Fear extinction during adolescence: neural mechanisms and implications for treating anxiety disorders

Abstract

Adolescent-onset anxiety disorders are more common and costly than those that emerge later in life. Unfortunately, approximately half of adolescents who receive cognitive behaviour therapy experience significant symptom relapse. This finding is consistent with adolescents’ performance on the preclinical model of fear extinction, such that they show impaired extinction retention. To understand why exposure-based treatments may be less effective during adolescence, I investigated the neurotransmitter systems involved in adolescent extinction. In my first series of experiments, described in Chapter 2, I examined whether the cannabinoid receptor 1 agonist WIN55212-2 ameliorates impaired extinction retention in adolescent rats. Unexpectedly, WIN55212-2 increased fear expression during extinction training and had no effect on extinction retention in both juvenile and adolescent rats. This finding was accompanied by an age-related decrease in the expression of cannabinoid receptor 1 protein in the medial prefrontal cortex and amygdala. In Chapter 3, I explored the role of NMDA receptors in extinction during adolescence. While NMDA receptors were required for extinction in rats conditioned and extinguished as adolescents, this was not the case for rats conditioned as juveniles and extinguished as adolescents. NMDA receptor-independent extinction in this latter group was not due to the interval between conditioning and extinction training, or the experience of a developmental transition. In Chapter 4, I investigated the role of opioid receptor mediated prediction error in extinction learning. Opioid receptors were utilised by juvenile rats, adult rats, and adolescent rats that were conditioned as juveniles during a single session of extinction training. In contrast, rats conditioned and extinguished as adolescents did not use opioid receptors until the second session of extinction training. Taken together, these experiments highlight the complex neurobiology of extinction during adolescence. Impaired extinction retention in rats conditioned and extinguished as adolescents is likely due to an under-recruitment of cannabinoid receptor 1, NMDA receptors, and opioid receptors on the first day of extinction training. The mechanisms by which altering the age at which adolescent rats acquire fear leads to engagement of opioid and NMDA receptors, and subsequently good extinction, remains to be understood. The clinical and theoretical implications of these findings are discussed.