Pharmacological and histological characterisation of nicotine-kindled seizures in mice.
The present study reports that it is possible to induce kindling by repeated injections of nicotine. The newly characterised nicotine-kindling model was compared with that of pentylenetetrazole (PTZ) kindling. Mice were kindled by repeated injection of PTZ (37 mg/kg), or nicotine (2.3 mg/kg), and the effect of the anti-epileptic drugs (AED) levetiracetam (LEV), tiagabine (TGB) and phenytoin (PHT) on seizures in kindled and naive mice were investigated. C-Fos immunoreactivity (Fos IR) was used to investigate differences in neuronal activity pattern between PTZ-, nicotine kindled and naive animals. PTZ kindled animals mainly showed increased Fos IR in limbic regions, whereas Fos IR in nicotine kindled animals was increased in the entorhinal cortex, medial habenula and the compact part of substantia nigra. Fully kindled PTZ-induced seizures were inhibited by LEV (ED50=13.6+/-7.8 mg/kg), TGB (ED50=0.3+/-0.04 mg/kg) but not PHT (ED50>40 mg/kg) whereas fully kindled nicotine-induced seizures were inhibited by LEV (ED50=1.4+/-0.4 mg/kg), TGB (ED50=0.3+/-0.06 mg/kg) and PHT (ED50=9.2+/-2.4 mg/kg). These differences in efficacy of AEDs were not due to changes in plasma levels in the various models. In conclusion, repeated administration of nicotine can induce a kindling-like phenomenon and the model showed significantly different Fos IR pattern and pharmacology to that of PTZ kindling.
Bastlund
Jesper F
JF
Department of Neuropharmacology, H. Lundbeck A/S, Copenhagen, Denmark. jfb@lundbeck.com
Berry
David
D
Watson
William P
WP
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D007150:Immunohistochemistry; D007696:Kindling, Neurologic / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D009538:Nicotine / Q000494:pharmacology / Q000633:toxicity*; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism*
D009538:Nicotine