Prevention of neuroleptic-induced dopamine D2 receptor supersensitivity by chronic iron salt treatment.
The ability of neuroleptics to induce dopamine D2 receptor supersensitivity has been linked to the onset of tardive dyskinesia, the major side-effect of these drugs. Brain iron metabolism has been shown to be involved in the regulation of dopamine D2 receptors. We now examined the effect of chronic treatment with FeCl2 on chlorpromazine-induced D2 receptor supersensitivity. The results show that FeCl2 (5 mg/kg per day for 21 days) given to rats treated with chlorpromazine (10 mg/kg per day, for 21 days) prevented the onset of supersensitive biochemical and behavioral (apomorphine) expressions of DA D2 receptor. Inclusion of iron did not affect the chlorpromazine-induced sedation or hypothermia. Moreover, the combined chronic iron-chlorpromazine treatment produced the same net effects as chronic chlorpromazine on striatal amounts of dopamine, DOPAC (dihydroxyphenylacetic acid) and HVA (homovanillic acid). Chlorpromazine medication caused a decrease in liver non-haem iron levels (40%) but not in brain iron. The effect of the neuroleptic drug on iron stores and the involvement of iron in the neuroleptic-induced dopamine supersensitivity suggest that mobilization of iron from the periphery into the brain may play an important role in the mechanism of action of the neuroleptics.
Department of Pharmacology, Faculty of Medicine, Rappaport Family Research Institute, Technion, Haifa, Israel.
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Ben-Shachar
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Pinhassi
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Youdim
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000037:antagonists & inhibitors*; D001058:Apomorphine / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects; D002746:Chlorpromazine / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism; D005296:Ferrous Compounds / Q000494:pharmacology*; D005609:Free Radicals; D006454:Hemoglobins / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D007501:Iron / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009410:Nerve Degeneration / Q000187:drug effects; D011388:Prolactin / Q000097:blood; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017448:Receptors, Dopamine D2; D013134:Spiperone / Q000378:metabolism
D014150:Antipsychotic Agents; D005296:Ferrous Compounds; D005609:Free Radicals; D006454:Hemoglobins; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D015102:3,4-Dihydroxyphenylacetic Acid; D013134:Spiperone; D011388:Prolactin; D007501:Iron; D001058:Apomorphine; C029451:ferrous chloride; D002746:Chlorpromazine; D004298:Dopamine; D006719:Homovanillic Acid