Mice lacking Melanin Concentrating Hormone 1 receptor are resistant to seizures

Abstract

The Melanin Concentrating Hormone (MCH) system is widely expressed throughout the central nervous system and regulates a variety of physiological functions. It has been reported that acute central administration of MCH inhibits pentylenetetrazol (PTZ)-induced seizures in rats. In the present study MCH1 receptor knockout mice (MCH1R-KO) were used to investigate the role of MCH signaling in modulating seizure susceptibility. Seizure behaviors were compared between MCH1R-KO and wild type (MCH1R-WT) mice following administration of the convulsant compounds PTZ or pilocarpine. PTZ injection induced clonic seizures in MCH1R-WT mice but failed to induce them in MCH1R-KO mice. More than twice as many injections of intermittently administered low dose PTZ were required to induce clonic seizures in MCH1R-KO mice than in MCH1R-WT mice. Following pilocarpine injection, MCH1R-WT mice experienced clonic seizures and most had tonic seizures and entered status epilepticus, while all MCH1R-KO mice were completely resistant to these effects. MCH1R-KO mice were also observed to be strongly protected from the development of PTZ kindling. Genetic deletion of MCH1R conferred resistance to all seizure models tested in this study. The data indicate that the MCH system is involved in the regulation of PTZ and pilocarpine seizure threshold.