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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Date
2020-06
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Addis Abeba University
Abstract
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
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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.
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Keywords
Khat, Y-maze, elevated plus maze, endocannabinoid system, tyrosine hydroxylase, dopamine transporter, locomotor activity, MPTP, JWH133,WIN-55,212-2.