title: Anatomical specificity in the modulation of activity-regulated genes after acute or chronic lurasidone treatment.
abstract: Lurasidone is a novel second generation antipsychotic drug characterized by a multi-receptor profile. Besides the high affinity for 5-HT2A and D2 receptors, it is also characterized by potent 5-HT7 receptor antagonism, which may be beneficial for mood and cognition. Considering that dose-dependent changes in receptor occupancy may differentially impact gene transcription, we aimed at investigating the effects of acute and chronic treatments with different doses of lurasidone (1, 3 and 10mg/kg) in rats on the expression of the activity-regulated genes Arc, Zif268 and Npas4, which are markers of neuronal activation and are also associated with neuroadaptive mechanisms. Our results show dose-dependent and anatomically-selective differences after acute and chronic lurasidone treatment. Indeed, the effects produced by acute treatment seem to reflect the modulatory activity of lurasidone at selected neurotransmitter receptors. In fact, low doses of the drug acted in the hippocampus, while high doses acted in the striatum, reflecting the high predominance of D2 receptor expression in this brain region. On the contrary, chronic treatment with lurasidone revealed a different profile of IEGs modulation, possibly reflecting neuroadaptive changes set in motion in response to repetitive drug exposure. In summary, the multi-receptor profile of lurasidone leads to the recruitment of different brain structures in a dose-related manner and this may be important for its therapeutic properties, particularly with respect to antidepressant activity and cognition.
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, I-20133 Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Luoni
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, I-20133 Milan, Italy.
authors.forename: Fabio F
authors.initials: FF
authors.lastname: Rocha
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, I-20133 Milan, Italy; Center of Excellence on Neurodegenerative Diseases, University of Milan, I-20133 Milan, Italy. Electronic address: M.Riva@unimi.it.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Riva
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis*; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D054833:Isoindoles / Q000008:administration & dosage / Q000494:pharmacology*; D000069056:Lurasidone Hydrochloride; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009473:Neuronal Plasticity / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D051792:Basic Helix-Loop-Helix Proteins; D019208:Brain-Derived Neurotrophic Factor; D003598:Cytoskeletal Proteins; D051766:Early Growth Response Protein 1; D054833:Isoindoles; D000069056:Lurasidone Hydrochloride; D009419:Nerve Tissue Proteins; D013844:Thiazoles; C486110:Egr1 protein, rat; C516513:Npas4 protein, rat; C092069:activity regulated cytoskeletal-associated protein
keywords: Arc; Lurasidone; Neuroplasticity; Npas4; Zif268