title: Effects of an epilepsy-causing mutation in the SCN1A sodium channel gene on cocaine-induced seizure susceptibility in mice.
abstract: BACKGROUND
  High doses of cocaine can elicit seizures in humans and in laboratory animals. Several mechanisms have been proposed for the induction of seizures by cocaine, including enhanced monoaminergic signaling, blockade of ion channels, and alterations in GABA and glutamate transmission. Mutations in the SCN1A gene, which encodes the central nervous system (CNS) voltage-gated sodium channel (VGSC) Nav1.1, are responsible for several human epilepsy disorders including Dravet syndrome and genetic (generalized) epilepsy with febrile seizures plus (GEFS+). Mice heterozygous for the R1648H GEFS+ mutation (RH mice) exhibit reduced interneuron excitability, spontaneous seizures, and lower thresholds to flurothyl- and hyperthermia-induced seizures. However, it is unknown whether impaired CNS VGSC function or a genetic predisposition to epilepsy increases susceptibility to cocaine-induced seizures.
  
  
  OBJECTIVE
  Our primary goal was to determine whether Scn1a dysfunction caused by the RH mutation alters sensitivity to cocaine-induced behavioral and electrographic (EEG) seizures. We also tested novelty- and cocaine-induced locomotor activity and assessed the expression of Nav1.1 in midbrain dopaminergic neurons.
  
  
  RESULTS
  We found that RH mice had a profound increase in cocaine-induced behavioral seizure susceptibility compared to wild-type (WT) controls, which was confirmed with cortical EEG recordings. By contrast, although the RH mice were hyperactive in novel environments, cocaine-induced locomotor activity was comparable between the mutants and WT littermates. Finally, immunofluorescence experiments revealed a lack of Nav1.1 immunoreactivity in dopaminergic neurons.
  
  
  CONCLUSIONS
  These data indicate that a disease-causing CNS VGSC mutation confers susceptibility to the proconvulsant, but not motoric, effects of cocaine.
authors.affiliation: Neuroscience Graduate Program, Emory University, Atlanta, GA 30322, USA.
authors.forename: Ryan H
authors.initials: RH
authors.lastname: Purcell
authors.forename: Ligia A
authors.initials: LA
authors.lastname: Papale
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Makinson
authors.forename: Nikki T
authors.initials: NT
authors.lastname: Sawyer
authors.forename: Jason P
authors.initials: JP
authors.lastname: Schroeder
authors.forename: Andrew
authors.initials: A
authors.lastname: Escayg
authors.forename: David
authors.initials: D
authors.lastname: Weinshenker
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004569:Electroencephalography; D004827:Epilepsy / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D012640:Seizures / Q000139:chemically induced* / Q000235:genetics
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568249:Scn1a protein, mouse; D003042:Cocaine; D004298:Dopamine