BASAL GANGLIA GABA(A) AND DOPAMINE D-1 BINDING-SITE CORRELATES OF HALOPERIDOL-INDUCED ORAL DYSKINESIAS IN RAT

Chronic haloperidol treatment in the laboratory rat induces spontaneou s orofacial movements in some but not all of the animals, a behavior w hich has been described in the literature as vacuous chewing movements (VCMs). In an attempt to understand the neurochemical mechanism of th ese rat dyskinesias, we measured regional dopamine D1, D2, and GABAA b inding density in rats with and without VCMs after chronic haloperidol treatment and in untreated controls using in vitro receptor autoradio graphy and correlated the binding changes with the dyskinetic behavior . Chronic haloperidol treatment produced an overall increase in dopami ne D2 family receptor binding in the caudate putamen and in nucleus ac cumbens in both groups of treated rats, those with and without VCMs. I n the haloperidol-treated rats with VCMs, a significant increase in GA BAA 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 d opamine D1 receptor density occur in SNR, These receptor alterations a re consistent with a process of haloperidol-induced neuronal death of striatonigral fibers. However, we have failed to identify cellular evi dence of such toxicity. Alternatively, the receptor changes may reflec t 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 haloperi dol treatment. Increased nigral dopamine would itself cause the releas e of G;ABA, presynaptically, onto nigral efferent neurons. This would overinhibit nigral GABA-containing efferent neuronal pathways, disinhi biting motor areas in the thalamus, and result in dyskinesias. In supp ort of the latter interpretation is the finding of a correlation in th e mediodorsal thalamus between VCMs and GABAA binding. These findings may have implications for the pathophysiology of neuroleptic-induced d yskinesias in humans. (C) 1994 Academic Press, Inc.