Deficits in opioid receptor-mediated prediction error contribute to impaired fear extinction during adolescence

Abstract

Adolescent-onset anxiety disorders are more common and costly than those that emerge later in life. Unfortunately, nearly half of adolescents undergoing cognitive behavioural therapies, including exposure therapies, show significant symptom relapse. Such poor treatment outcomes are consistent with preclinical work examining fear extinction, in which adolescents show persistent fear to extinguished cues. Both extinction and exposure are dependent on the generation of prediction error (i.e., the difference between the expected and actual outcome of a cue presentation), a process which involves the opioid system. We investigated the contribution of prediction error signalling to extinction during adolescence using the opioid receptor antagonist naloxone. We demonstrated that unlike in juvenile and adult rats, fear expression during extinction training and test in adolescent rats was unaffected by naloxone, suggesting that adolescent rats are impaired in using prediction error signalling to extinguish fear under typical conditions. However, in two circumstances where adolescents exhibit good extinction retention, opioid receptor blockade impaired extinction retention, suggesting that the recruitment of prediction error signalling mechanisms promotes extinction in this age group, just as it does in adults. Importantly, additional extinction training may be required to enable prediction error mechanisms to be recruited during adolescence.