Berberis vulgaris attenuates chronic haloperidol-induced oral dyskinesia and reinstates dopaminergic modulation in rat caudate.

Farhat Batool1,2. 1Department of Biochemistry, University of Karachi, Karachi, Pakistan, Pakistan, 2Post Doctoral Fellow School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK, Nottingham, UK

Chronic neuroleptic-induced orofacial movements in rats have been extensively employed as an animal model of Tardive dyskineisa (TD). Caudate, a region of brain involved in the control of motor activity, is rich in dopaminergic (DA) nerve terminals. Dopamine D2 receptor antagonism is postulated to be a key to antipsychotic efficacy in the treatment of schizophrenia. Studies have shown that Berberis Vulgaris Linn (B. Vulgaris) exerted antidepressant-like effect in various behavioural paradigms of despair possibly by modulating brain biogenic amines (norepinephrine, serotonin or dopamine). The present study was therefore designed to evaluate the protective effects of aqueous fruit extract of B. Vulgaris in the amelioration of haloperidol-induced vacuous chewing movements (VCMs), tongue protrusions and vertical jaw movements in the rat model for TD.

Male Albino Wistar rats (n=24) were randomly assigned as: Test group (n=12) receiving daily haloperidol (3.0 mg/kg i.p.) and Control group (n=12) receiving saline injections, with an equal volume of 1.0 ml/kg body weight, for a period of 21 days. 10-days post-treatment, animals were further subdivided into four groups (n=6 in each group). Aqueous extract of B. Vulgaris (50 mg/ml) was administered daily via feeding tube into 1 group each of saline and haloperidol treated rats, while others groups were receiving vehicle. . Quantification of VCMs and vertical jaw movements were monitored during a 5-minute observation period successively in each group of rats. On the last day of experiments, changes in extracellular levels of dopamine (DA), dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) in caudate were determined by High Performance Liquid Chromatography with Electrochemical Detection (HPLC-EC). The protocol for experimentation was approved and performed in strict accordance with the Guide for the Care and Use of Laboratory Animals (Institutional Animal Ethical Committee IAEC; University of Karachi, Pakistan).

Treatment with B. Vulgaris at 50 mg/ml (2.0+0.01 n=6) produced a significant reduction in VCMs and orofacial movements starting after 10-days post-treatment with haloperidol (p<0.01, two-way ANOVA as compared to vehicle control (0.9% Saline)). Caudate levels of DA and HVA were significantly (p<0.01, two-way ANOVA) altered in group of haloperidol treated rats administered with B. Vulgaris fruit extract (50mg/ml) (685.7+9.7 n=6 DA) (356.7+7.8 n=6 HVA) when compared with their respective controls. Important findings of the present study is that, the repeated haloperidol treatment produced VCM in 30% of the treated rats and the concomitant treatment with B. Vulgaris attenuated both the prevalence and intensity of VCMs in a time-dependent manner.

In conclusion, these findings strongly suggest the role of postsynaptic DA-D2 receptors in the precipitation of haloperidol-induced EPS symptoms while long-term oral administration of aqueous B. Vulgaris presented neuroprotective effects in the caudate suggesting its role in attenuation of orofacial dyskinesia. Hence, this mechanism would possibly help in the development of neutraceuticals extending the nutrient therapy in schizophrenia.

Batool et al. Med Sci Monit 16: 292, 2010.

Batool et al. Journal of Food and Drug Analysis 17: 257, 2009.