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

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.

The Association Between Type 2 Diabetes Mellitus and Parkinson’s Disease

“…Systemic insulin resistance may do so through hyperglycaemia and its consequences [10], microvascular disease, chronic inflammation, and dysfunction of the blood brain barrier, which may be compounded by associated comorbidities such as hypertension, dyslipidaemia and renal impairment [51]. Local brain insulin resistance may act via protein deposition and aggregation, and failure of clearance mechanisms, independent of systemic insulin resistance [51,53].…”

Glucagon-like peptide 1 receptor (GLP1R) haplotypes correlate with altered response to multiple antipsychotics in the CATIE trial

“…For example, in animal models GLP1R agonists attenuate condition place preference for cocaine; mitigate the effects of alcohol and amphetamine; demonstrate neuroprotective activity in Alzheimer's and Parkinson's diseases; and show direct antipsychotic-like effect comparable to haloperidol (Erreger et al, 2012;Graham et al, 2013;Holscher, 2014;Dixit et al, 2013). Recently, Sharma and colleagues demonstrated that the GLP1R agonist liraglutide can ameliorate some of the negative metabolic and behavioral effects of olanzapine treatment in rats (Sharma et al, 2014a). Finally, the DPP-IV inhibitor sitagliptin, which increases GLP1 concentrations by slowing GLP1 breakdown by DPP-IV, extends the time to tolerance of the anxiolytic effect of ethanol and delays onset of ethanol withdrawal induced anxiety in rats (Sharma et al, 2014b).…”

Alleviation of Depression by Glucagon-Like Peptide 1 Through the Regulation of Neuroinflammation, Neurotransmitters, Neurogenesis, and Synaptic Function

“…A previous study reported that GLP-1Rs are observed in brain regions related to energy balance and regulation of moods, such as the amygdala, hippocampus, and dorsal raphe nucleus (Merchenthaler et al, 1999). Some studies have also shown the presence of GLP-1Rs in mood-related brain regions and demonstrated its powerful role in emotional processing within the CNS (Merchenthaler et al, 1999;Sharma et al, 2015).…”