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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.
Synapse 2011; 65(2):119-24S

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.

Authors+Show Affiliations

Department of Neuroscience, Centre for Addiction and Mental Health, Clarke Division, Toronto, Ontario, Canada M5T 1R8.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

20524177

Citation

Chen, Sheng, et al. "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." Synapse (New York, N.Y.), vol. 65, no. 2, 2011, pp. 119-24.
Chen S, Seeman P, Liu F. 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. Synapse. 2011;65(2):119-24.
Chen, S., Seeman, P., & Liu, F. (2011). 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. Synapse (New York, N.Y.), 65(2), pp. 119-24. doi:10.1002/syn.20825.
Chen S, Seeman P, Liu F. 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. Synapse. 2011;65(2):119-24. PubMed PMID: 20524177.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Chen,Sheng, AU - Seeman,Philip, AU - Liu,Fang, PY - 2010/6/5/entrez PY - 2010/6/5/pubmed PY - 2011/4/2/medline SP - 119 EP - 24 JF - Synapse (New York, N.Y.) JO - Synapse VL - 65 IS - 2 N2 - 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. SN - 1098-2396 UR - https://www.unboundmedicine.com/medline/citation/20524177/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_ L2 - https://doi.org/10.1002/syn.20825 DB - PRIME DP - Unbound Medicine ER -