Effect of fluoxetine on disease progression in a mouse model of ALS

J. E. Koschnitzky, K. A. Quinlan, T. J. Lukas, E. Kajtaz, E. J. Kocevar, W. F. Mayers, T. Siddique, C. J. Heckman

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to amyotrophic lateral sclerosis (ALS) patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine whether SSRIs impact disease progression, fluoxetine (Prozac, 5 or 10 mg/kg) was administered to mutant superoxide dismutase 1 (SOD1) mice during one of three age ranges: neonatal [postnatal day (P)5-11], adult presymptomatic (P30 to end stage), and adult symptomatic (P70 to end stage). Long-term adult fluoxetine treatment (started at either P30 or P70 and continuing until end stage) had no significant effect on disease progression. In contrast, neonatal fluoxetine treatment (P5-11) had two effects. First, all animals (mutant SOD1G93A and control: nontransgenic and SOD1WT) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1G93A mice reached end stage ~8 days (~6% decrease in life span) sooner than vehicle and low-dose animals because of an increased rate of motor impairment. Fluoxetine increases synaptic serotonin (5-HT) levels, which is known to increase spinal motoneuron excitability. We confirmed that 5-HT increases spinal motoneuron excitability during this neonatal time period and therefore hypothesized that antagonizing 5-HT receptors during the same time period would improve disease outcome. However, cyproheptadine (1 or 5 mg/kg), a 5-HT receptor antagonist, had no effect on disease progression. These results show that a brief period of antidepressant treatment during a critical time window (the transition from neonatal to juvenile states) can be detrimental in ALS mouse models.

Original languageEnglish (US)
Pages (from-to)2164-2176
Number of pages13
JournalJournal of neurophysiology
Volume111
Issue number11
DOIs
StatePublished - Jun 1 2014

Keywords

  • Amyotrophic lateral sclerosis
  • Antidepressant
  • Fluoxetine
  • Motoneuron excitability
  • Prozac

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology

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