Glutamatergic mechanisms in addiction

Glutamate plays a role in various aspects of addiction: Glutamatergic pathways, especially the projection from the prefrontal cortex to the midbrain dopamine neurons and to the nucleus accumbens, are integral parts of the brain reward system. The temporal and spatial pattern of dopamine activity in these nuclei is shaped by glutamate. Experimental interference with glutamatergic mechanisms alters the rewarding effects of addictive drugs. Most importantly, glutamatergic mechanisms mediate the plastic changes that characterize the transition from controlled drug-intake to addiction. A process of sensitization may underly this transition since sensitization renders the brain re-ward system hyperreactive to addictive drugs. Similar to addiction sensitization is build up gradually and is very stable, nearly inextinguishable; it is therefore considered to play a major role in the formation of an "addiction memory". In withdrawal states glutamatergic activity is assumed to be increased. Reports of reinstatement of drug-seeking behaviour by glutamate-agonists in rats fit to this view as well as the therapeutical efficacy of the anticraving drug acamprosate which is a NMDA receptor-antagonist.