Neuroleptic-induced supersensitivity and brain iron: I. Iron deficiency and neuroleptic-induced dopamine D2 receptor supersensitivity.
Previous studies have shown that nutritional iron deficiency in rats reduces brain iron content, resulting in dopamine D2 receptor subsensitivity, as indicated by a decrease in [3H]spiperone binding in caudate nucleus and in behavioral responses to apomorphine. Both phenomena can be reversed by iron supplementation. The possibility that neuroleptic-induced dopamine D2 receptor supersensitivity involves an alteration in brain iron content was investigated in nutritionally iron-deficient and control rats chronically treated with haloperidol (5 mg/kg daily for 14 or 21 days). Neuroleptic treatment was initiated either (a) concurrently with iron deficiency or (b) 2 weeks after the start of iron deficiency. The results show that dopamine D2 receptor subsensitivity, a feature of iron deficiency, is absent in haloperidol-treated, iron-deficient groups. On the contrary, these animals demonstrated biochemical and behavioral dopamine D2 receptor supersensitivity that is relatively greater than that observed with control, haloperidol-treated animals. Haloperidol (5 mg/kg daily for 21 days) as well as chlorpromazine (10 mg/kg daily for 21 days) caused a significant reduction (20-25%) in liver nonheme iron stores as compared with values in control rats. However, in iron-deficient rats, in which liver iron stores were almost totally depleted, haloperidol had no effect. The ability of chronic haloperidol treatment to prevent the reduction of dopamine D2 receptor number during iron deficiency may be associated with alteration of body iron status. Thus, less iron may result in an increase in free haloperidol available to the dopamine D2 receptor.
Ben-Shachar
D
D
Department of Pharmacology, Faculty of Medicine, Technion, Haifa, Israel.
Youdim
M B
MB
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D007501:Iron / Q000378:metabolism*; D000090463:Iron Deficiencies; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000502:physiology*; D017448:Receptors, Dopamine D2; D013997:Time Factors
D014150:Antipsychotic Agents; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D007501:Iron; D006220:Haloperidol