WAGRij 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

Van Rijn, C. M. and Gaetani, S. and Santolini, I. and Badura, A. and Gabova, A. and Fu, J. and Watanabe, M. and Cuomo, V. and Van Luijtelaar, G. and Nicoletti, F. and Ngomba, R. T. (2010) WAGRij 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. Epilepsia, 51 (8). pp. 1511-1521. ISSN 0013-9580

Full content URL: http://onlinelibrary.wiley.com/doi/10.1111/j.1528-...

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Abstract

Purpose: Genetically epileptic WAGRij rats develop spontaneous absence-like seizures after 3 months of age. We used WAGRij 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 WAGRij 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 WAGRij rats systemically injected with the potent CB1 receptor agonist, R(+)WIN55,212-2 (3-12 mgkg, s.c.), given alone or combined with the CB1 receptor antagonistinverse agonist, AM251 (12 mgkg, s.c.). Results: Data showed a reduction of CB1 receptor mRNA and protein levels in the reticular thalamic nucleus, and a reduction in CB 1 receptor protein levels in ventral basal thalamic nuclei of 8-month-old WAGRij 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 CB 1 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.

Keywords:1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo1,2,3 de1,4benzoxazine, cannabinoid 1 receptor, benzoxazine derivative, morpholine derivative, naphthalene derivative, piperidine derivative, pyrazole derivative, animal experiment, animal model, article, controlled study, drug dose comparison, in situ hybridization, male, neuromodulation, nonhuman, priority journal, protein expression, rat, seizure, spike, spike wave, thalamus nucleus, Western blotting, Wistar albino Glaxo rat, absence, analysis of variance, animal, August Copenhagen Irish rat, disease model, drug effect, drug potentiation, electroencephalography, gene expression regulation, genetics, metabolism, methodology, movement (physiology), pathology, pathophysiology, rat strain, Analysis of Variance, Animals, Benzoxazines, Disease Models, Animal, Epilepsy, Absence, Morpholines, Movement, Naphthalenes, Piperidines, Pyrazoles, Rats, Rats, Inbred ACI, Rats, Mutant Strains, Receptor, Cannabinoid, CB1, Thalamic Nuclei
Subjects:B Subjects allied to Medicine > B210 Pharmacology
B Subjects allied to Medicine > B140 Neuroscience
Divisions:College of Science > School of Pharmacy
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ID Code:22156
Deposited On:03 Feb 2016 15:43

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