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Addiction - Models Of Addiction

genetic alcohol systems mice genes

Progress in genetic analysis of addiction in animal models has been more successful. The pharmacologic effects of abused substances can readily be demonstrated in many model systems, from worms to rodents. Rodents can be trained to voluntarily consume alcohol and other abused substances. Once trained, these rodents will expend energy to continue to receive drugs and will display withdrawal symptoms when denied drugs. Chromosomal regions with naturally occurring variants that affect voluntary consumption, intoxication, and withdrawal have been mapped in mice. The specific genes responsible for these effects have not yet been identified.

Cell biology and neurochemistry studies in humans and model systems have identified many molecules that have altered abundance and distribution, enzymes with altered activity, and genes with altered expression resulting from substance abuse. In particular, the dopamine and serotonin neurotransmitter systems have been the focus of intense studies. These are brain systems directly involved in many basic responses, including pleasure and reward systems.

To directly test the role of specific genes and pathways, mice have been engineered to delete or over-express genes. Mice lacking any of these genes (called PKCε, DRD2, and DBH) are more sensitive to the effects of alcohol and consume less alcohol. In contrast, mice lacking any one of four other genes (PKA regulatory IIβ, NPY, or 5-HT1b) are less sensitive to the effects of alcohol and consume more alcohol. Mice cannot be trained to self-administer alcohol if they lack the Mu opioid receptor, which is involved in transmitting signals to the body's own internal opiate system.

Mutant fruit flies with altered responses to alcohol intoxication have also been created. Two mutants, called "cheapdate" and "amnesiac," arise from different mutations in the same gene. These mutations affect the cellular level of the signal transduction molecule cyclic-AMP. As the names imply, flies with cheapdate mutations are very sensitive to the affects of alcohol, and flies with amnesiac mutations are unable to learn.

The major conclusion from work in model systems is that the pathways and systems involved in addiction are central to normal behaviors with instinctive reward processes, such as feeding and procreation. Addiction is a process that involves learning and the subversion of these basic reward pathways.

Kirk C. Wilhelmsen

Bibliography

American Psychiatric Association Task Force on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994.

Begleiter, Henri, and Benjamin Kissan, eds. The Genetics of Alcoholism. New York: Oxford University Press, 1995.

Tamara J. Phillips, et al. "Alcohol Preference and Sensitivity Are Markedly Reduced in Mice Lacking Dopamine D2 Receptors." Nature Neuroscience 1 (1998): 610-615.

Theile, Todd, et al. "Ethanol Consumption and Resistance Are Inversely Related to Neuropeptide Y Levels." Nature 396 (1998): 366-369.

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