Exercise exerts an anxiolytic effect against repeated restraint stress through 5-HT_2A-mediated suppression of the adenosine A_2A receptor in the basolateral amygdala

Repeated or chronic stressful stimuli induce emotion- and mood-related abnormalities, such as anxiety and depression. Conversely, regular exercise exerts protective effects. Here, we found that exercise recovered anxiety-like behaviors, as measured using the open field and elevated plus maze tests in an anxiety mouse model. In addition to behavioral improvement, exercise enhanced the synaptic density of the 5-hydroxytryptamine 2A receptor (5-HT_2AR), but not the 5-HT_1AR in the basolateral amygdala (BLA) region in this mouse model. Furthermore, global treatment with a selective 5-HT_2AR antagonist (MDL11930) generated an anxiety phenotype. Thus, synaptic recruitment of 5-HT_2AR in BLA neurons may mediate the anxiolytic effects of exercise. The exercise regimen also reduced adenosine A_2A receptor (A_2AR)-mediated protein kinase A (PKA) activation, and the anxiolytic effect of the exercise was blunted by local activation of A_2AR within the BLA using CGS21680, a selective A_2AR agonist. Particularly, A_2AR-mediated PKA activity was shown to be dependent on 5-HT_2AR signaling in the BLA. These results imply that repeated stress upregulates A_2AR-mediated adenosine signaling to facilitate PKA activation, whereas regular exercise inhibits A_2AR function by increasing 5-HT_2AR in the BLA. Accordingly, this integrated modulation of 5-HT and adenosine signaling, via 5-HT_2AR and A_2AR respectively, may be a mechanism underlying the anxiolytic effect of regular exercise.