Genetic deletion of the norepinephrine transporter decreases vulnerability to seizures.
Norepinephrine (NE) has been reported to modulate neuronal excitability and act as endogenous anticonvulsant. In the present study we used NE transporter knock-out mice (NET-KO), which are characterized by high levels of extracellular NE, to investigate the role of endogenous NE in seizure susceptibility. Seizure thresholds for cocaine (i.p.), pentylenetetrazol (i.v.) and kainic acid (i.v.) were compared in NET-KO, heterozygous (NET-HT) and wild type (NET-WT) female mice. The dose-response curve for cocaine-induced convulsions was significantly shifted to the right in NET-KO mice, indicating higher seizure thresholds. The threshold doses of pentylenetetrazol that induced clonic and tonic seizures were also significantly higher in NET-KO when compared to NET-WT mice. Similarly, NET-KO mice displayed higher resistance to convulsions engendered by kainic acid. For all drugs tested, the response of NET-HT mice was always intermediate. These data provide further support for a role of endogenous NE in the control of seizure susceptibility.
Kaminski
Rafal M
RM
Integrative Neuroscience Section, NIDA/IRP, Baltimore, MD, USA. kaminskr@mail.nih.gov
Shippenberg
Toni S
TS
Witkin
Jeffrey M
JM
Rocha
Beatriz A
BA
D000818:Animals; D003042:Cocaine; D003292:Convulsants / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D017353:Gene Deletion; D007608:Kainic Acid; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010433:Pentylenetetrazole; D012640:Seizures / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology*; D027981:Symporters / Q000235:genetics*
D003292:Convulsants; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493228:Slc6a2 protein, mouse; D027981:Symporters; D003042:Cocaine; D007608:Kainic Acid; D010433:Pentylenetetrazole