International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


POSTER 105 - A SCREEN FOR GENES OF ADDICTION: ENU MUTAGENESIS ON A DOPAMINE TRANSPORTER NULL BACKGROUND

A.R. Mohn
Duke University Medical Center

1) Hooker PE,1) Gainetdinov RR, 2) Caron MG
1) Duke University Medical Center 2) Howard Hughes Medical Institute, Duke University Medical Center

Psychostimulants such as cocaine, amphetamine, and methamphetamine elicit their psychoactive and addictive effects in large part by the disruption of dopamine transporter function. Dopamine transporter null mice (dat-/-) exhibit physiological and behavioral states similar to chronic psychostimulant exposure, including elevated extracellular dopamine, postsynaptic receptor downregulation, and hyperactivity. Mice with this genetic alteration can be used in a screen to identify new genes that modify the dat-/- phenotype. Such genes will be expected to interact with the dopamine system directly or indirectly. Because dopaminergic pathways are strongly implicated in reward mechanisms, a subset of these genes may in fact play a role in the process of addiction. Towards this goal, we have begun a dominant modifier screen, breeding ENU-induced mutations onto a dat null background. We have generated dat+/- and dat-/- G2 mice, which have been screened initially by assessing intrinsic locomotor activity. Dat-/- mice with a significantly attenuated or exacerbated phenotype have been identified as putative mutants carrying dominant modifying mutations. Further breeding and secondary phenotypic screens related to drug addiction will be performed before the process of chromosome positioning and eventual gene identification begins.A.R.M. is supported by NIMH training grant  5F32MH1276802. M.G.C. is an investigator of the Howard Hughes Medical Institute. This work was supported by a grant to the Consortium for Mouse Genetics of Addiction from the Zaffaroni Foundation.


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