and dependence. In the rodent, the majority of such models have sought to increase alcohol self-administration using genetic or environmental manipulations, or their combination. Strictly genetic manipulations (e.g. comparison of inbred strains or targeted mutants of specific genes, selective breeding) have not yielded rat or mouse genotypes that will voluntarily self-administer alcohol to the point of intoxication unless rather extreme measures are taken. While some behavioral manipulations (e.g., scheduling and/or limiting access to alcohol, or alternating access with periods of dependence and withdrawal) can induce mice or rats to self-administer enough alcohol to become intoxicated, these typically require significant food or water restriction and/or a long time to perform. Susceptible (i.e., relatively high-intake) genotypes do not appear to be preferentially susceptible to these effective behavioral manipulations.

Some human alcoholics repeatedly drink to intoxication, even in the face of substantial physical and social feedback opposing this behavior. Thus, we sought to develop a mouse genetic animal model that self-administers sufficient alcohol to become intoxicated. Using a novel paradigm, limited access drinking in the circadian dark, we are selectively breeding High Drinking in the Dark (HDID) mice to ingest 20% alcohol until they reach blood alcohol levels (BALs) exceeding 100 mg%. These mice should be useful for mechanistic studies, and for pharmacological experiments designed to limit alcohol self-administration. These studies are supported by the Integrative Neuroscience Initiative on Alcoholism of the NIH-NIAAA (AA13519), the Portland Alcohol Research Center of the NIH-NIAAA (AA10760) and the US Department of Veterans Affairs.

Selected publications

Sex differences in acute ethanol withdrawal severity after adrenalectomy and gonadectomy in Withdrawal Seizure-Prone and Withdrawal Seizure-Resistant mice.Strong MN, Kaufman KR, Crabbe JC, Finn DA.Alcohol. 2009 Aug;43(5):367-77.
 
Binge drinking upregulates accumbens mGluR5-Homer2-PI3K signaling: functional implications for alcoholism. Cozzoli DK, Goulding SP, Zhang PW, Xiao B, Hu JH, Ary AW, Obara I, Rahn A, Abou-Ziab H, Tyrrel B, Marini C, Yoneyama N, Metten P, Snelling C, Dehoff MH, Crabbe JC, Finn DA, Klugmann M, Worley PF, Szumlinski KK.J Neurosci. 2009 Jul 8;29(27):8655-68.    
 
A line of mice selected for high blood ethanol concentrations shows drinking in the dark to intoxication.Crabbe JC, Metten P, Rhodes JS, Yu CH, Brown LL, Phillips TJ, Finn DA.Biol Psychiatry. 2009 Apr 15;65(8):662-70. Epub 2008 Dec 18.