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GLP-1 receptor agonist liraglutide reverses long-term atypical antipsychotic treatment associated behavioral depression and metabolic abnormalities in rats

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Abstract

Mood disorder patients that are on long-term atypical antipsychotics treatment frequently experience metabolic dysfunctions. In addition to this, accumulating evidences points to increased risk of structural abnormalities, brain volume changes, altered neuroplasticity and behavioral depression with long-term antipsychotics use. However, there is paucity of preclinical evidences for long-term antipsychotic associated depression-like behavior. The objectives of the present study were: (1) to evaluate influence of long-term antipsychotic (olanzapine) treatment on rat behavior in forced swim test (FST) as a model for depression and; (2) to examine impact of glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide - an antidiabetic medication for type II diabetes, on long-term olanzapine associated metabolic and behavioral changes in rats. Daily olanzapine treatment (0.5 mg/kg; p.o.) for 8-9 weeks significantly increased body weights, food and water intake, plasma cholesterol and triglycerides and immobility time in FST with parallel reduction in plasma HDL cholesterol levels. These results points to development of metabolic abnormalities and depression-like behavior with long-term olanzapine treatment. Acute liraglutide (50 μg/kg; i.p.) and imipramine (10 mg/kg, i. p.) treatment per se significantly decreased duration of immobility in FST compared to vehicle treated rats. Additionally, 3-week liraglutide treatment (50 μg/kg; i.p., daily) partially reversed metabolic abnormalities and depression-like behavior with long-term olanzapine-treatment in rats. None of these treatment regimens affected locomotor behavior of rats. In summary, add-on GLP-1 receptor agonists promise novel alternatives to counteract long-term antipsychotics associated behavioral and metabolic complications.

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Authors and Affiliations

  1. Department of Pharmacology, S.T.E.S.s Smt. Kashibai Navale College of Pharmacy, Kondhwa (Bk), Pune, MS, 411048, India

    Ajaykumar N. Sharma & Sagar S. Ligade

  2. Center for Molecular Psychiatry and Experimental Models in Psychiatry, Department of Psychiatry & Behavioral Sciences, University of Texas Health Science Center at Houston, UT Center of Excellence on Mood Disorders, 1941 East Road, Houston, TX, 77054, USA

    Ajaykumar N. Sharma

  3. Boonshoft School of Medicine, Department of Pharmacology and Toxicology, Wright State University, Dayton, OH, 45435, USA

    Ajaykumar N. Sharma, Khalid M. Elased & James B. Lucot

  4. Department of Chemistry, University School of Louisville, Louisville, KY, 40292, USA

    Jay N. Sharma

  5. Department of Medicine, Division of Cardiology, Cardiovascular Institute Stanford University School of Medicine, Stanford, CA, 94305, USA

    Praveen Shukla

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  1. Ajaykumar N. Sharma
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  2. Sagar S. Ligade
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  3. Jay N. Sharma
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Correspondence to Ajaykumar N. Sharma or Praveen Shukla.

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Sharma, A.N., Ligade, S.S., Sharma, J.N. et al. GLP-1 receptor agonist liraglutide reverses long-term atypical antipsychotic treatment associated behavioral depression and metabolic abnormalities in rats. Metab Brain Dis 30, 519–527 (2015). https://doi.org/10.1007/s11011-014-9591-7

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