The renin-angiotensin system (RAS) is a key regulator of body homeostasis and is involved in modulating brain functions. Two opposing arms are thought to constitute the RAS: the pressor arm consists of Ang II, and AT1 receptors, mediating vasoconstrictor, proliferative, and proinflammatory effects, and the AT2 receptor, which opposes the effects of the AT1R. The depressor arm includes angiotensin-converting enzyme type 2 (ACE2) and Ang-(1-7), which mediate vasodilatory, antiproliferative, anti-inflammatory, and neuroprotective effects through the Mas receptor (MasR). This study aimed to elucidate the effects of systemic ACE2 blockade on the control of exploratory, anxiety-, and depression-like behaviors, motor coordination, and thermal nociception in mice. Male ICR mice were administered acutely or chronically with the selective ACE2 inhibitor MLN-4760 and subsequently tested for exploratory and anxiety-like behavior, depression-like behavior, motor coordination and thermal nociception. Data analysis showed that mice with chronic ACE2 inhibition exhibited depression-like behavior and impaired motor coordination. Acute enzyme inhibition stimulated exploratory and anxiolytic behavior: greater total distance and center distance in the Open Field and more time spent in the open arms of the Elevated plus maze. Acute MLN-4760 injection also increased the thermal nociceptive threshold. In conclusion, these preliminary data indicate that both acute and chronic ACE2 inhibition affects the regulation of motivated behavior and nociception, but further study is needed to elucidate their structural and cellular mechanisms of action. Acknowledgments: This work was financially supported by the Bulgarian National Scientific Fund project КП-06-Н71/9 of the Ministry of Education and Science, Bulgaria.