Extinction training regulates tyrosine hydroxylase during withdrawal from cocaine self-administration.
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.
Schmidt
E F
EF
Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
Sutton
M A
MA
Schad
C A
CA
Karanian
D A
DA
Brodkin
E S
ES
Self
D W
DW
D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D005108:Extinction, Psychological / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009714:Nucleus Accumbens / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000378:metabolism*
D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine