title: Olanzapine-induced early cardiovascular effects are mediated by the biological clock and prevented by melatonin.
abstract: Second generation antipsychotics (SGA) are associated with adverse cardiometabolic side effects contributing to premature mortality in patients. While mechanisms mediating these cardiometabolic side effects remain poorly understood, three independent studies recently demonstrated that melatonin was protective against cardiometabolic risk in SGA-treated patients. As one of the main target areas of circulating melatonin in the brain is the suprachiasmatic nucleus (SCN), we hypothesized that the SCN is involved in SGA-induced early cardiovascular effects in Wistar rats. We evaluated the acute effects of olanzapine and melatonin in the biological clock, paraventricular nucleus and autonomic nervous system using immunohistochemistry, invasive cardiovascular measurements, and Western blot. Olanzapine induced c-Fos immunoreactivity in the SCN followed by the paraventricular nucleus and dorsal motor nucleus of the vagus indicating a potent induction of parasympathetic tone. The involvement of a SCN-parasympathetic neuronal pathway after olanzapine administration was further documented using cholera toxin-B retrograde tracing and vasoactive intestinal peptide immunohistochemistry. Olanzapine-induced decrease in blood pressure and heart rate confirmed this. Melatonin abolished olanzapine-induced SCN c-Fos immunoreactivity, including the parasympathetic pathway and cardiovascular effects while brain areas associated with olanzapine beneficial effects including the striatum, ventral tegmental area, and nucleus accumbens remained activated. In the SCN, olanzapine phosphorylated the GSK-3β, a regulator of clock activity, which melatonin prevented. Bilateral lesions of the SCN prevented the effects of olanzapine on parasympathetic activity. Collectively, results demonstrate the SCN as a key region mediating the early effects of olanzapine on cardiovascular function and show melatonin has opposing and potentially protective effects warranting additional investigation.
authors.affiliation: Hypothalamic Integration Mechanisms Laboratory, Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), México city, DF, México.|Departamento de Psiquiatría y Salud Mental, Facultad de Medicina, UNAM, México city, DF, México.|Division of Bipolar Disorder Research, Department of Psychiatry and Behavioral Neuroscience, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Francisco
authors.identifier: http://orcid.org/0000-0002-5894-3701
authors.initials: F
authors.lastname: Romo-Nava
authors.affiliation: Hypothalamic Integration Mechanisms Laboratory, Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), México city, DF, México.|Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, BA, The Netherlands.
authors.forename: Frederik N
authors.initials: FN
authors.lastname: Buijs
authors.affiliation: Laboratorio de Neurofarmacología, Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, México city, DF, México.
authors.forename: Marcela
authors.initials: M
authors.lastname: Valdés-Tovar
authors.affiliation: Laboratorio de Neurofarmacología, Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, México city, DF, México.
authors.forename: Gloria
authors.initials: G
authors.lastname: Benítez-King
authors.affiliation: Hypothalamic Integration Mechanisms Laboratory, Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), México city, DF, México.
authors.forename: MariCarmen
authors.initials: M
authors.lastname: Basualdo
authors.affiliation: Endocrinology of Reproduction Laboratory, Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas UNAM, México city, DF, México.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Perusquía
authors.affiliation: Departamento de Psiquiatría y Salud Mental, Facultad de Medicina, UNAM, México city, DF, México.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Heinze
authors.affiliation: Departamento de Anatomía, Facultad de Medicina, UNAM, México city, DF, México.
authors.forename: Carolina
authors.initials: C
authors.lastname: Escobar
authors.affiliation: Hypothalamic Integration Mechanisms Laboratory, Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), México city, DF, México.
authors.forename: Ruud M
authors.initials: RM
authors.lastname: Buijs
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000633:toxicity*; D001683:Biological Clocks / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000494:pharmacology / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D008550:Melatonin / Q000494:pharmacology / Q000627:therapeutic use*; D009714:Nucleus Accumbens / Q000187:drug effects; D000077152:Olanzapine; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013493:Suprachiasmatic Nucleus / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000187:drug effects
chemical_list: D002492:Central Nervous System Depressants; D016760:Proto-Oncogene Proteins c-fos; D001569:Benzodiazepines; D008550:Melatonin; D000077152:Olanzapine
keywords: blood pressure; cardiovascular; melatonin; olanzapine; suprachiasmatic nucleus