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Journal of Neuroscience, Vol 12, 2165-2176, Copyright © 1992 by Society for Neuroscience
Neurofilament proteins and the mesolimbic dopamine system: common regulation by chronic morphine and chronic cocaine in the rat ventral tegmental area
D Beitner-Johnson, X Guitart and EJ Nestler
Department of Pharmacology, Yale University School of Medicine, Connecticut Mental Health Center, New Haven 06508.
The ventral tegmental area (VTA) and its dopaminergic projections appear to
mediate some of the rewarding properties of opiates, cocaine, and other
drugs of abuse. In a previous study, we demonstrated that chronic morphine
and cocaine exert common actions on tyrosine hydroxylase, the rate-limiting
enzyme in catecholamine biosynthesis, in this dopaminergic brain reward
region (Beitner-Johnson and Nestler, 1991). In the present study, we
investigated the effects of chronic morphine and cocaine on other
phosphoproteins in the VTA by back phosphorylation and two-dimensional
electrophoretic analysis. It was found that a number of phosphoproteins, in
addition to tyrosine hydroxylase, were regulated similarly by the two drug
treatments in this brain region. Several of these morphine- and
cocaine-regulated phosphoproteins were identified as neurofilament (NF)
proteins. Chronic, but not acute, administration of either morphine or
cocaine was found to decrease levels of the three NF proteins, NF-200
(NF-H), NF-160 (NF-M), and NF-68 (NF-L), by between 15% and 50% in the VTA
by back phosphorylation, immunolabeling, and Coomassie blue staining. Such
regulation of NF proteins was selective, in that no detectable changes were
observed in the levels of eight other major cytoskeletal or
cytoskeletal-associated proteins analyzed. Furthermore, NF levels were not
altered by chronic treatment with either imipramine or haloperidol, two
psychotropic drugs without reinforcing properties, or by chronic stress.
Morphine and cocaine regulation of NFs showed regional specificity, as NF
levels were not altered in the substantia nigra, or other parts of the
brain or spinal cord, by these drug treatments. NFs are thought to function
as determinants of neuronal morphology and to be associated with axonal
transport. Thus, decreased NF levels in the VTA in response to chronic
morphine and chronic cocaine could lead to drug-induced alterations in the
structural and functional properties of this brain region, which may
represent, in turn, part of a common biochemical basis of morphine and
cocaine addiction and craving.
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