Endocannabinoid CB1 receptors are involved in antiepileptogenic effect of low frequency electrical stimulation during perforant path kindling in rats.

Epilepsy Res. 2018 May 22;144:71-81. doi: 10.1016/j.eplepsyres.2018.05.008.

[Epub ahead of print]

Mardani P¹, Oryan S², Sarihi A³, Alaei E³, Komaki A³, Mirnajafi-Zadeh J⁴.

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Abstract

INTRODUCTION:

Administration of low-frequency electrical stimulation (LFS) at the kindling site has an antiepileptogenic effect. In the present study, we investigated the role of cannabinoid receptors type 1 (CB1) in mediating the inhibitory effects of LFS on the development of perforant path kindled seizures.

METHODS:

For seizure generation, rats were kindled by electrical stimulation of perforant path in semi-rapid kindling manner (12 stimulations per day at 10 min intervals at afterdischarge threshold intensity).To determine the effect of LFS (0.1 ms pulse duration at 1 Hz, 800 pulses) on seizure generation, LFS was applied to the perforant path 5 min after the last kindling stimulation daily. AM281, a CB1 receptor antagonist, was microinjected into the lateral ventricle immediately after the last kindling stimulation (before LFS application) at the doses of 0.5 and 2 μg/μl during kindling procedure. The expression of cannabinoid receptors in the dentate gyrus was also investigated using immunohistochemistry.

RESULTS:

Application of LFS had inhibitory effect on development of kindled seizures (kindling rate). Microinjection of AM281 (0.5 μg/μl) immediately after the last kindling stimulation (before LFS application) reduced the inhibitory effect of LFS on the kindling rate and suppressed the effects of LFS on potentiation (increasing the magnitude) of both population spike amplitude and population excitatory postsynaptic potential slope during kindling acquisition. AM281 pretreatment also prevented the effects of LFS on kindling-induced increase in early and late paired pulse depression. The higher dose of AM281 (2 μg/μl) failed to exert the effects observed with its lower dose (0.5 μg/μl). In addition, there was a decreased CB1 receptors immunostaining in kindled animals compared to control. However, application of LFS following kindling stimulations led to overexpression of CB1 receptors in the dentate gyrus.

CONCLUSION:

Obtained results showed that activation of overexpressed cannabinoid CB1 receptors by endogenous cannabinoids may have a role in mediating the inhibitory effect of LFS on perforant path kindled seizures.

KEYWORDS:

Cannabinoid receptors; Kindling; Low frequency stimulation; Seizure

PMID: 29800824
DOI: 10.1016/j.eplepsyres.2018.05.008