Ultrastructural correlates of haloperidol‐induced oral dyskinesias in rat striatum

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Abstract
Neuroleptics given chronically to rats induce behavioral sequelae which mimic tardive dyskinesia in some respects. The intent of this study was to investigate the ultrastructural correlates of oral dyskinesias (vacuous chewing movements [VCMs]), induced by chronic haloperidol treatment. After 6 months of treatment, rats were divided into low or high VCM groups. Rats in the high VCM group were either sacrificed on drug or were withdrawn from drug for 4 weeks. Ultrastructural analyses of the striatum indicated that synaptic density: (1) was significantly decreased in both the low and high VCM groups compared to normal controls; (2) was more profoundly decreased in the high VCM group as compared to the low VCM group; and (3) recovered to normal following drug withdrawal. Compared to controls, the density of asymmetric synapses was reduced by a similar magnitude in both the low and high VCM groups, suggesting that this change is a result of haloperidol treatment and independent of VCMs. Conversely, the density of symmetric synapses was reduced compared to normal, only in the high VCM group, suggesting that this change is specifically related to the expression of VCMs. In addition, mitochondria1 profiles were hypertrophied and less frequent in the high VCM group in comparison to controls; size, but not number, recovered following drug withdrawal. These results identify distinct ultrastructural correlates of chronic haloperidol treatment that are unique to rats that develop VCMs and suggest that these ultrastructural features may play a role in the pathophysiology of oral dyskinesias in rats.