Basal ganglia GABAA and dopamine D1 binding site correlates of haloperidol-induced oral dyskinesias in rat.
Chronic haloperidol treatment in the laboratory rat induces spontaneous orofacial movements in some but not all of the animals, a behavior which has been described in the literature as vacuous chewing movements (VCMs). In an attempt to understand the neurochemical mechanism of these rat dyskinesias, we measured regional dopamine D1, D2, and GABAA binding density in rats with and without VCMs after chronic haloperidol treatment and in untreated controls using in vitro receptor autoradiography and correlated the binding changes with the dyskinetic behavior. Chronic haloperidol treatment produced an overall increase in dopamine D2 family receptor binding in the caudate putamen and in nucleus accumbens in both groups of treated rats, those with and without VCMs. In the haloperidol-treated rats with VCMs, a significant increase in GABAA receptor density occurred in the substantia nigra pars reticulata (SNR), with a trend in those rats without VCMs. However, only in those haloperidol-treated animals with VCMs did a significant decrease in dopamine D1 receptor density occur in SNR. These receptor alterations are consistent with a process of haloperidol-induced neuronal death of striatonigral fibers. However, we have failed to identify cellular evidence of such toxicity. Alternatively, the receptor changes may reflect increased dendritic dopamine release in SNR, or, more speculatively a functional response to chronically diminished striatonigral pathway activity. Perhaps the release of dopamine from dendrites of the local DA-containing neurons might be variably enhanced with ongoing haloperidol treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Shirakawa
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University of Maryland, Department of Psychiatry, Maryland Psychiatric Research Center, Baltimore 21228.
Tamminga
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CA
D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism*; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D006220:Haloperidol / Q000633:toxicity*; D008297:Male; D009055:Mouth; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D012016:Reference Values
D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; D006220:Haloperidol