Antipsychotic drug binding in the substantia nigra: An examination of high metoclopramide binding in the brains of normal,Alzheimer's disease,Huntington's disease,and Multiple Sclerosis patients,and its relation to tardive dyskinesia |
| |
Authors: | Sheng Chen Philip Seeman Fang Liu |
| |
Institution: | 1. Department of Neuroscience, Centre for Addiction and Mental Health, Clarke Division, Toronto, Ontario, Canada M5T 1R8;2. Department of Pharmacology, University of Toronto, 260 Heath St., West, Suite 605, Toronto, Canada M5P 3L6 |
| |
Abstract: | This project was done in order to determine why the annual incidence of metoclopramide‐associated tardive dyskinesia is much higher than that for the commonly used antipsychotics. To test the hypothesis that metoclopramide tardive dyskinesia may be associated with high concentrations of metoclopramide in the substantia nigra under clinical conditions, the nonspecific binding of tritiated antipsychotics to the dissected melaninized regions of postmortem human substantia nigra was measured. The nonspecific binding at 1 nM 3H]ligand was 7.3, 4.2, 2.6, 0.91 and 0.66 fmoles/mg for 3H]haloperidol, 3H]clozapine, 3H]raclopride, 3H]metoclopramide, and 3H]olanzapine, respectively. After adjusting these values for the known free concentrations of these drugs in plasma or spinal fluid, the amounts that would be bound under clinical conditions would be 231, 113, 15, 11, and 3.4 fmoles/mg for metoclopramide, clozapine, raclopride, haloperidol, and olanzapine, respectively. Using rat striatum as baseline to define antipsychotic binding to nonnigral tissue, the excess amount of binding to the Alzheimer nigral tissue under clinical conditions would be 209, 19, 0, 3.4 and 0.8 fmole/mg for metoclopramide, clozapine, raclopride, haloperidol, and olanzapine, respectively, with a similar pattern for nigral tissues from Huntington and Multiple Sclerosis patients. The high accumulation of metoclopramide is sufficiently high to cause nigral nerve cell membrane damage by metoclopramide's detergent‐like action, possibly explaining metoclopramide's toxic ability to elicit early tardive dyskinesia. In addition, the nonspecific binding of metoclopramide was much higher in Alzheimer‐diseased substantia nigra, consistent with the fact that older individuals are relatively more vulnerable to metoclopramide tardive dyskinesia. Synapse, 2011. © 2010 Wiley‐Liss, Inc. |
| |
Keywords: | antipsychotics metoclopramide tardive dyskinesia schizophrenia haloperidol olanzapine clozapine substantia nigra |
|
|