Dysregulation of brain adenosine is detrimental to the expression of conditioned freezing but not general Pavlovian learning

► Brain adenosine modulation on Pavlovian learning is investigated in two mutant models. ► Up- and down-regulation of cortical adenosine severely impaired conditioned freezing. ► The conditioned freezing impairment does not generalize to other Pavlovian paradigms. ► Adenosine homeostasis is critically important for maintaining normal brain function. ► Regional specific effects are relevant for development of adenosine-based therapies.