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

J Neurophysiol. 2014 Jun 1;111(11):2164-76. doi: 10.1152/jn.00425.2013. Epub 2014 Mar 5.

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 SOD1(G93A) and control: nontransgenic and SOD1(WT)) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1(G93A) 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.

Keywords: Prozac; amyotrophic lateral sclerosis; antidepressant; fluoxetine; motoneuron excitability.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amyotrophic Lateral Sclerosis / diagnosis
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Animals
  • Antidepressive Agents, Second-Generation / administration & dosage
  • Behavior, Animal / drug effects*
  • Disease Models, Animal*
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Fluoxetine / administration & dosage*
  • Longitudinal Studies
  • Mice
  • Mice, Transgenic
  • Rotarod Performance Test
  • Serotonin Uptake Inhibitors / administration & dosage
  • Treatment Outcome
  • Tremor / diagnosis
  • Tremor / physiopathology*
  • Tremor / prevention & control*

Substances

  • Antidepressive Agents, Second-Generation
  • Serotonin Uptake Inhibitors
  • Fluoxetine