QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.137240v1 326/3/905    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Coccurello, R. Articles by Moles, A. Search for Related Content PubMed PubMed Citation Articles by Coccurello, R. Articles by Moles, A.

BEHAVIORAL PHARMACOLOGY

Olanzapine (LY170053, 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] Benzodiazepine), but Not the Novel Atypical Antipsychotic ST2472 (9-Piperazin-1-ylpyrrolo[2,1-b][1,3]benzothiazepine), Chronic Administration Induces Weight Gain, Hyperphagia, and Metabolic Dysregulation in Mice

Institute of Neuroscience, National Research Council, Rome, Italy (R.Coc., A.M.); and Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Pomezia (Rome), Italy (R.Coc., A.C., R.Con., O.G., F.B., P.C.)

A mouse model of atypical antipsychotic-associated adverse effects was used to compare the liability to induce weight gain, food intake, and metabolic alterations after chronic olanzapine (OL; LY170053, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5] benzodiazepine) and ST2472 (ST; 9-piperazin-1-ylpyrrolo[2,1-b][1,3]benzothiazepine) administration. By adding two equipotent doses (3 and 6 mg/kg) of either OL or ST to a high-sweet, high-fat (HS-HF) diet, mice were allowed to self-administer drugs up to 50 days. Body weight and food intake were evaluated daily. Locomotor activity was recorded over 48 h at two different time points. Dyslipidemia was measured by central visceral obesity. Blood serum levels of insulin (IN), glucose (Glu), triglycerides (TGs), nonesterified fatty acids (NEFAs), cholesterol (Ch), and ketone (Ke) bodies were quantified. OL treatment at 3 mg/kg enhanced body weight, whereas at the highest dose, the increase became evident only during the last 10 days of treatment. OL (3 mg/kg) increased HS-HF intake over time, whereas the highest dose reduced intake during the second 10 and final 10 days of administration. Both compounds induced nocturnal hypomotility at the highest dose. In contrast to ST, 3 mg/kg OL elevated serum levels of IN, Glu, TG, NEFA, Ch, and Ke, whereas 6 mg/kg OL elevated those of Glu, TG, and Ch. In contrast, ST did not affect weight gain, food intake, and metabolic markers. Given the similarities between OL-induced obesogenic effects and medical reports, this study further supports the view that ST may represent a new class of agents characterized by a low propensity to induce side effects with promising clinical safety.

Address correspondence to: Dr. Anna Moles, Institute of Neuroscience, National Research Council, Via del Fosso di Fiorano, 64-00143 Rome, Italy. E-mail: anna.moles{at}ipsifar.rm.cnr.it