Facilitation of fear extinction by midbrain periaqueductal gray infusions of RB101(S), an inhibitor of enkephalin-degrading enzymes

Abstract

Mu-opioid receptors in the ventrolateral quadrant midbrain periaqueductal gray (vIPAG) contribute to extinction of conditioned fear. The present experiment studied whether fear extinction could be facilitated by infusions of a peptidase inhibitor that reduces catabolism of vIPAG enkephalins. Rats were trained to fear an auditory conditioned stimulus. Fear was then extinguished. Extinction training was preceded by infusions of vehicle or RB101(S), an inhibitor of enkephalin catabolising enzymes. RB101(S) dose dependently facilitated extinction as indexed by performance during extinction and on a drug-free test. This facilitation was not observed when RB101(S) was infused outside the vIPAG. These results confirm that vIPAG endogenous opioids contribute to fear extinction and show that extinction can be facilitated by manipulations that increase vIPAG opioid neuromodulation.