Several lines of experimental evidence on wild type and cannabinoid receptor manipulated rnanimals have shown the role of the endocannabinoid system on the effect of psychoactive rnsubstances, including opioids,nicotine and cocaine. Since the mesocorticolimbic dopaminergic rnpathway plays a vital role in mediating some of the behavioral effects of both khat and rncannabinoids, studying the interaction of the endocannabinoid system and khat would provide an rninsight in the identification of drug targets and development of new pharmacologic approaches to rntreatment of central nervous system disorders associated with dopamine dysregulation.The rnobjective of this study was therefore to investigate the involvement of the endocannabinoid rnsystem in modulating the neurobehavioral effects of khat in mice.A battery of behavioral tests rnincluding Y-maze, elevated plus maze and locomotor activity were used to assess behavioral rneffects. In addition, immunohistochemistry and reverse transcriptase polymerase chain reaction rn(RT-PCR) technique were employed to investigate tyrosine hydroxylase immunoreactivity and rnexpression of dopamine transporter mRNA, respectively. The experiments were performed using rnadult male BALB/c albino, C57BL/6J and DAT-Cnr2cKO mice. The BALB/c albino mice were rnused for acute studies, whereas, the C57BL/6J and DAT-Cnr2 mice were used for sub-acute rnstudies. In the acute study khat extract and the different drugs were administered as a single dose, rnhowever, in the sub-acute study khat and drugs were administered once per day for seven rnconsecutive days.Khat extract was administered in a dose of 300 mg/kg; WIN-55,212-2 (non-rnselective cannabinoid receptor agonist), 1 mg/kg; JWH133 (cannabinoid type 2 receptor agonist), rn5 mg/kg; AM251 (cannabinoid type 1 receptor antagonist), 1 mg/kg and AM630 (cannabinoid rntype 2 receptor antagonist); 1 mg/kg. The results show that, acute administration of khat with rnWIN-55,212-2, enhanced locomotor activity, anxiolytic and working memory related behavior of rnIrnkhat.Sub-acute co-administration of khatwith JWH133reducedhyperlocomotor behavior of khat, rnhowever, cell type specific deletion of cannabinoid receptor type 2 on dopaminergic rnneuronsincreased the effect of khat on locomotor activity. Furthermore,khat attenuated 1-methyl-rn4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)induced motor deficits, which is enhanced by rnJWH133. JWH133 didnâ€™t alter the effect of khat on tyrosine hydroxylase immunoreactivity and rndopamine transporter mRNA expression when given together with khat. Taken together, the rnresults suggest that the endocannabinoid system modulates the neurobehavioral effects of khat, rnwhere, cannabinoid type 1 receptors negatively modulate the neurobehavioral effects of khat but rncannabinoid type 2 receptors selectively interact with khat-mediated effectswhich could be rnutilized as therapeutic target in central nervous system movement disorders associated with rndopamine dysregulation.