The GLP-1 receptor agonist liraglutide reverses mania-like alterations and memory deficits induced by D-amphetamine and augments lithium effects in mice: Relevance for bipolar disorder

Prog Neuropsychopharmacol Biol Psychiatry. 2020 Apr 20:99:109872. doi: 10.1016/j.pnpbp.2020.109872. Epub 2020 Jan 16.

Abstract

Metabolic and psychiatric disorders present a bidirectional relationship. GLP-1 system, known for its insulinotropic effects, has also been associated with numerous regulatory effects in cognitive and emotional processing. GLP-1 receptors (GLP-1R) agonists present neuroprotective and antidepressant/anxiolytic properties. However, the effects of GLP-1R agonism in bipolar disorder (BD) mania and the related cognitive disturbances remains unknown. Here, we investigated the effects of the GLP-1R agonist liraglutide (LIRA) at monotherapy or combined with lithium (Li) against D-amphetamine (AMPH)-induced mania-like symptoms, brain oxidative and BDNF alterations in mice. Swiss mice received AMPH 2 mg/kg or saline for 14 days. Between days 8-14, they received LIRA 120 or 240 μg/kg, Li 47.5 mg/kg or the combination Li + LIRA, on both doses. After behavioral evaluation the brain areas prefrontal cortex (PFC), hippocampus and amygdala were collected. AMPH induced hyperlocomotion, risk-taking behavior and multiple cognitive deficits which resemble mania. LIRA reversed AMPH-induced hyperlocomotion, working and recognition memory impairments, while Li + LIRA240 rescued all behavioral changes induced by AMPH. LIRA reversed AMPH-induced hippocampal oxidative and neurotrophic changes. Li + LIRA240 augmented Li antioxidant effects and greatly reversed AMPH-induced BDNF changes in PFC and hippocampus. LIRA rescued the weight gain induced by Li in the course of mania model. Therefore, LIRA can reverse some mania-like behavioral alterations and combined with Li augmented the mood stabilizing and neuroprotective properties of Li. This study points to LIRA as a promising adjunctive tool for BD treatment and provides the first rationale for the design of clinical trials investigating its possible antimanic effect.

Keywords: Bipolar disorder; Brain-derived neurotrophic factor (BDNF); Cognitive impairment; D-amphetamine; GLP-1; Liraglutide; Mania; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bipolar Disorder / chemically induced
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / psychology
  • Dextroamphetamine / toxicity*
  • Drug Synergism
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Lipid Peroxidation / drug effects
  • Lipid Peroxidation / physiology
  • Liraglutide / administration & dosage*
  • Lithium / administration & dosage*
  • Male
  • Mania / chemically induced
  • Mania / drug therapy*
  • Mania / psychology
  • Memory Disorders / chemically induced
  • Memory Disorders / drug therapy*
  • Memory Disorders / psychology
  • Mice

Substances

  • Glucagon-Like Peptide-1 Receptor
  • Liraglutide
  • Lithium
  • Dextroamphetamine