Iron modulates neuroleptic-induced effects related to the dopaminergic system

Long-term neuroleptic medication to schizophrenic patients is often associated with extrapyramidal side effects, of which tardive dyskinesia is the most severe. The mechanism by which neuroleptics induce these side effects is unclear. The dopaminergic system is the main target with which the neuroleptics interact in the brain. Intact dopaminergic function is dependent on normal iron metabolism. Thus, the relationship between iron and the neuroleptics may elucidate some new aspects of their mechanism of action. Indeed, peripheral iron status plays a crucial role in neuroleptic-induced dopamine supersensitivity. Moreover, neuroleptics such as haloperidol and chlorpromazine, alter the blood brain barrier (BBB) of the rat and enhance the normally restricted iron transport into the brain. Increased brain iron levels may be related to the toxic effects of these drugs since clozapine, an atypical neuroleptic with a low incidence of extrapyramidal side effects, prohibits iron uptake into the brain but causes sedimentation of iron in brain blood vessels. The demonstration that peripheral iron concentrations affect neuroleptic-induced dopamine receptor supersensitivity as well as iron transport into the brain may have therapeutic significance. In addition, the different potentials of typical and atypical neuroleptics to increase iron transport into the brain may be related to the severity of the side effects they induce and to the pathophysiology of tardive dyskinesia.