Coadministration of haloperidol and SCH-23390 prevents the increase in "perforated" synapses due to either drug alone.
Perforated synapses, which have a discontinuous density along the postsynaptic membrane, undergo changes in numbers under various experimental conditions. We have previously shown that 14-day administration of haloperidol, a typical neuroleptic which induces extrapyramidal side effects (EPS) and tardive dyskinesia (TD) in patients, causes an increase in the percentage of perforated synapses within the caudate nucleus. This increase was reversed if the animals were taken off the drug for an equal period of time (14 days). There was no effect within the nucleus accumbens. The atypical antipsychotic drug, clozapine, which when administered precipitates a very much lower incidence of EPS and TD, had no effect on the percentage of perforated synapses within either the caudate or nucleus accumbens. Because clozapine binds to both dopamine (DA) D1 and D2 receptors, it was of interest to determine if any changes in perforated synapses occurred following administration of the specific D1 antagonist, SCH-23390. Furthermore, because the action of D2 agonist may be dependent on the activation of the D1 receptor, we asked whether concomitant blockade of the D1 receptor could prevent the increase in perforated synapses due to the action of haloperidol, a drug which upregulates D2 receptors. We found that 14-day treatment with SCH-23390 (1.0 mg/kg per day) or haloperidol (0.5 mg/kg per day) caused an increase in the percentage of perforated synapses within the caudate but not the nucleus accumbens. There was a corresponding increase in DA D1 and D2 receptors in the caudate following administration of SCH-23390 or haloperidol, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Meshul
C K
CK
Laboratory Service, Veteran Affairs Medical Center, Portland, Oregon 97201.
Janowsky
A
A
Casey
D E
DE
Stallbaumer
R K
RK
Taylor
B
B
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002421:Caudate Nucleus / Q000187:drug effects / Q000648:ultrastructure; D006220:Haloperidol / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008854:Microscopy, Electron; D009714:Nucleus Accumbens / Q000187:drug effects / Q000648:ultrastructure; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D013569:Synapses / Q000187:drug effects* / Q000648:ultrastructure
D001552:Benzazepines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D006220:Haloperidol