One year of continuous treatment with haloperidol or clozapine fails to induce a hypersensitive response of caudate putamen neurons to dopamine D1 and D2 receptor agonists.
In a "blind" experimental design, the sensitivity of caudate-putamen (CPu) cells to the selective dopamine (DA) D1 receptor agonist SKF-38393 and D2 receptor agonist LY171555 (quinpirole) in rats treated with either haloperidol (HAL), clozapine or tap water for 1 year was compared using the techniques of single cell recording and microiontophoresis. Although the maximum binding value for D2 receptors was elevated in chronic HAL-treated rats, there was no sign of electrophysiological supersensitivity of CPu neurons to the selective DA D1 and D2 receptor agonists. CPu cells were subsensitive to LY-171555 in HAL-treated rats without a drug withdrawal period. This suggests that residual HAL in the rat brain actively blocked the D2 DA receptors. In contrast, in clozapine-treated rats with or without a drug withdrawal period, the sensitivity of CPu cells to either the D1 or D2 agonists was not altered. Coadministration of SKF-38393 and LY-171555 onto the CPu neurons primarily produced an additive effect and only two cells both from the HAL group showed a synergistic action. The majority of CPu cells failed to respond to iontophoretic application of CCK-8S in either the control or antipsychotic drug-treated rats. If these findings can be extended to humans, they do not support the view that tardive dyskinesia is the result of CPu DA receptor supersensitivity.
Jiang
L H
LH
Department of Psychiatry and Behavioral Sciences, State University of New York, Stony Brook.
Kasser
R J
RJ
Altar
C A
CA
Wang
R Y
RY
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D003024:Clozapine / Q000008:administration & dosage / Q000494:pharmacology*; D003984:Dibenzazepines / Q000494:pharmacology*; D015259:Dopamine Agents / Q000494:pharmacology*; D004347:Drug Interactions; D004873:Ergolines / Q000494:pharmacology*; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects; D011699:Putamen / Q000187:drug effects* / Q000378:metabolism; D019257:Quinpirole; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism
D003984:Dibenzazepines; D015259:Dopamine Agents; D004873:Ergolines; D011954:Receptors, Dopamine; D019257:Quinpirole; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D003024:Clozapine; D006220:Haloperidol