Age-related susceptibility to chronic haloperidol-induced orofacial dyskinesia: Biochemical and neurochemical evidence

Objective: Aging is a continuous and intrinsic process of systems deterioration with time. Although the mean prevalence of tardive dyskinesia (TD), a neurological disorder associated with chronic haloperidol administration, is 20-25%, the cumulative rate of this disorder increases significantly in patients aged 55 years or more. The present study investigated the effect of aging on spontaneous development of orofacial dyskinesia and tried to find out the interactive substrate which is activated by chronic neuroleptic treatment and results in premature emergence of TD in adult animals. Materials and Methods: Various behavioral (orofacial dyskinetic movements, stereotypy, locomotor activity, and percent retention); biochemical (lipid peroxidation, reduced glutathione levels, and antioxidant enzyme levels: SOD and catalase); and neurochemical (neurotransmitter levels) parameters were assessed in young (60-80 gm), matured adult (180-200 gm), and aged (380-400 gm) rats. Results: Aging resulted in significant increase in hyperkinetic motor activities, vacuous chewing movements (VCMs), tongue protrusions, facial jerking, and development of dopamine supersensitivity (increased locomotor activity and stereotypy); there was also associated oxidative damage in all regions of the brain. The extracellular dopamine levels were also significantly decreased (45%) in the forebrain of aged animals. Chronic administration of haloperidol to aged animals further significantly increased all the parameters as compared to age-matched control animals. Chronic administration of haloperidol to matured adult animals showed similar changes, especially hyperkinetic movements, and oxidative damage in different parts of the brain. There was no significant change in young animals on chronic administration of haloperidol. Conclusion: The findings of the present study suggest that free radical generation and development of dopamine supersensitivity are the prime interactive substrates that are activated by chronic neuroleptic treatment in matured animals and are responsible for the development of TD, whereas these paradigms are increased with aging and result in spontaneous orofacial hyperkinetic movements.