| The effects of chronic morphine and chronic cocaine on protein phosphorylation were studied in the mesolimbic dopamine system of the rat brain. These drug treatments were found to regulate the same subset of phosphoproteins in the ventral tegmental area (VTA), and these proteins were termed "MCRPPs": Morphine and Cocaine-Regulated PhosphoProteins. One of these proteins, tyrosine hydroxylase, was regulated both in cell bodies of the VTA and in nerve terminals of the nucleus accumbens. As tyrosine hydroxylase is the rate-limiting enzyme in catecholamine biosynthesis, drug-regulation of this enzyme may reflect alterations in dopaminergic neurotransmission in these brain regions. Several other phosphoproteins regulated similarly by chronic morphine and chronic cocaine were identified as neurofilament proteins. Morphine- and cocaine-regulation of phosphoproteins showed regional specificity, in that such regulation was not observed in a number of other brain regions, including the substantia nigra, which is also comprised of dopaminergic neurons, but is generally not implicated in drug reward. Morphine- and cocaine-regulation of these phosphoproteins also exhibited pharmacological specificity, in that no alterations in levels of tyrosine hydroxylase or neurofilaments in the VTA were observed in rats treated chronically with two non-abused psychotropic drugs, imipramine or haloperidol. Another morphine-regulated phosphoprotein (MRPP-51) was identified as glial fibrillary acidic protein (GFAP). Morphine-regulation of GFAP was regionally specific, and was observed in rats treated chronically with morphine, but not with chronic cocaine. Levels of phosphoproteins were also studied in two inbred rat strains, Lewis and Fischer rats, which represent genetically divergent populations of rats that show different levels of preference for several types of drugs of abuse. Levels of several of these phosphoproteins in the mesolimbic dopamine system of drug-naive Lewis rats, compared to Fischer rats, closely resembled the effects of chronic morphine and cocaine in outbred Sprague-Dawley rats. It was also found that neurofilaments are substantially enriched in the VTA, compared to most other regions of the rat brain, suggesting that the VTA may display some specialized function subserved by neurofilament proteins. The results are consistent with the possibility that these phosphoproteins may mediate aspects of drug reinforcement and contribute to individual vulnerability to drug addiction. |
