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.