title: Effects of selective serotonin and norepinephrine reuptake inhibitors on depressive- and impulsive-like behaviors and on monoamine transmission in experimental temporal lobe epilepsy.
abstract: 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.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
authors.forename: Udaya
authors.initials: U
authors.lastname: Kumar
authors.affiliation: Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
authors.forename: Jesus-Servando
authors.initials: JS
authors.lastname: Medel-Matus
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center-San Antonio, San Antonio, Texas, U.S.A.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Redwine
authors.affiliation: Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
authors.forename: Don
authors.initials: D
authors.lastname: Shin
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center-San Antonio, San Antonio, Texas, U.S.A.
authors.forename: Julie G
authors.initials: JG
authors.lastname: Hensler
authors.affiliation: Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.|Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.|UCLA Children's Discovery and Innovation Institute, Los Angeles, California, U.S.A.
authors.forename: Raman
authors.initials: R
authors.lastname: Sankar
authors.affiliation: Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.|UCLA Children's Discovery and Innovation Institute, Los Angeles, California, U.S.A.
authors.forename: Andrey
authors.initials: A
authors.lastname: Mazarati
mesh_terms: D000818:Animals; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D007175:Impulsive Behavior / Q000187:drug effects* / Q000502:physiology; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D012701:Serotonin; D009638:Norepinephrine
keywords: Attention-deficit/hyperactivity disorder; Depression; Epilepsy; Norepinephrine reuptake inhibitor; Selective serotonin reuptake inhibitor
references.citation: Brain. 2008 Aug;131(Pt 8):2071-83
references.pmid: 18559371
references.citation: J Neurochem. 2005 Dec;95(5):1495-503
references.pmid: 16219029
references.citation: CNS Drug Rev. 2004 Spring;10(1):23-44
references.pmid: 14978512
references.citation: Curr Psychiatry Rep. 2010 Oct;12(5):366-73
references.pmid: 20652773
references.citation: Front Behav Neurosci. 2014 Jun 06;8:199
references.pmid: 24936175
references.citation: J Psychopharmacol. 2015 Dec;29(12):1221-30
references.pmid: 26349559
references.citation: Neuropsychopharmacology. 2002 Dec;27(6):949-59
references.pmid: 12464452
references.citation: Mol Neurobiol. 2011 Dec;44(3):449-64
references.pmid: 22076606
references.citation: Ann Neurol. 2015 Jul;78(1):128-36
references.pmid: 25869354
references.citation: Eur J Pharmacol. 2000 Jun 30;399(1):17-27
references.pmid: 10876018
references.citation: Neurotherapeutics. 2012 Apr;9(2):477-85
references.pmid: 22427156
references.citation: Brain Res. 1998 Jun 8;795(1-2):157-69
references.pmid: 9622618
references.citation: Behav Brain Res. 2005 Feb 28;157(2):323-30
references.pmid: 15639183
references.citation: Psychopharmacology (Berl). 2009 Jan;202(1-3):497-504
references.pmid: 18535818
references.citation: Epilepsy Behav. 2014 Feb;31:267-75
references.pmid: 24262783
references.citation: J Child Adolesc Psychopharmacol. 2007 Aug;17(4):433-45
references.pmid: 17822339
references.citation: Int J Neuropsychopharmacol. 2002 Jun;5(2):115-20
references.pmid: 12135535
references.citation: Future Neurol. 2009 Sep 1;4(5):663-668
references.pmid: 20161538
references.citation: Epilepsia. 2015 Feb;56(2):218-24
references.pmid: 25594106
references.citation: J Child Adolesc Psychopharmacol. 2008 Dec;18(6):565-71
references.pmid: 19108661
references.citation: Clin Ter. 2012 Jul;163(4):e255-62
references.pmid: 23007832
references.citation: Neuropsychiatr Dis Treat. 2009;5:137-50
references.pmid: 19557108
references.citation: Psychopharmacology (Berl). 2005 Nov;182(3):335-44
references.pmid: 16001105
references.citation: Epilepsia. 2002 Nov;43(11):1337-45
references.pmid: 12423383
references.citation: Eur J Clin Pharmacol. 2002 Sep;58(6):379-86
references.pmid: 12242596
references.citation: Eur J Pharmacol. 1999 Jan 29;366(1):35-9
references.pmid: 10064149
references.citation: Neuropsychopharmacology. 2011 May;36(6):1305-16
references.pmid: 21346733
references.citation: Neurobiol Dis. 2010 Feb;37(2):461-7
references.pmid: 19900553
references.citation: Epilepsy Behav. 2012 Jun;24(2):156-68
references.pmid: 22632406
references.citation: J Psychopharmacol. 2016 Jan;30(1):13-22
references.pmid: 26464458
references.citation: Expert Rev Neurother. 2010 Apr;10(4):587-601
references.pmid: 20367210
references.citation: Neuropsychopharmacology. 2002 May;26(5):565-73
references.pmid: 11927181
references.citation: Neurobiol Dis. 2008 Jan;29(1):142-60
references.pmid: 17931873
references.citation: Epilepsia. 2012 May;53(5):870-8
references.pmid: 22429158
references.citation: Eur J Pharmacol. 2002 Jun 7;445(1-2):37-42
references.pmid: 12065192
references.citation: J Neurophysiol. 2012 Mar;107(6):1731-7
references.pmid: 22190618
references.citation: Epilepsia. 2014 May;55(5):644-53
references.pmid: 24621352
references.citation: Neurobiol Dis. 2009 Jun;34(3):457-61
references.pmid: 19285131