Objective: To reproduce the side effects of antipsychotic drugs (drug-induced Parkinsonism and tardive dyskinesia) in rats and elucidate its pathomechanism by examining morphological changes in the neurons that make up the basal ganglia circuit.

Background: Recently, the use of second-generation antipsychotic drugs to replace first-generation drugs has increased. While second-generation antipsychotics are considered to have fewer side effects, drug-induced Parkinsonism (DIP) and tardive dyskinesia (TD) occur in approximately 30% and 20% of patients, respectively. It has been speculated that their acute administration produces DIP by blocking D2 receptors on striatal indirect pathway neurons, whereas chronic administration produces TD by increasing the number of D2 receptors, increasing dopamine input and indirect pathway inhibition.

Method: Twenty male Wistar rats were administered either haloperidol decanoate (n = 15) or a placebo (n = 5) every three weeks for six months. After treatment, vacuous chewing movement (VCM), which is equivalent to the TD, was measured. We also assessed the rotarod and open-field tests, which reflect DIP. Rats with a VCM of eight or more per 2 min were classified into the severe TD group, whereas those with fewer were classified into the mild TD group. Three weeks after treatment, the internal and external segments of the globus pallidus (GPi and GPe) and the output targets of the direct and indirect pathways from the striatum, respectively, were observed using electron microscopy (EM), while protein expression was evaluated by western blotting.

Results: Rats treated with haloperidol exhibited VCMs. Treatment resulted in impaired performance in the rotarod and open field tests. EM revealed a significant enlargement of the area of the axon terminals in the GPi in the treatment group compared with the control. No significant differences were observed in these areas between the mild and severe TD groups. The expression of dynorphin, a direct pathway marker, decreased with haloperidol treatment, albeit without a significant difference between the mild and severe TD groups. Enkephalin expression, a marker of indirect pathway, was significantly lower in the severe TD group. The tyrosine hydroxylase levels were not significantly different among the three groups.

Conclusion: Haloperidol-induced movement disorders involve both indirect and direct pathways.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/drug-induced-parkinsonism-and-tardive-dyskinesia-in-rats-chronically-treated-with-haloperidol/