Pro-addictive and anti-addictive factors for drug dependence.

Drug dependence is defined as a chronically relapsing disorder that is characterized by compulsive drug taking, inability to limit intake, and intense drug cravings. The positive reinforcing/rewarding effects of drugs primarily depend on the mesocorticolimbic dopamine system innervating the nucleus accumbens while the craving for drugs is associated with activation of the prefrontal cortex. The chronic intake of drugs causes homeostatic molecular and functional changes in synapses, which may be critically associated with the development of drug dependence. Recent studies have demonstrated that various cytokines and proteinases are produced in the brain on treatment with drugs of abuse, and play a role in drug dependence. These endogenous modulators of drug dependence are divided into two groups, pro-addictive and anti-addictive factors. The former including tissue plasminogen activator, matrix metalloproteinase (MMP)-2 and MMP-9 act to potentiate the rewarding effects of drugs, while the latter such as tumor necrosis factor-alpha and glial cell line-derived neurotrophic factor reduce the reward. These findings suggest that an imbalance between pro-addictive and anti-addictive factors contributes to the development and relapse of drug dependence. Targeting these endogenous modulators would provide new therapeutic approaches to the treatment of drug dependence.