GLP-1R activation alters performance in cognitive tasks in a sex-dependent manner

Rationale The activation of the glucagon-like peptide-1 receptor (GLP-1R) has been purported to have antidepressant-like and cognitive-enhancing effects. Many people suffering from major depressive disorder (MDD) also experience deficits in cognition. While currently approved antidepressant pharmacotherapies can alleviate the mood symptoms in some patients, they do not treat the cognitive ones. Objectives We tested whether systemic administration of a GLP-1R agonist would alter location discrimination, a cognitive task that is diminished in humans with MDD. Methods Male and female laboratory mice (6–8 weeks old, N = 6–14/sex) were trained in a touchscreen operant task of location discrimination. Upon reaching baseline criterion, mice were administered vehicle or a GLP-1R agonist, Exendin-4, systemically prior to testing in probe trials of varying difficulty. Results Following GLP-1R activation, males showed modest yet non-significant performance in the location discrimination task. Females, however, showed enhanced performance during the most difficult probe tests following Exendin-4 administration. Conclusions GLP-1R activation appears to enhance overall performance in the location discrimination task and does so in a sex- and difficulty-dependent manner. These preliminary yet impactful data indicate that GLP-1R agonists may be useful as an adjunctive pharmacotherapy to treat cognitive deficits associated with MDD and/or multiple neurological disorders.