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Author Notes:

Address correspondence to: David Weinshenker, Ph.D., Department of Human Genetics, Emory University School of Medicine, Whitehead 301, 615 Michael St., Atlanta, GA 30322. Phone: (404) 727-3106, Fax: (404) 727-3949, dweinshenker@genetics.emory.edu

The mouse model of GEFS+ described in this manuscript is licensed to Allergan by Andrew Escayg.

The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policy.

The remaining authors have no conflicts of interest.


Research Funding:

This work was supported by the National Institute of Drug Abuse (DA027535 to DW) and National Institute of Neurological Disorders and Stroke (NS072221 to AE).

This research was also supported in part by the National Institute of Neurological Disorders and Stroke core facilities grant P30N5055077 to the Emory University Microscopy Core.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Pharmacology & Pharmacy
  • Psychiatry
  • Neurosciences & Neurology
  • Cocaine
  • SCN1A
  • Sodium channel
  • Epilepsy
  • EEG
  • Immunofluorescence

Effects of an epilepsy-causing mutation in the SCN1A sodium channel gene on cocaine-induced seizure susceptibility in mice


Journal Title:

Психофармакология и биологическая нарко / Psychopharmacology and Biological Narcology


Volume 228, Number 2


, Pages 263-270

Type of Work:

Article | Post-print: After Peer Review


Rationale: High doses of cocaine can elicit seizures in humans and in laboratory animals. Several mechanisms have been propose d 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) Na v 1.1, 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. Objectives: 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 Na v 1.1 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 Na v 1.1 immunoreactivity in dopaminergic neurons. Conclusion: These data indicate that a disease-causing CNS VGSC mutation confers susceptibility to the proconvulsant, but not motoric, effects of cocaine.

Copyright information:

© 2013 Springer-Verlag Berlin Heidelberg.

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