WAG/Rij rats show a reduced expression of CB₁ receptors in thalamic nuclei and respond to the CB₁ receptor agonist, R(+)WIN55,212-2, with a reduced incidence of spike-wave discharges.

Abstract

PURPOSE:

Genetically epileptic WAG/Rij rats develop spontaneous absence-like seizures after 3 months of age. We used WAG/Rij rats to examine whether absence seizures are associated with changes in the expression of type-1 cannabinoid (CB₁) receptors.

METHODS:

Receptor expression was examined by in situ hybridization and western blot analysis in various brain regions of "presymptomatic" 2-month old and "symptomatic" 8-month-old WAG/Rij rats relative to age-matched nonepileptic control rats. Furthermore, we examined whether pharmacologic activation of CB₁ receptor affects absence seizures. We recorded spontaneous spike-wave discharges (SWDs) in 8-month old WAG/Rij rats systemically injected with the potent CB₁ receptor agonist, R(+)WIN55,212-2 (3-12 mg/kg, s.c.), given alone or combined with the CB₁ receptor antagonist/inverse agonist, AM251 (12 mg/kg, s.c.).

RESULTS:

Data showed a reduction of CB₁ receptor mRNA and protein levels in the reticular thalamic nucleus, and a reduction in CB₁ receptor protein levels in ventral basal thalamic nuclei of 8-month-old WAG/Rij rats, as compared with age-matched ACI control rats. In vivo, R(+)WIN55,212-2 caused a dose-dependent reduction in the frequency of SWDs in the first 3 h after the injection. This was followed by a late increase in the mean SWD duration, which suggests a biphasic modulation of SWDs by CB₁ receptor agonists. Both effects were reversed or attenuated when R(+)WIN55,212-2 was combined with AM251.

DISCUSSION:

These data indicate that the development of absence seizures is associated with plastic modifications of CB₁ receptors within the thalamic-cortical-thalamic network, and raise the interesting possibility that CB₁ receptors are targeted by novel antiabsence drugs.

• Authors: Clementina M van Rijn, Silvana Gaetani, Ines Santolini, Aleksandra Badura, Aleksandra Gabova, Jin Fu, Masashiko Watanabe, Vincenzo Cuomo, Gilles van Luijtelaar, Ferdinando Nicoletti, Richard T Ngomba
• Journal: Epilepsia (Epilepsia) Vol. 51 Issue 8 Pg. 1511-21 (Aug 2010) ISSN: 1528-1167 [Electronic] United States
• PMID: 20132294 (Publication Type: Journal Article)
• Copyright: Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.

Chemical References

• Benzoxazines
• Morpholines
• Naphthalenes
• Piperidines
• Pyrazoles
• Receptor, Cannabinoid, CB1
• AM 251
• (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone

Topics

• Analysis of Variance
• Animals
• Benzoxazines (pharmacology, therapeutic use)
• Disease Models, Animal
• Electroencephalography (methods)
• Epilepsy, Absence (drug therapy, genetics, pathology)
• Gene Expression Regulation (drug effects)
• Male
• Morpholines (pharmacology, therapeutic use)
• Movement (drug effects)
• Naphthalenes (pharmacology, therapeutic use)
• Piperidines (pharmacology)
• Pyrazoles (pharmacology)
• Rats
• Rats, Inbred ACI
• Rats, Mutant Strains
• Receptor, Cannabinoid, CB1 (agonists, genetics, metabolism)
• Thalamic Nuclei (drug effects, physiopathology)