<p>Rapid-acting antidepressants (RAADs) such as ketamine are currently under development. The aim of this study is to characterize the neural circuits affected by ketamine and NLX-101, a selective 5-HT_1A receptor biased agonist which has shown promising effects, by using [¹⁸F]FDG PET imaging in rats that had received chronic administration of corticosterone (CORT), a model of anxiety-depression. In a longitudinal study, regional changes in brain activity were investigated in 24 selected CORT rats. Each animal underwent PET scans in 3 conditions, i.e. with ketamine (10 mg/kg), NLX-101 (0.16 mg/kg) or saline on day 0 and five days later to assess sustained effects. The anxious-depressive phenotype produced by CORT was supported by behavioural and biological observations. Changes in [¹⁸F]FDG uptake were determined using voxel-based and region of interest analyses. Metabolic connectivity analysis was also performed to investigate the acute and delayed effects of the treatments. Voxel-based and region-of-interest analyses showed marked hypometabolism in regions implicated in depression, particularly cingulate cortex (−7%) and lateral septum (−9%) as well as the striatum (−10%). Acute effects of NLX-101 and ketamine were observed in the lateral septum, resulting in an increase in brain glucose metabolism (p &lt; 0,05). Interestingly, connectivity analyses also showed effects of NLX-101 in the frontal cortex, the thalamus and amygdala (p &lt; 0.05), suggesting that the two molecules converge on common brain regions. This study is the first to show brain activation patterns of RAADs in a CORT rat model by functional PET imaging. NLX-101 appears to exert antidepressant effects by preferentially activating postsynaptic 5-HT_1A heteroreceptors in primary regions common to ketamine. These results support investigation of cortical 5-HT_1A receptors as a target for new generation biased agonist antidepressants.</p><p></p>