Neuropeptide Y suppresses absence seizures in a genetic rat model primarily through effects on Y2 receptors

Neuropeptide Y (NPY) potently suppresses absence seizures in a model of genetic generalized epilepsy, genetic absence epilepsy rats of Strasbourg (GAERS). Here we investigated the Y-receptor subtype(s) on which NPY exerts this anti-absence effect. A dual in vivo approach was used: the cumulative duration of seizures was quantified in adult male GAERS in 90-min electroencephalogram recordings following intracerebroventricular (i.c.v.) injection of: (i) subtype-selective agonists of Y-1 ([Leu(31)Pro(34)]NPY, 2.5 nmol), Y-2 (Ac[Leu(28,31)]NPY24-36, 3 nmol), Y-5 receptors [hPP1(-17),Ala(31),Aib(32)]NPY, 4 nmol), NPY (3 nmol) or vehicle; and following (ii) i.c.v. injection of antagonists of Y-1 (BIBP3226, 20 nmol), Y-2 (BIIE0246, 20 nmol) and Y-5 (NPY5RA972, 20 nmol) receptors or vehicle, followed by NPY (3 nmol). Injection of the Y-1- and Y-5-selective agonists resulted in significantly less mean seizure suppression (37.4% and 53.9%, respectively) than NPY (83.2%; P < 0.05), while the Y-2 agonist had similar effects to NPY (62.3% suppression, P = 0.57). Food intake was not increased following injection of the Y-2 agonist, while significant increases in food intake were seen following NPY and the other Y-subtype agonists. Compared with vehicle, NPY injection suppressed seizures following the Y-1 and Y-5 antagonists (45.3% and 80.1%, respectively, P < 0.05), but not following the Y-2 antagonist (5.1% suppression, P = 0.46). We conclude that NPY Y-2 receptors are more important than Y-1 and Y-5 receptors in mediating the effect of NPY to suppress absence seizures in a genetic rat model. Y-2 receptor agonists may represent targets for novel drugs against genetic generalized epilepsies without resulting in appetite stimulation.