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Divergent Effects of Systemic and Intracollicular CB Receptor Activation Against Forebrain and Hindbrain-Evoked
Victor R Santos1,2, Robert Hammack1,3, Evan Wicker1
1Department of Pharmacology and Physiology, Georgetown University School of Medicine, Washington, DC, United States.
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.
Insights
Systemic cannabinoid (CB) agonists reduce audiogenic seizures in rats, but not focal seizures. CB receptors in the deep superior colliculus are not essential for these anti-seizure effects.
Area of Science:
- Neuroscience
- Pharmacology
- Epilepsy Research
Background:
- Cannabinoid (CB) receptor agonists are emerging as potential anti-seizure therapies.
- Understanding the specific roles of CB receptors in seizure control is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the anti-seizure effects of systemic CB receptor agonist WIN 55,212-2 (WIN) in two epilepsy models.
- To compare these effects with focal administration of CB1/2 agonist CP 55940 into the deep superior colliculus (DLSC).
- To determine if CB1 receptors in the DLSC mediate the anti-convulsant actions of systemic WIN.
Main Methods:
- Systemic administration of WIN 55,212-2 in Genetically Epilepsy Prone Rat (GEPR)-3 and Area Tempestas (AT) seizure models.
- Focal administration of CP 55940 into the DLSC.
- Microinjection of CB1 receptor antagonist SR141716 into the DLSC prior to systemic WIN administration.
Main Results:
- Systemic WIN dose-dependently reduced audiogenic seizures (AGSs) in GEPR-3 rats but had no effect on AT seizures.
- Focal CP 55940 administration into the DLSC reduced seizures in both AGS and AT models.
- DLSC pretreatment with SR141716 did not alter the anti-convulsant effect of systemic WIN.
Conclusions:
- CB receptors in the DLSC may contribute to anti-seizure effects, but are not essential for systemically administered CB agonists.
- Systemic CB agonists may act through different pathways or brain regions to exert anti-convulsant effects.
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