Molecular mechanisms of drug addiction in the mesolimbic dopamine pathway

Studies of intracellular messenger proteins have offered a novel approach by which to obtain a more complete understanding of the molecular mechanisms underlying drug addiction. We have identified some common biochemical adaptations induced by chronic morphine, cocaine and, in preliminary studies, alcohol, in the mesolimbic dopamine system. These adaptations include decreased levels of specific G-protein subunits and increased levels of the cyclic AMP second messenger and protein phosphorylation pathway in the nucleus accumbens (NAcc), and increased levels of tyrosine hydroxylase and decreased levels of neurofilament proteins in the ventral tegmental pathway. In addition, inherent differences in these same proteins have been demonstrated between Lewis and Fischer rats, inbred strains that show different behavioral responses to several drugs of abuse, and among individual outbred Sprague-Dawley rats which correlate with individual differences in several drug-related behaviors. These studies promise to reveal mechanisms by which drugs of abuse induce addictive changes in brain function, as well as some of the genetic and environmental factors that contribute to individual vulnerability to drug addiction.