Effects of an epilepsy-causing mutation in the SCN1A sodium channel gene on cocaine-induced seizure susceptibility in mice
| Autor: | David Weinshenker, Nikki T. Sawyer, Ligia A. Papale, Ryan H. Purcell, Andrew Escayg, Christopher D. Makinson, Jason P. Schroeder |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Interneuron Dopamine Central nervous system Fluorescent Antibody Technique Pharmacology Biology Motor Activity Article Epilepsy Electrocardiography Mice Dravet syndrome Cocaine Seizures medicine Animals Genetic Predisposition to Disease Dose-Response Relationship Drug Sodium channel Dopaminergic Glutamate receptor Flurothyl Electroencephalography medicine.disease NAV1.1 Voltage-Gated Sodium Channel medicine.anatomical_structure Mutation |
| Zdroj: | Psychopharmacology. 228(2) |
| ISSN: | 1432-2072 |
| Popis: | 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. 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. 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. These data indicate that a disease-causing CNS VGSC mutation confers susceptibility to the proconvulsant, but not motoric, effects of cocaine. |
| Databáze: | OpenAIRE |
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