Assessment of behavioral flexibility in mice with conditional deletion of metabotropic glutamate receptor 2 from Emx1-lineage neurons

Convergent lines of evidence from animal models suggest that disrupted metabotropic glutamate receptor 2 (mGlu2) function promotes high levels of drug consumption for a variety of psychoactive drugs including alcohol, opioids, and psychostimulants. In both rodents and humans, impaired behavioral flexibility prior to first drug use correlates with high levels of drug consumption later in life. Thus, we posited that deletion of mGlu2 from brain regions that contribute to behavioral flexibility, including cortical regions, could predispose animals to high levels of drug consumption by impairing behavioral flexibility. To evaluate the role of mGlu2 in behavioral flexibility, we generated mice with a floxed Grm2 allele (Grm2f/f) and selectively disrupted mGlu2 expression in neurons of the Emx1 lineage (primarily telencephalonic projection neurons) by crossing these mice with an Emx1-IRES-Cre driver line. Behavioral flexibility, including sensitivity to change in either outcome value or action-outcome contingency, was evaluated in adult male and female mice trained to press a lever for a food reinforcer. Contrary to our hypothesis, mGlu2 deletion did not facilitate habitual responding assessed by devaluation, contingency degradation, or omission tests. Male Grm2f/f;Emx1-IRES-Cre+/- mice showed modest impairment in reversal learning compared with littermate controls. Finally, we saw a sex-specific effect of mGlu2 deletion on response vigor in male mice trained on a random ratio reinforcement schedule. However, we did not find evidence of a general reduction in motivation in a progressive ratio test. These findings suggest that loss of mGlu2 from cortical circuitry is unlikely to create a predisposition to inflexible behavior that facilitates excessive drug consumption.