Involvement of the Endocannabinoid System in Modulating the Neurobehavioral Effects of Catha edulis (Vahl) Endl. (Khat) in Mice,Implication for Diseases Associated with Dopamine Dysregulation

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Addis Abeba University


Several lines of experimental evidence on wild type and cannabinoid receptor manipulated animals have shown the role of the endocannabinoid system on the effect of psychoactive substances, including opioids,nicotine and cocaine. Since the mesocorticolimbic dopaminergic pathway plays a vital role in mediating some of the behavioral effects of both khat and cannabinoids, studying the interaction of the endocannabinoid system and khat would provide an insight in the identification of drug targets and development of new pharmacologic approaches to treatment of central nervous system disorders associated with dopamine dysregulation.The objective of this study was therefore to investigate the involvement of the endocannabinoid system in modulating the neurobehavioral effects of khat in mice.A battery of behavioral tests including Y-maze, elevated plus maze and locomotor activity were used to assess behavioral effects. In addition, immunohistochemistry and reverse transcriptase polymerase chain reaction (RT-PCR) technique were employed to investigate tyrosine hydroxylase immunoreactivity and expression of dopamine transporter mRNA, respectively. The experiments were performed using adult male BALB/c albino, C57BL/6J and DAT-Cnr2cKO mice. The BALB/c albino mice were used for acute studies, whereas, the C57BL/6J and DAT-Cnr2 mice were used for sub-acute studies. In the acute study khat extract and the different drugs were administered as a single dose, however, in the sub-acute study khat and drugs were administered once per day for seven consecutive days.Khat extract was administered in a dose of 300 mg/kg; WIN-55,212-2 (non- selective cannabinoid receptor agonist), 1 mg/kg; JWH133 (cannabinoid type 2 receptor agonist), 5 mg/kg; AM251 (cannabinoid type 1 receptor antagonist), 1 mg/kg and AM630 (cannabinoid type 2 receptor antagonist); 1 mg/kg. The results show that, acute administration of khat with WIN-55,212-2, enhanced locomotor activity, anxiolytic and working memory related behavior of I khat.Sub-acute co-administration of khatwith JWH133reducedhyperlocomotor behavior of khat, however, cell type specific deletion of cannabinoid receptor type 2 on dopaminergic neuronsincreased the effect of khat on locomotor activity. Furthermore,khat attenuated 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)induced motor deficits, which is enhanced by JWH133. JWH133 didn’t alter the effect of khat on tyrosine hydroxylase immunoreactivity and dopamine transporter mRNA expression when given together with khat. Taken together, the results suggest that the endocannabinoid system modulates the neurobehavioral effects of khat, where, cannabinoid type 1 receptors negatively modulate the neurobehavioral effects of khat but cannabinoid type 2 receptors selectively interact with khat-mediated effectswhich could be utilized as therapeutic target in central nervous system movement disorders associated with dopamine dysregulation.



Khat, Y-maze, elevated plus maze, endocannabinoid system, tyrosine hydroxylase, dopamine transporter, locomotor activity, MPTP, JWH133,WIN-55,212-2.