Reversal of neuroleptic-induced orofacial dyskinesia by 5-HT3 receptor antagonists

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Abstract

Tardive dyskinesia, a syndrome of abnormal, involuntary hyperkinetic movements that occurs during long-term neuroleptic therapy is a major limitation of chronic neuroleptic therapy. The pathophysiology of tardive dyskinesia is still an enigma. The objective of the present study was to elucidate the role of 5-HT3 receptor involvement in neuroleptic-induced vacuous chewing movements in rats. Rats chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) significantly developed vacuous chewing movements, as compared to vehicle-treated controls. Both ondansetron and tropisetron dose-dependently (0.25, 0.5 and 1.0 mg/kg, i.p.) reversed the haloperidol-induced vacuous chewing movements. Serotonin acting through 5-HT3 receptors might play a significant role in the pathophysiology of tardive dyskinesia, and 5-HT3 receptor ligands can be exploited as novel therapeutic agents for the treatment of tardive dyskinesia.

Introduction

Tardive dyskinesia is a syndrome of a potentially irreversible, involuntary hyperkinetic disorder that occurs during chronic neuroleptic treatment, and is a major limitation of neuroleptic therapy Egan et al., 1997, Casey, 1995. In spite of the vast frequency of its occurrence, relatively little is known about the pathophysiological basis of the disorder. Dopamine receptor supersensitivity has been proposed as one of the pathological factors responsible for tardive dyskinesia, but this does not adequately describe, not only the time course of onset of tardive dyskinesia, but also the persistence of the syndrome after neuroleptic withdrawal Fibiger and Lloiyd, 1984, Tarsy and Baldessarini, 1977, Casey, 2000, Andreassen and Jorgessen, 2000. Several other alternative hypothesis have been proposed, but most of them are inconclusive. Similarly, different suppressive agents have been tried with limited success Egan et al., 1997, Gupta et al., 1999.

The therapeutic success of clozapine and other newer atypical antipsychotics has focused its attention on the role of the serotonergic system in the pathophysiology of schizophrenia and extrapyramidal side-effects. Electrophysiological, biochemical and behavioural evidence shows that serotonin modulates the dopaminergic system. This modulation is most evident when the dopaminergic system has been activated (Palfreyman et al., 1993). Clozapine has previously been shown to interact with multiple receptors (Watling et al., 1990). Clozapine shows more affinity towards 5-HT2 and 5-HT3 receptor subtypes Seeman, 1992, Farde et al., 1994, and is virtually devoid of extrapyramidal side-effects at therapeutic doses. A high density of serotonin receptors, especially 5-HT1, 5-HT2 and 5-HT3 receptor subtypes in the basal ganglia region, and their interactions with the dopaminergic system leads to the hypothesis that serotonin might play a significant role in movement disorders of basal ganglia origin. Biochemical studies showed that there are interactions between dopamine and serotonin in the central nervous system. The ventral striatum and nucleus accumbens septi receive a serotonergic input from the raphe nucleus (Fuxe, 1965), as do the dopaminergic cell bodies in the substantia nigra and ventral tegmental area, the important areas involved in movement control (Neal-Beliveau et al., 1993). This serotonergic input has been shown to make direct synaptic contact with dopaminergic neurones in both substantia nigra and ventral tegmental area (Nedergaard et al., 1988). Alterations in the serotonergic neurotransmission area are also known to alter dopamine-mediated behaviours such as stereotypy and hyperactivity Fink and Oelssner, 1981, Lucki and Harvey, 1979. Serotonin modulates striatal dopamine release and could influence dyskinetic movements Seibyl et al., 1989, Egan et al., 1997. Cyprohepatdine, a non-selective 5-HT receptor antagonist, is reported to improve dyskinetic symptoms (Goldman, 1976). 5-HT3 receptors in the CNS appear to subserve a number of important modulatory actions of serotonin. The ability of dopamine to inhibit the firing rate of medial prefrontal neurones can be potentiated by 5-HT3 receptor agonists and is blocked by 5-HT3 receptor antagonists. 5-HT3 receptor agonists stimulate dopamine release (Balandina et al., 1988) and potentiate dopamine-mediated behaviors, and antagonists reverse these effects (Palfreyman et al., 1993). However, very little is known about the role of 5-HT3 receptors in mediating vacuous chewing movements. Stimulation of 5-HT3 receptors gave mixed results. The highly selective 5-HT receptor agonist, biguanide, had no effect on oral behaviour, while another agonist, 2-Me-5-HT, increased vacuous chewing movement frequency (Liminga et al., 1993). The ability of 5-HT3 receptor antagonists to modulate cerebral dopaminergic function in rats and primates has provided a rationale for the evaluation of 5-HT3 receptor antagonists in disorders where excessive dopaminergic activity has been postulated.

We have now examined the efficacy of selective 5-HT3 receptor antagonists, namely ondansetron and tropisetron, to ameliorate the dyskinetic symptoms in a putative animal model of tardive dyskinesia.

Section snippets

Animals

Male Wistar rats, bred in the Central Animal House facility of Panjab University and weighing between 180–220 g, were used. The animals were housed under standard laboratory conditions, maintained on a 12-h light and dark cycle, and had free access to food and water. The animals were allowed to adapt to laboratory conditions before the test. All experiments were carried out between 0900 and 1500 h. The experimental protocols were approved by the Institutional Ethical Committee and conducted

Results

Animals repeatedly treated with haloperidol developed profound vacuous chewing movements, in a time-dependent fashion, which plateaued after 21 days and persisted for more than 40 days post-treatment (Fig. 1). Ondansetron (0.25, 0.5 and 1 mg/kg) dose-dependently reduced haloperidol-induced vacuous chewing movements (Fig. 2). Tropisetron (0.25, 0.5 and 1.0 mg/kg) similarly reversed the haloperidol-induced vacuous chewing movements in a dose-dependent manner, with a ceiling effect at 0.5 mg/kg

Discussion

In the present study, both ondansetron and tropisetron, selective 5-HT3 antagonists, dose-dependently reduced haloperidol-induced vacuous chewing movements.

The involvement of the serotonergic system in the modulation of extrapyramidal motor effects is suggested by the absence of extrapyramidal side-effects with atypical anti-psychotics like clozapine. These agents are known to have high affinity towards 5-HT1C, 5-HT2 receptors Stockmeier et al., 1993, Lieberman, 1993, a high ratio of 5-HT2 to

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