The effects of chronic norepinephrine transporter inactivation on seizure susceptibility in mice

Todd H. Ahern, Martin A. Javors, Douglas A. Eagles, Jared Martillotti, Heather A. Mitchell, Larry Cameron Liles, David Weinshenker

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Epilepsy and depression are comorbid disorders, but the mechanisms underlying their relationship have not been identified. Traditionally, many antidepressants have been thought to increase seizure incidence, although this remains controversial, and it is unclear which medications should be used to treat individuals suffering from both epilepsy and depression. Since the neurotransmitter norepinephrine (NE) has both antidepressant and anticonvulsant properties, we speculated that NE transporter (NET) inhibitor antidepressants might be therapeutic candidates for comorbid individuals. To test this idea, we assessed the effects of chronic administration (via osmotic minipump) of the selective NET inhibitor reboxetine on flurothyl-induced seizures in mice. We found that reboxetine had both proconvulsant and anticonvulsant properties; it lowered both seizure threshold and maximal seizure severity. NET knockout (NET KO) mice essentially phenocopied the effects of reboxetine on flurothyl-induced seizures, and the trends were extended to pentylenetetrazole and maximal electroshock seizures (MES). Furthermore, reboxetine had no further effect in NET KO mice, demonstrating the specificity of reboxetine for the NET. We next tested the chronic and acute effects of other classes of antidepressants (desipramine, imipramine, sertraline, bupropion, and venlafaxine) on seizure susceptibility. Only venlafaxine was devoid of proconvulsant activity, and retained some anticonvulsant activity. These results suggest that chronic antidepressant drug treatment has both proconvulsant and anticonvulsant effects, and that venlafaxine is a good candidate for the treatment of epilepsy and depression comorbidity.

Original languageEnglish (US)
Pages (from-to)730-738
Number of pages9
JournalNeuropsychopharmacology
Volume31
Issue number4
DOIs
StatePublished - Apr 2006

Fingerprint

Norepinephrine Plasma Membrane Transport Proteins
Seizures
Antidepressive Agents
Anticonvulsants
Flurothyl
Epilepsy
Depression
Bupropion
Sertraline
Electroshock
Pentylenetetrazole
Desipramine
Imipramine
Knockout Mice
Neurotransmitter Agents
Comorbidity
Norepinephrine
reboxetine
Incidence

Keywords

  • Antidepressant
  • Epilepsy
  • Norepinephrine
  • Norepinephrine transporter
  • Seizure

ASJC Scopus subject areas

  • Pharmacology

Cite this

Ahern, T. H., Javors, M. A., Eagles, D. A., Martillotti, J., Mitchell, H. A., Liles, L. C., & Weinshenker, D. (2006). The effects of chronic norepinephrine transporter inactivation on seizure susceptibility in mice. Neuropsychopharmacology, 31(4), 730-738. https://doi.org/10.1038/sj.npp.1300847

The effects of chronic norepinephrine transporter inactivation on seizure susceptibility in mice. / Ahern, Todd H.; Javors, Martin A.; Eagles, Douglas A.; Martillotti, Jared; Mitchell, Heather A.; Liles, Larry Cameron; Weinshenker, David.

In: Neuropsychopharmacology, Vol. 31, No. 4, 04.2006, p. 730-738.

Research output: Contribution to journalArticle

Ahern, TH, Javors, MA, Eagles, DA, Martillotti, J, Mitchell, HA, Liles, LC & Weinshenker, D 2006, 'The effects of chronic norepinephrine transporter inactivation on seizure susceptibility in mice', Neuropsychopharmacology, vol. 31, no. 4, pp. 730-738. https://doi.org/10.1038/sj.npp.1300847
Ahern, Todd H. ; Javors, Martin A. ; Eagles, Douglas A. ; Martillotti, Jared ; Mitchell, Heather A. ; Liles, Larry Cameron ; Weinshenker, David. / The effects of chronic norepinephrine transporter inactivation on seizure susceptibility in mice. In: Neuropsychopharmacology. 2006 ; Vol. 31, No. 4. pp. 730-738.
@article{281edf67546d4930aa58beb2911d6253,
title = "The effects of chronic norepinephrine transporter inactivation on seizure susceptibility in mice",
abstract = "Epilepsy and depression are comorbid disorders, but the mechanisms underlying their relationship have not been identified. Traditionally, many antidepressants have been thought to increase seizure incidence, although this remains controversial, and it is unclear which medications should be used to treat individuals suffering from both epilepsy and depression. Since the neurotransmitter norepinephrine (NE) has both antidepressant and anticonvulsant properties, we speculated that NE transporter (NET) inhibitor antidepressants might be therapeutic candidates for comorbid individuals. To test this idea, we assessed the effects of chronic administration (via osmotic minipump) of the selective NET inhibitor reboxetine on flurothyl-induced seizures in mice. We found that reboxetine had both proconvulsant and anticonvulsant properties; it lowered both seizure threshold and maximal seizure severity. NET knockout (NET KO) mice essentially phenocopied the effects of reboxetine on flurothyl-induced seizures, and the trends were extended to pentylenetetrazole and maximal electroshock seizures (MES). Furthermore, reboxetine had no further effect in NET KO mice, demonstrating the specificity of reboxetine for the NET. We next tested the chronic and acute effects of other classes of antidepressants (desipramine, imipramine, sertraline, bupropion, and venlafaxine) on seizure susceptibility. Only venlafaxine was devoid of proconvulsant activity, and retained some anticonvulsant activity. These results suggest that chronic antidepressant drug treatment has both proconvulsant and anticonvulsant effects, and that venlafaxine is a good candidate for the treatment of epilepsy and depression comorbidity.",
keywords = "Antidepressant, Epilepsy, Norepinephrine, Norepinephrine transporter, Seizure",
author = "Ahern, {Todd H.} and Javors, {Martin A.} and Eagles, {Douglas A.} and Jared Martillotti and Mitchell, {Heather A.} and Liles, {Larry Cameron} and David Weinshenker",
year = "2006",
month = "4",
doi = "10.1038/sj.npp.1300847",
language = "English (US)",
volume = "31",
pages = "730--738",
journal = "Neuropsychopharmacology",
issn = "0893-133X",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - The effects of chronic norepinephrine transporter inactivation on seizure susceptibility in mice

