title: The effect of prolonged simvastatin application on serotonin uptake, membrane microviscosity and behavioral changes in the animal model.
abstract: Simvastatin and other statins (HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors) are extensively used in clinical practices and are very effective in decreasing serum low-density lipoprotein cholesterol. However, their effect on cholesterol synthesis in central nervous system and its behavioral consequences have not been fully understood yet. We have studied selected biologic traits potentially affected by statin treatment - serotonin (5-HT) uptake in platelets, membrane microviscosity in erythrocytes, cholesterol level in the brain (amygdala; hippocampus and prefrontal cortex), as well as behavioral changes in an elevated plus maze and open field test in male Long-Evans rats, which were treated by simvastatin (30mg/kg per day) for 2 or 4weeks. We demonstrated: 1) a decrease in both serotonin transporter (SERT) activity and membrane microviscosity after treatment with simvastatin, 2) lower cholesterol content in all tested brain regions in animals from the simvastatin treated group, and 3) longer time spent in the open arms and a higher number of entrances to the closed arms in the elevated plus maze by animals from the simvastatin group compared to animals from the control group, but no differences in behavior in the open field test. Taken together, our results confirmed complex alterations, including behavioral changes, after the cholesterol lowering treatment. Furthermore, we discuss the possibility that the behavioral changes, traditionally interpreted as an anxiolytic effect, may be interpreted as increased impulsivity. We also confirmed that such behavioral changes may be attributed to changes in serotonergic neurotransmission.
authors.affiliation: Department of Psychiatry, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Vevera
authors.affiliation: Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14220 Prague, Czech Republic; National institute of Mental Health, Topolova 748, Klecany 250 67, Czech Republic. Electronic address: Karel.Vales@fgu.cas.cz.
authors.forename: Karel
authors.initials: K
authors.lastname: Valeš
authors.affiliation: Department of Psychiatry, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic.
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Fišar
authors.affiliation: Department of Psychiatry, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Hroudová
authors.affiliation: Department of Psychiatry, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic.
authors.forename: Namrata
authors.initials: N
authors.lastname: Singh
authors.affiliation: Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14220 Prague, Czech Republic.
authors.forename: Aleš
authors.initials: A
authors.lastname: Stuchlík
authors.affiliation: Department of Organic Technology, Institute of Chemical Technology, Technicka 5, 166 28 Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Kačer
authors.affiliation: Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14220 Prague, Czech Republic; National institute of Mental Health, Topolova 748, Klecany 250 67, Czech Republic; Department of Zoology, Ecology and Ethology Research Group, Faculty of Science, Charles University in Prague, Prague, Czech Republic. Electronic address: Tereza.Nekovarova@fgu.cas.cz.
authors.forename: Tereza
authors.initials: T
authors.lastname: Nekovářová
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D002784:Cholesterol / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects*; D005106:Exploratory Behavior / Q000187:drug effects; D005454:Fluorescence Polarization; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D023421:Models, Animal; D010949:Plasma / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D012701:Serotonin / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D000924:Anticholesteremic Agents; D012701:Serotonin; D002784:Cholesterol; D019821:Simvastatin
keywords: Behavior; Brain; Cholesterol; Rats; Serotonergic neurotransmission; Statins