title: Galanin contributes to monoaminergic dysfunction and to dependent neurobehavioral comorbidities of epilepsy.
abstract: Status epilepticus (SE) in rats, along with chronic epilepsy, leads to the development of behavioral impairments resembling depressive disorder and/or attention deficit/hyperactivity disorder (ADHD), thus reflecting respective comorbidities in epilepsy patients. Suppressed neurotransmitter tone in the raphe nucleus (RN)-prefrontal cortex (PFC) serotonergic pathway and in the locus coeruleus (LC)-PFC noradrenergic pathway underlies depressive- and impulsive-like behavioral deficits respectively. We examined possible mechanisms leading to the monoamine dysfunction in brainstem efferents, namely modulatory effects of the neuropeptide galanin on serotonin (5-HT) and norepinephrine (NE) signaling. SE was induced in young adult male Wistar rats by LiCl and pilocarpine. Epileptic rats were categorized vis-à-vis behavioral deficits as not impaired, "depressed" and "impulsive". Depressive- and impulsive-like behaviors were examined in the forced swimming test (FST). The strength of serotonergic transmission in RN-PFC and of noradrenergic transmission in LC-PFC was analyzed using in vivo fast scan cyclic voltammetry. Galanin receptor type 1 (GalR1)/type 2 (GalR2) antagonist M40, and a preferential GalR2 antagonist M871 were administered over 3days locally into either RN or LC by means of ALZET osmotic minipumps connected to locally implanted infusion cannulas. Intra-RN injection of M40 improved serotonergic tone and depressive-like behavior in epileptic "depressed" rats. Intra-LC injection of M40 improved noradrenergic tone and impulsive-like behavior in epileptic "impulsive" rats. The effects of M40 were only observed in impaired subjects. The treatment did not modify neurotransmission and behavior in naïve and epileptic not impaired rats; in "depressed" rats the effects were limited to serotonergic transmission and immobility, while in "impulsive" rats - to noradrenergic transmission and struggling behavior. Intra-RN administration of M871 exacerbated depressive-like behavior, but had no effects on any other of the examined parameters in any category of animals. These findings suggest that endogenous galanin, acting through GalR1 may be involved in the pathophysiology of epilepsy-associated depression and ADHD via inhibiting RN-PFC serotonergic and LC-PFC noradrenergic transmissions respectively.
authors.affiliation: Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Jesus-Servando
authors.initials: JS
authors.lastname: Medel-Matus
authors.affiliation: Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Don
authors.initials: D
authors.lastname: Shin
authors.affiliation: Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Children's Discovery and Innovation Institute, UCLA, Los Angeles, CA, USA.
authors.forename: Raman
authors.initials: R
authors.lastname: Sankar
authors.affiliation: Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Children's Discovery and Innovation Institute, UCLA, Los Angeles, CA, USA. Electronic address: mazarati@ucla.edu.
authors.forename: Andrey
authors.initials: A
authors.lastname: Mazarati
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000378:metabolism*; D003863:Depression / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D038983:Galactolipids / Q000494:pharmacology; D019004:Galanin / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D007175:Impulsive Behavior / Q000187:drug effects / Q000502:physiology; D018021:Lithium Chloride / Q000627:therapeutic use; D008125:Locus Coeruleus / Q000000981:diagnostic imaging / Q000473:pathology*; D008297:Male; D018721:Muscarinic Agonists / Q000633:toxicity; D010446:Peptide Fragments / Q000494:pharmacology; D010862:Pilocarpine / Q000633:toxicity; D011903:Raphe Nuclei / Q000187:drug effects / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D013226:Status Epilepticus / Q000139:chemically induced / Q000150:complications*; D013550:Swimming / Q000523:psychology
chemical_list: D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D038983:Galactolipids; C079517:M40; D018721:Muscarinic Agonists; D010446:Peptide Fragments; C412404:di-O-12-methyl-tetradecanoyl-3-O-galactopyranosyl-glycerol; D010862:Pilocarpine; D012701:Serotonin; D019004:Galanin; D018021:Lithium Chloride
keywords: Attention deficit/hyperactivity disorder; Comorbidity; Depression; Epilepsy; Galanin; Locus coeruleus; Norepinephrine; Prefrontal cortex; Raphe nucleus; Serotonin