AU - Ahern, Todd H.

AU - Javors, Martin A.

AU - Eagles, Douglas A.

AU - Martillotti, Jared

AU - Mitchell, Heather A.

AU - Liles, Larry Cameron

AU - Weinshenker, David

PY - 2006/4

Y1 - 2006/4

N2 - Epilepsy and depression are comorbid disorders, but the mechanisms underlying their relationship have not been identified. Traditionally, many antidepressants have been thought to increase seizure incidence, although this remains controversial, and it is unclear which medications should be used to treat individuals suffering from both epilepsy and depression. Since the neurotransmitter norepinephrine (NE) has both antidepressant and anticonvulsant properties, we speculated that NE transporter (NET) inhibitor antidepressants might be therapeutic candidates for comorbid individuals. To test this idea, we assessed the effects of chronic administration (via osmotic minipump) of the selective NET inhibitor reboxetine on flurothyl-induced seizures in mice. We found that reboxetine had both proconvulsant and anticonvulsant properties; it lowered both seizure threshold and maximal seizure severity. NET knockout (NET KO) mice essentially phenocopied the effects of reboxetine on flurothyl-induced seizures, and the trends were extended to pentylenetetrazole and maximal electroshock seizures (MES). Furthermore, reboxetine had no further effect in NET KO mice, demonstrating the specificity of reboxetine for the NET. We next tested the chronic and acute effects of other classes of antidepressants (desipramine, imipramine, sertraline, bupropion, and venlafaxine) on seizure susceptibility. Only venlafaxine was devoid of proconvulsant activity, and retained some anticonvulsant activity. These results suggest that chronic antidepressant drug treatment has both proconvulsant and anticonvulsant effects, and that venlafaxine is a good candidate for the treatment of epilepsy and depression comorbidity.

AB - Epilepsy and depression are comorbid disorders, but the mechanisms underlying their relationship have not been identified. Traditionally, many antidepressants have been thought to increase seizure incidence, although this remains controversial, and it is unclear which medications should be used to treat individuals suffering from both epilepsy and depression. Since the neurotransmitter norepinephrine (NE) has both antidepressant and anticonvulsant properties, we speculated that NE transporter (NET) inhibitor antidepressants might be therapeutic candidates for comorbid individuals. To test this idea, we assessed the effects of chronic administration (via osmotic minipump) of the selective NET inhibitor reboxetine on flurothyl-induced seizures in mice. We found that reboxetine had both proconvulsant and anticonvulsant properties; it lowered both seizure threshold and maximal seizure severity. NET knockout (NET KO) mice essentially phenocopied the effects of reboxetine on flurothyl-induced seizures, and the trends were extended to pentylenetetrazole and maximal electroshock seizures (MES). Furthermore, reboxetine had no further effect in NET KO mice, demonstrating the specificity of reboxetine for the NET. We next tested the chronic and acute effects of other classes of antidepressants (desipramine, imipramine, sertraline, bupropion, and venlafaxine) on seizure susceptibility. Only venlafaxine was devoid of proconvulsant activity, and retained some anticonvulsant activity. These results suggest that chronic antidepressant drug treatment has both proconvulsant and anticonvulsant effects, and that venlafaxine is a good candidate for the treatment of epilepsy and depression comorbidity.

KW - Antidepressant

KW - Epilepsy

KW - Norepinephrine

KW - Norepinephrine transporter

KW - Seizure

UR - http://www.scopus.com/inward/record.url?scp=33645017331&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33645017331&partnerID=8YFLogxK

U2 - 10.1038/sj.npp.1300847

DO - 10.1038/sj.npp.1300847

M3 - Article

C2 - 16052243

AN - SCOPUS:33645017331

VL - 31

SP - 730

EP - 738

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

SN - 0893-133X

IS - 4

ER -