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. Increased nigral dopamine would itself cause the release of GABA, presynaptically, onto nigral efferent neurons. This would overinhibit nigral GABA-containing efferent neuronal pathways, disinhibiting motor areas in the thalamus, and result in dyskinesias. In support of the latter interpretation is the finding of a correlation in the mediodorsal thalamus between VCMs and GABAA binding. These findings may have implications for the pathophysiology of neuroleptic-induced dyskinesias in humans.
ASJC Scopus subject areas
- Developmental Neuroscience