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The Journal of Neuroscience, 2001, 21:RC137:1-5

RAPID COMMUNICATION
Extinction Training Regulates Tyrosine Hydroxylase during Withdrawal from Cocaine Self-Administration

Eric F. Schmidt, Michael A. Sutton, Christina A. Schad, David A. Karanian, Edward S. Brodkin, and David W. Self

Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Yale University School of Medicine, New Haven, Connecticut 06508

Chronic exposure to drugs of abuse is known to modulate tyrosine hydroxylase (TH) levels in the mesolimbic dopamine system. In this study, 12 d of cocaine self-administration in rats (4 hr/d) reduced TH immunoreactivity by 29% in the nucleus accumbens (NAc) shell, but not core, after a 1 week withdrawal period. In contrast, TH immunoreactivity in the NAc was completely restored in animals that experienced extinction training (4 hr/d) during the same withdrawal period. Extinction training also increased TH levels in the ventral tegmental area (VTA) by 45%, whereas TH was not altered in the VTA by cocaine withdrawal alone. Thus, extinction-induced normalization of NAc TH levels could involve increased TH synthesis, stability, and/or transport from the VTA to the NAc. A similar extinction training regimen failed to alter TH levels in the NAc or VTA of rats trained to self-administer sucrose pellets, indicating that TH regulation in cocaine-trained animals is not a generalized effect of extinction learning per se. Rather, these data suggest that neuroadaptative responses during cocaine withdrawal ultimately are determined by a complex interaction between chronic drug exposure and drug-seeking experience. The ability of extinction training to restore NAc TH levels is hypothesized to accelerate recovery from dopamine depletion and anhedonia during cocaine withdrawal.

Key words: tyrosine hydroxylase; cocaine; dopamine; nucleus accumbens; ventral tegmental area; self-administration; extinction; withdrawal; addiction

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