title: Effect of fluoxetine on disease progression in a mouse model of ALS.
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.
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: J E
authors.initials: JE
authors.lastname: Koschnitzky
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: K A
authors.initials: KA
authors.lastname: Quinlan
authors.affiliation: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: T J
authors.initials: TJ
authors.lastname: Lukas
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: E
authors.initials: E
authors.lastname: Kajtaz
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: E J
authors.initials: EJ
authors.lastname: Kocevar
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: W F
authors.initials: WF
authors.lastname: Mayers
authors.affiliation: Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and.
authors.forename: T
authors.initials: T
authors.lastname: Siddique
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago, Illinois c-heckman@northwestern.edu.
authors.forename: C J
authors.initials: CJ
authors.lastname: Heckman
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology*; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000008:administration & dosage*; D008137:Longitudinal Studies; D051379:Mice; D008822:Mice, Transgenic; D045442:Rotarod Performance Test; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage; D016896:Treatment Outcome; D014202:Tremor / Q000175:diagnosis / Q000503:physiopathology* / Q000517:prevention & control*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Prozac; amyotrophic lateral sclerosis; antidepressant; fluoxetine; motoneuron excitability