The role of dopamine, dynorphin, and CART systems in the ventral striatum and amygdala in cocaine abuse.

Disturbance of the mesolimbic dopamine system has long been hypothesized for the underlying neurobiology of cocaine addiction. Recently, increased attention has been directed towards the opioid neuropeptide system, in particular dynorphin; inasmuch as opioid peptide-containing neurons are regulated by dopamine, these peptides have potent effects on mood and reward, and cocaine consistently modulates dynorphin activity. Our experiments have been directed towards characterizing the specific alterations of dopamine and dynorphin systems during different stages following cocaine administration, as well as assessing the contribution of nucleus accumbens and amygdala dopamine levels to cocaine-intake behavior. We have used the techniques of in vivo microdialysis to measure and manipulate extracellular concentrations of dopamine in animals that self-administer cocaine, and in situ hybridization to study mRNA expression levels of prodynorphin and dopamine receptors. It is clear from these studies that different stages of the cocaine use cycle are characterized by distinct patterns of prodynorphin and dopamine D1 mRNA expression levels. Moreover, cocaine-intake behavior is sensitive to very specific concentrations of dopamine in the nucleus accumbens as well as in the amygdala. Recently, the CART (cocaine and amphetamine-regulated transcript) peptide was proposed as a novel target for the actions of psychostimulant drugs. We have noted differences between male and female rats in the mesolimbic mRNA expression of CART that might be relevant for gender differences apparent in drug abuse.