Enkephalin knockdown in the basolateral amygdala reproduces vulnerable anxiety-like responses to chronic unpredictable stress.

The endogenous enkephalins (ENKs) are potential candidates participating in the naturally occurring variations in coping styles and determining the individual capacities for adaptation during chronic stress exposure. Here we demonstrate that there is a large variance in individual behavioral, as well as in physiological outcomes, in a population of Sprague-Dawley rats subjected to 3 weeks of chronic unpredictable stress (CUS). Separation of resilient and vulnerable subpopulations reveals specific long-term neuroadaptation in the ENKergic brain circuits. ENK mRNA expression was greatly reduced in the posterior basolateral nucleus of amygdala (BLAp) in vulnerable individuals. In contrast, ENK mRNA levels were similar in resilient and control (unstressed) individuals. Another group of rats were used for lentiviral-mediated knockdown of ENK to assess whether a decrease of ENK expression in the BLAp reproduces the behavioral disturbances found in vulnerable individuals. ENK knockdown specifically located in the BLAp was sufficient to increase anxiety in the behavioral tests, such as social interaction and elevated plus maze when compared with control individuals. These results show that specific neuroadaptation mediated by the ENKergic neurotransmission in the BLAp is a key regulator of resilience, whereas a decrease of the ENK in the BLAp is a maladaptation mechanism, which mediates the behavioral dichotomy observed between vulnerable and resilient following 3 weeks of CUS.