Dopamine mechanisms of cocaine addiction

The ability of cocaine to induce a compulsive addictive behavior is the most astonishing feature of this drug. Attempting to understand the mechanisms underlying cocaine's addictive properties, two major questions should be considered: a) why and how organism's interaction with cocaine results in the development of new, drug-seeking and drug-taking behavior and b) why and how cocaine maintains this behavior when the drug is available. Since a large body of neuropharmacological evidence suggest that the mesocorticolimbic dopamine (DA) system has exclusive importance for the development and maintenance of cocaine addictive behavior, and cocaine is known to interfere in activity of this brain system, examination of mesocorticolimbic DA activity during cocaine self-administration behavior may provide some clues for understanding the drug's additive properties and regulation of this maladaptive goal-directed behavior. The aim of this paper is to discuss the literature and own experimental data on cocaine's action on the mesocorticolimbic DA system that may be involved in mediating its addictive properties. Based on these data, it is suggested that an inhibiting action of cocaine on reuptake of released DA, although essential, but not sufficient mechanism for the development and maintenance of addictive behavior. It is hypothesized, that coexistence of functionally antagonistic, inhibiting actions of cocaine on the mesolimbic DA release and reuptake of released DA may be responsible for biphasic fluctuations in DA transmission that appear to be a critical component of central oscillatory mechanism which drives and regulates cyclic drug-taking behavior.