Effects of selective serotonin and norepinephrine reuptake inhibitors on depressive- and impulsive-like behaviors and on monoamine transmission in experimental temporal lobe epilepsy

Epilepsia. 2016 Mar;57(3):506-15. doi: 10.1111/epi.13321. Epub 2016 Jan 27.


Objective: Examine therapeutic potential of a selective serotonin reuptake inhibitor (SSRI) and a norepinephrine reuptake inhibitor (NERI) in an animal model of comorbidity between epilepsy, depression-like, and impulsive-like impairments.

Methods: Epilepsy was induced in male Wistar rats by LiCl and pilocarpine. An SSRI fluoxetine (FLX), and an NERI reboxetine (RBX) were administered either alone or as a combination over 1 week. Depressive-like and impulsive-like behaviors were examined using the forced swim test. Fast scan cyclic voltammetry was used to analyze serotonergic transmission in the raphe nucleus (RN)-prefrontal cortex (PFC) pathway, and noradrenergic transmission in locus coeruleus (LC)-PFC, and LC-RN projections. Monoamine levels in PFC were measured using high-performance liquid chromatography (HPLC). Functional capacities of 5-HT1A receptors and α2A adrenoreceptors in PFC were analyzed by autoradiography.

Results: Epileptic rats showed behavioral signs of depression and hyperimpulsivity, suppressed serotonergic and noradrenergic tones, decreased levels of serotonin (5-HT), and norepinephrine (NE); 5-HT1A receptor and α2A adrenoreceptors functions remained intact. FLX failed to improve behavioral deficits, but effectively raised 5-HT level and marginally improved RN-PFC serotonergic transmission. RBX reversed impulsive-like behavior, normalized content of NE and noradrenergic tone in LC-PFC and LC-RN. FLX-RBX combination fully reversed depressive-like behavior, and normalized RN-PFC serotonergic transmission. None of the treatment modified the function of 5-HT and NE receptors.

Significance: Depressive- and impulsive-like behaviors in the pilocarpine model of epilepsy stem respectively from dysfunctions of serotonergic and noradrenergic ascending pathways. At the same time, epilepsy-associated depression is SSRI resistant. The finding that an SSRI-NERI combination exerts antidepressant effect, along with RBX-induced improvement of LC-RN noradrenergic transmission point toward the involvement of LC-RN noradrenergic input in enabling therapeutic potential of FLX. Medications that improve serotonergic and noradrenergic transmission, such as serotonin-norepinephrine reuptake inhibitors may be effective in treating epilepsy-associated SSRI-resistant depression, as well as concurrent depression and attention-deficit/hyperactivity disorder (ADHD).

Keywords: Attention-deficit/hyperactivity disorder; Depression; Epilepsy; Norepinephrine reuptake inhibitor; Selective serotonin reuptake inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Depression / drug therapy*
  • Depression / metabolism
  • Depression / psychology
  • Disease Models, Animal*
  • Epilepsy, Temporal Lobe / drug therapy*
  • Epilepsy, Temporal Lobe / metabolism
  • Epilepsy, Temporal Lobe / psychology
  • Impulsive Behavior / drug effects*
  • Impulsive Behavior / physiology
  • Locus Coeruleus / drug effects
  • Locus Coeruleus / metabolism
  • Male
  • Norepinephrine / antagonists & inhibitors
  • Norepinephrine / metabolism
  • Rats
  • Rats, Wistar
  • Serotonin / metabolism
  • Serotonin and Noradrenaline Reuptake Inhibitors / pharmacology
  • Serotonin and Noradrenaline Reuptake Inhibitors / therapeutic use*
  • Treatment Outcome


  • Serotonin and Noradrenaline Reuptake Inhibitors
  • Serotonin
  • Norepinephrine