Biochemical adaptations in the mesolimbic dopamine system in response to heroin self-administration.
Previous studies have shown that chronic, forced exposure to opiates produces specific biochemical adaptations in the ventral tegmental area (VTA) and nucleus accumbens (NAc). The functional consequences of these adaptations have been hypothesized to contribute to certain motivational aspects of drug addiction. In this study, the possibility that similar adaptations could occur in response to intermittent heroin self-administration was tested by comparing homogenates of VTA and NAc from rats self-administering heroin, rats receiving yoked injections of heroin, and rats receiving yoked injections of saline (controls). Tyrosine hydroxylase (TH) immunoreactivity was increased (31-38%) in the VTA and decreased (11%) in the NAc of heroin-exposed rats relative to controls. Heroin exposure also increased cAMP-dependent protein kinase (PKA) activity in both particulate (19-27%) and soluble (17-20%) fractions of the NAc, and decreased (16-17%) the level of Gi alpha immunoreactivity in this brain region. In contrast, no significant biochemical changes were found in the substantia nigra or caudate-putamen, indicating a selective effect on the mesolimbic dopamine system. Overall, adaptations in the VTA and NAc of heroin-exposed rats were similar to, but generally smaller in magnitude than, adaptations produced by chronic morphine administration. However, in contrast to morphine-treated animals, heroin-exposed animals failed to display overt signs of opiate physical dependence, suggesting that adaptations in motivational systems may occur more readily than adaptations in brain regions associated with physical dependence.
Self
D W
DW
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
McClenahan
A W
AW
Beitner-Johnson
D
D
Terwilliger
R Z
RZ
Nestler
E J
EJ
D000222:Adaptation, Physiological; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D003932:Heroin / Q000008:administration & dosage* / Q000494:pharmacology; D008032:Limbic System / Q000378:metabolism*; D009020:Morphine / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D013681:Tegmentum Mesencephali / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D005904:Glial Fibrillary Acidic Protein; D003932:Heroin; D009020:Morphine; D014446:Tyrosine 3-Monooxygenase; D017868:Cyclic AMP-Dependent Protein Kinases; D004298:Dopamine