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.
OBJECTIVE
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.


CONCLUSIONS
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.
van Rijn
Clementina M
CM
Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, The Netherlands. t.vanrijn@donders.ru.nl
Gaetani
Silvana
S
Santolini
Ines
I
Badura
Aleksandra
A
Gabova
Aleksandra
A
Fu
Jin
J
Watanabe
Masashiko
M
Cuomo
Vincenzo
V
van Luijtelaar
Gilles
G
Nicoletti
Ferdinando
F
Ngomba
Richard T
RT
D000704:Analysis of Variance; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000379:methods; D004832:Epilepsy, Absence / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D009068:Movement / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology* / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011912:Rats, Inbred ACI; D011922:Rats, Mutant Strains; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D013787:Thalamic Nuclei / Q000187:drug effects* / Q000503:physiopathology
D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone