The dopamine hypothesis of drug addiction: Hypodopaminergic state

Drug addiction is a brain disorder caused by the repetitive use of various chemicals which alter normal functioning of the central nervous system with consequent behavioral abnormalities. In the search to understand which neuro- transmitter systems play upon this behavioral pathology, dopamine has long been thought to play a prima donna role. However, its primary role is commonly and erroneously attributed to the increase in activity after acute administration of addicting drugs. On the contrary, the mesolimbic dopamine transmission ap- pears to be drastically reduced in its tonic activity when measured in animal models, which mimic the human condition of drug addiction, and in the avail- able human studies conducted in addicted subjects. This paper is a systematic review of the pertinent literature which strongly supports this concept. Various experimental approaches such as electrophysiological, biochemical, behavioral, biomolecular and even anatomical, show that dopamine neurons work insuY- ciently in the crucial phases of the entire drug addiction cycle such as withdrawal from chronic treatment. This hypodopaminergic state is viewed as one of the main causes that triggers drug-seeking and taking, even after prolonged drug-free periods, perpetuating the vicious cycle. In addition, albeit reduced in its activity, the system remains hyperresponsive to abused drugs conferring long-lasting vulnerability to the system. We propose that decreased dopamine function in addicted subjects results in a decreased interest to non drug-related stimuli and increased sensitivity to the drug of choice. Targeting the dopamine system with pharmacological agents, not necessarily classic receptor-oriented drugs, aimed at restoring dopamine transmission may reveal useful new avenues in the treatment of this socially debilitating brain pathology.