Involvement of CB2 Receptors in the Neurobehavioral Effects of Catha Edulis (Vahl) Endl. (Khat) in Mice.

Berhanu Geresu,Branden Sanabria,Emmanuel S Onaivi,Zhicheng Lin,Ephrem Engidawork,Ana Canseco-Alba,Qing-Rong Liu

doi:10.3390/molecules24173164

Abstract

There is behavioral evidence for the interaction between crude khat extract and the endocannabinoid system, whereby the endocannabinoid system alters khat extract-mediated behavioral effects through modulation of the monoaminergic system. The objective of this study was to investigate the role of the endocannabinoid system on the neurobehavioral effect of khat extract in mice following concomitant administration of khat extract and the CB2R agonist, JWH133. Locomotor activity test, immunohistochemistry, and reverse transcriptase polymerase chain reaction technique were utilized to assess locomotor activity, tyrosine hydroxylase immunoreactivity, and expression of dopamine transporter mRNA gene. The results show sub-acute administration of khat extract alone increased locomotor activity in mice and co-administration of the CB2R agonist, JWH133, reduced khat extract induced hyperlocomotor activity. The data revealed that cell type specific deletion of CB2Rs on dopaminergic neurons increased the hyperlocomotor behavior of khat extract. Furthermore, the results revealed that khat extract attenuated MPTP induced motor deficits, which is enhanced by JWH133. Khat extract also increased expression of tyrosine hydroxylase positive cells and expression of dopamine transporter mRNA gene in wild type mice. Nevertheless, JWH133 did not alter the effect of khat extract on tyrosine hydroxylase immunoreactivity and dopamine transporter mRNA expression when given together with khat extract. Taken together, the results suggest that the CB2Rs selectively interact with khat extract-mediated locomotor effects and could be utilized as therapeutic target in central nervous system movement disorders associated with dopamine dysregulation.

Highlights

Khat, Catha edulis (Vahl) Endl., has been consumed for centuries by people living around the horn of Africa and the Middle East [1,2]
An independent t-test showed that administration of khat extract at 300 mg/kg to the wild type (WT) mice significantly (p < 0.001) increased both
An independent t-test showed that administration of khat extract at 300 mg/kg to the WT mice significantly (p < 0.001) increased both the administration of khat extract at 300 mg/kg to the WT mice significantly (p < 0.001) increased both the total distance travelled byby and stereotypic box compared compared to the total distance travelled and stereotypiccount countby by32.7%

Summary

Introduction

Catha edulis (Vahl) Endl., has been consumed for centuries by people living around the horn of Africa and the Middle East [1,2]. Khat chewing results in different CNS (central nervous system) effects including euphoria, excitation, anorexia, increased respiration, hyperthermia, analgesia, increased sensory stimulation [5,6], increased locomotion, and altered performance in several behavioral experiments in rodents [7,8,9]. The ECS modulates numerous central nervous system (CNS) functions, including the classic cannabinoid tetrad of thermoregulation, antinociception, locomotor activity, and catalepsy [11], as well as feeding behavior [12], food reinforcement [13], and cognition [14]. CB1Rs have been well characterized using conditional Cnr mutant mice [15,16,17,18] CB2Rs were previously thought to be in immune cells, were referred to as peripheral CB2Rs, and were less investigated for neuronal CNS function [10]. Conditional Cnr mutant mice have been generated using the

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