Abstract
Haloperidol-induced dyskinesia has been linked to a reduction in dopamine activity characterized by the inhibition of dopamine receptive sites on D2-receptor (D2R). As a result of D2R inhibition, calcium-linked neural activity is affected and seen as a decline in mo-tor-cognitive function after prolonged haloperidol use in the treatment of psychotic disorders. In this study, we have elucidated the relationship between haloperidol-induced tardive dyskinesia and the neural activity in motor cortex (M1), basal nucleus (CPu), prefrontal cortex (PFC) and hippocampus (CA1). Also, we explored the role of Vitamin D3 receptor (VD3R) activation as a therapeutic target in improving motor-cognitive functions in dyskinetic mice. Dyskinesia was induced in adult BALB/c mice after 28 days of haloperidol treatment (10 mg/Kg; intraperitoneal). We established the presence of abnormal involuntary movements (AIMs) in the haloperidol treated mice (-D2) through assessment of the threshold and amplitude of abnormal involuntary movements (AIMs) for the Limbs (Li) and Orolingual (Ol) area (Li and Ol AIMs). As a confirmatory test, the dyskinetic mice (-D2) showed high global AIMs score when compared with the VD3RA intervention group (-D2/+VDR) for Li and Ol AIMs. Furthermore, in the behavioral tests, the dyskinetic mice exhibited a decrease in latency of fall (LOF; Rotarod-P 2/+VDR), 100 mg/Kg for 7 days, CPu-CA1 burst activity was restored leading to a decrease in abnormal movement, and an increase in motor function. Ultimately, we deduced that VD3RA activation reduced the threshold of abnormal movement in haloperidol induced dyskinesia.
Highlights
Antipsychotics are often employed in the management of depression, schizophrenia and other neurological disorders; prolonged use of these drugs often results in tardive dyskinesia (TD) and other associated movement disorders [1]
The basic and amplitude scores were converted to the global abnormal involuntary movements (AIMs) score (Basic X Amplitude) for the –D2 group after 28 days of haloperidol treatment to confirm dyskinesia, and –D2/+VDR treatments 7 days after VD3RA intervention (Day 35)
After 7 days of VD3RA intervention (–D2/+VDR), the AIMs score decreased significantly when compared with the –D2 at 0 - 15 and 15 - 30 minutes (Figure 3(a))
Summary
Antipsychotics are often employed in the management of depression, schizophrenia and other neurological disorders; prolonged use of these drugs often results in tardive dyskinesia (TD) and other associated movement disorders [1]. Previous studies have shown that haloperidol-induced motor disorders involve partial inhibition of dopamine receptive sites on D2-receptor which prevents the heretomeric combination of D1 and D2 receptors during dopaminergic neurotransmission [4]. Several studies have shown a decline in motor function and cognition after a prolonged use of these drugs in treatment of depression and schizophrenia [7] [8]. The significance of the D2R stimulation and calcium current supports the wide role of dopamine in various brain centers involved in motor and memory functions [5] [9]. Our previous experiments have shown that activation of Vitamin D3 receptor (VD3R) reduces calcium toxicity through central and peripheral mechanisms, and improves motor-cognitive function in mice after haloperidol induced parkinsonism [13]. We studied the role of VD3R activation in improving motor-cognitive functions through restoration of epoch neural activities in the brain areas of dyskinetic mice
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