title: Behavioural and neuroplastic properties of chronic lurasidone treatment in serotonin transporter knockout rats.
abstract: Second-generation antipsychotics (SGA) are multi-target agents widely used for the treatment of schizophrenia and bipolar disorder that also hold potential for the treatment of impaired emotional control, thanks to their diverse receptor profiles as well as their potential in modulating neuroadaptive changes in key brain regions. The aim of this study was thus to establish the ability of lurasidone, a novel SGA characterized by a multi-receptor signature, to modulate behavioural and molecular defects associated with a genetic model of impaired emotional control, namely serotonin transporter knockout (SERT KO) rats. At behavioural level, we found that chronic lurasidone treatment significantly increased fear extinction in SERT KO rats, but not in wild-type control animals. Moreover, at molecular level, lurasidone was able to normalize the reduced expression of the neurotrophin brain-derived neurotrophic factor in the prefrontal cortex of SERT KO rats, an effect that occurred through the regulation of specific neurotrophin transcripts (primarily exon VI). Furthermore, chronic lurasidone treatment was also able to restore the reduced expression of different GABAergic markers that is present in these animals. Our results show that lurasidone can improve emotional control in SERT KO rats, with a primary impact on the prefrontal cortex. The adaptive changes set in motion by repeated treatment with lurasidone may in fact contribute to the amelioration of functional capacities, closely associated with neuronal plasticity, which are deteriorated in patients with schizophrenia, bipolar disease and major depression.
authors.affiliation: Center of Neuropharmacology, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Luoni
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Hulsken
authors.forename: Greta
authors.initials: G
authors.lastname: Cazzaniga
authors.forename: Giorgio
authors.initials: G
authors.lastname: Racagni
authors.forename: Judith R
authors.initials: JR
authors.lastname: Homberg
authors.forename: Marco A
authors.initials: MA
authors.lastname: Riva
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects*; D004195:Disease Models, Animal; D005108:Extinction, Psychological / Q000187:drug effects; D005239:Fear / Q000187:drug effects / Q000523:psychology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D054833:Isoindoles / Q000494:pharmacology / Q000627:therapeutic use*; D000069056:Lurasidone Hydrochloride; D019964:Mood Disorders / Q000188:drug therapy* / Q000235:genetics; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000235:genetics; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000235:genetics / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D000928:Antidepressive Agents; D000943:Antigens, Differentiation; D019208:Brain-Derived Neurotrophic Factor; D054833:Isoindoles; D000069056:Lurasidone Hydrochloride; D012333:RNA, Messenger; D018079:Receptors, GABA; D011965:Receptors, Glucocorticoid; D050486:Serotonin Plasma Membrane Transport Proteins; D013844:Thiazoles; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C508094:Gadd45b protein, rat; D000097642:GADD45 Proteins; C118623:Slc32a1 protein, rat