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

• Published in: Progress in neuro-psychopharmacology & biological psychiatry Vol. 99; p. 109872
• Main Authors: Chaves Filho, Adriano José Maia, Cunha, Natássia Lopes, de Souza, Alana Gomes, Soares, Michele Verde-Ramo, Jucá, Paloma Marinho, de Queiroz, Tatiana, Oliveira, João Victor Souza, Valvassori, Samira S., Barichello, Tatiana, Quevedo, Joao, de Lucena, David, Macedo, Danielle S.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 20.04.2020
• Subjects: Animals; Bipolar disorder; Bipolar Disorder - chemically induced; Bipolar Disorder - drug therapy; Bipolar Disorder - psychology; Brain-derived neurotrophic factor (BDNF); Cognitive impairment; D-amphetamine; Dextroamphetamine - toxicity; Drug Synergism; GLP-1; Glucagon-Like Peptide-1 Receptor - agonists; Lipid Peroxidation - drug effects; Lipid Peroxidation - physiology; Liraglutide; Liraglutide - administration & dosage; Lithium - administration & dosage; Male; Mania; Mania - chemically induced; Mania - drug therapy; Mania - psychology; Memory Disorders - chemically induced; Memory Disorders - drug therapy; Memory Disorders - psychology; Mice; Oxidative stress; Oxidative stress; GLP-1; Brain-derived neurotrophic factor (BDNF); Mania; Bipolar disorder; D-amphetamine; Liraglutide; Cognitive impairment
• ISSN: 0278-5846; 1878-4216
• DOI: 10.1016/j.pnpbp.2020.109872

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. •AMPH induced risk-taking behavior and cognitive deficits that resemble mania.•LIRA reversed AMPH-induced hyperlocomotion, working and recognition memory impairments.•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 reversed AMPH-induced BDNF changes.