title: Consequences of long-term treatment with agomelatine on depressive-like behavior and neurobiological abnormalities in pinealectomized rats.
abstract: Previous data have shown that the rat model of melatonin deficit can cause a number of neurobiological aberrations. The aim of the present study was to determine whether the antidepressant drug agomelatine, a MT1/MT2 melatoninergic receptor agonist/5-HT2C receptor antagonist is able to prevent some of the behavioral, biochemical and cellular abnormalities induced by pinealectomy. The injection of agomelatine (40 mg/kg, i.p. for 5 weeks)/vehicle started after pinealectomy/sham procedure in Wistar rats. Animals were tested in different behavioral tests for anxiety and depression during the period of agomelatine treatment (chronic effect) and two months later (plastic effect). The effect of agomelatine on KCl-evoked serotonin (5-HT) release from the hippocampus, the activity of the hypothalamic-pituitary-adrenal (HPA) axis and neuronal loss in pinealectomized rats were assessed. Our results showed that agomelatine not only did not prevent the disturbed emotional arousal/anxiety behavior in pinealectomized rats during the treatment but the enhanced motor activity and decreased anxiety state was still observed two months after the discontinuation of treatment. However, the drug corrected a depressive-like behavior (chronic and plastic effect), alleviated the enhanced KCl-evoked 5-HT release in the hippocampus, recovered the suppressed negative feedback inhibition of HPA axis and exerted a neuroprotection in pinealectomized rats. Our findings suggest that pinealectomy can model melancholic depression disorder while the antidepressant action of agomelatine is associated with a correction of 5-HT release in the hippocampus, dysregulated HPA system and neuroprotection in limbic structures.
authors.affiliation: Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria. Electronic address: janetchekalarova@gmail.com.
authors.forename: Jana
authors.initials: J
authors.lastname: Tchekalarova
authors.affiliation: Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Zlatina
authors.initials: Z
authors.lastname: Nenchovska
authors.affiliation: Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Dimitrina
authors.initials: D
authors.lastname: Atanasova
authors.affiliation: Department of Biology, Medical University of Pleven, 1 Kliment Ohridski Str., Pleven 5800, Bulgaria.
authors.forename: Milena
authors.initials: M
authors.lastname: Atanasova
authors.affiliation: Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Lidia
authors.initials: L
authors.lastname: Kortenska
authors.affiliation: Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Stefanova
authors.affiliation: Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Liana
authors.initials: L
authors.lastname: Alova
authors.affiliation: Department of Anatomy, Medical Faculty, MU-Sofia, Bulgaria.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Lazarov
mesh_terms: D000081:Acetamides / Q000627:therapeutic use*; D000221:Adaptation, Ocular / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003866:Depressive Disorder / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D004334:Drug Administration Schedule; D005106:Exploratory Behavior / Q000187:drug effects; D005518:Food Preferences / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D010870:Pineal Gland / Q000293:injuries* / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D013550:Swimming / Q000523:psychology; D013997:Time Factors; D014316:Tritium / Q000378:metabolism; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D006993:Hypnotics and Sedatives; D012701:Serotonin; D014316:Tritium; C084711:agomelatine; D009281:Naphthalenes
keywords: Agomelatine; Behavior; HPA axis; Neuronal loss; Pinealectomy; Serotonin