Divergent Effects of Systemic and Intracollicular CB Receptor Activation Against Forebrain and Hindbrain-Evoked Seizures in Rats.

Victor R Santos,Robert Hammack,Prosper N’Gouemo,Patrick A Forcelli,Evan Wicker

doi:10.3389/fnbeh.2020.595315

Abstract

Cannabinoid (CB) receptor agonists are of growing interest as targets for anti-seizure therapies. Here we examined the effect of systemic administration of the CB receptor agonist WIN 55,212-2 (WIN) against audiogenic seizures (AGSs) in the Genetically Epilepsy Prone Rat (GEPR)-3 strain, and against seizures evoked focally from the Area Tempestas (AT). We compared these results to the effect of focal administration of the CB1/2 receptor agonist CP 55940 into the deep layers of the superior colliculus (DLSC), a brain site expressing CB1 receptors. While systemic administration of WIN dose-dependently decreased AGS in GEPR-3s, it was without effect in the AT model. By contrast, intra-DLSC infusion of CP 55940 decreased seizures in both models. To determine if the effects of systemic WIN were dependent upon activation of CB1 receptors in the DSLC, we next microinjected the CB1 receptor antagonist SR141716, before WIN systemic treatment, and tested animals for AGS susceptibility. The pretreatment of the DLSC with SR141716 was without effect on its own and did not alter the anti-convulsant action of WIN systemic administration. Thus, while CB receptors in the DLSC are a potential site of anticonvulsant action, they are not necessary for the effects of systemically administered CB agonists.

Highlights

The epilepsies, as a group, are one of the most common neurological disorders and are associated with substantial morbidity, mortality, and economic burden
Genetically Epilepsy-Prone Rat (GEPR)-3s were injected with either vehicle or WIN (1, 1.5, or 2 mg/kg) and re-tested for audiogenic seizures (AGSs) 30 min after injection
GEPR-3s were tested on a baseline AGS test and retested following systemic administration of vehicle or WIN paired with an intra-deep layers of the superior colliculus (DLSC) injection of vehicle or the CB1 receptor antagonist SR141716

Summary

INTRODUCTION

The epilepsies, as a group, are one of the most common neurological disorders and are associated with substantial morbidity, mortality, and economic burden. In the context of seizure suppression, the CB1 receptor co-localizes with GABA neurons in many brain regions it has been suggested that the primary cell type that expresses CB1 receptor is inhibitory (Katona et al, 1999, 2001) This is of particular interest in the context of the DLSC, as disinhibition of the DLSC by silencing GABAergic inputs from the substantia nigra pars reticulata (SNpr) is potently anticonvulsant (Wicker et al, 2019). Here, we sought to determine the effect of CB1 receptor agonists on brainstem seizures in GEPR-3 rats and forebrain seizures in the Area Tempestas model while comparing the effects of systemic and intra-DLSC delivery of CB1 agonist

MATERIALS AND METHODS

RESULTS

DISCUSSION

ETHICS STATEMENT