Behavioural pharmacology of cannabidiol in a MK-801 rodent model of aspects of schizophreni

2017-01-31T04:43:33Z (GMT) by Gururajan, Anand
One of the several theories which explain the pathophysiology of and account for the psychology of schizophrenia is based on the neurotransmitter, glutamate, and the glutamate pathways. Specifically, reduced glutamatergic neurotransmission affects several linked regions of the brain thus manifesting in the positive, negative and cognitive symptoms. This disturbance in glutamate neurotransmission can be mimicked acutely in a preclinical setting using glutamate receptor antagonists such as MK-801, therefore producing a model of several aspects of schizophrenia in which novel compounds can be assessed for antipsychotic potential. Cannabidiol (CBD) is a non-psychoactive phytocannabinoid that was first isolated from Minnesota hemp several decades ago and clinical studies have reported on its potential as an alternative therapeutic agent for the treatment of schizophrenia. However, only a few preclinical behavioural studies have been conducted to support or refute the purported clinical utility and identify the mechanism of action of CBD behind the antipsychotic effect. The main aim of this research project was to further investigate the antipsychotic potential of CBD using a rodent model of aspects of schizophrenia based on the glutamate hypothesis with several different behavioural testing paradigms. The first experiment conducted produced an MK-801-rodent model that displayed some of the positive (locomotor hyperactivity), negative (social withdrawal) and cognitive symptoms (deficits in PPI) of schizophrenia in the same rat. Additionally, investigations also revealed that varying specific aspects of experimental protocol had significant effects on the face validity of this model. The second experiment was performed to investigate the effect of CBD on MK-801-induced disruption of PPI, hyperactivity and social withdrawal. As a comparator, the clinically established atypical antipsychotic clozapine was also tested in the same model. Results showed that neither CBD nor clozapine had any effect on MK-801-induced disruption of PPI and this was in contrast to previous studies. However, differences in methodology are likely to be responsible for the discrepancies. While CBD did not inhibit MK-801-induced hyperactivity, it did partially restore social withdrawal. Clozapine did normalise locomotor activity and social behaviour. Following the observation that by itself neither CBD nor clozapine were able to normalise all of the MK-801-induced behaviours, a hypothesis was formed for the basis of the third experiment that a combination of clozapine and CBD would together be more effective. However no combination of clozapine and CBD that was tested was effective against MK- 801-induced disruption of PPI, hyperactivity or social withdrawal. While these results refute the hypothesis of the increased efficacy of a combination of clozapine and CBD, the possibility that the combination may be effective in ameliorating disruptions to normal rodent behaviour by other psychotomimetics such as apomorphine and phencyclidine should be considered. One of the key limitations of the open-field arena is the inability to discriminate between the effects of treatment on locomotor activity and social behaviour as these parameters are measured simultaneously. To overcome this, a paradigm was constructed and modified based on one designed recently. Using this paradigm, the effects of MK-801 on social behaviour and locomotor activity were clearly distinguishable. Pretreatment with clozapine and CBD normalised reductions in social behaviour but interestingly, CBD also increased social behaviour well beyond control levels in MK-801-treated rats. Both clozapine and CBD were also able to inhibit MK-801-induced hyperactivity. In conclusion, the four experiments that were conducted have produced equivocal evidence in terms of the antipsychotic potential of CBD. It appears as though the ability to observe this property of CBD is very much dependent on the type of neuropathology the model is based on as well as the experimental methodology. This perhaps highlights the need for a more directed approach across research groups in terms of the preclinical evaluation of novel antipsychotic compounds in general. Nevertheless, the results do add to the database of literature on the behavioural pharmacology of this cannabinoid and provide justification for future investigations.