Opioid Receptors in the Midbrain Periaqueductal Gray Regulate Extinction of Pavlovian Fear Conditioning

Abstract

Four experiments studied the role of opioid receptors in the midbrain periaqueductal gray matter (PAG), an important structure eliciting conditioned fear responses, in the extinction of Pavlovian fear. Rats received pairings of an auditory conditioned stimulus (CS) with a foot shock unconditioned stimulus (US). The freezing conditioned response (CR) elicited by the CS was then extinguished via nonreinforced presentations of the CS. Microinjection of the opioid receptor antagonist naloxone into the ventrolateral PAG (vlPAG) before nonreinforced CS presentations impaired development of extinction, but such microinjections at the end of extinction did not reinstate an already extinguished freezing CR. This role for opioid receptors in fear extinction was specific to the vlPAG because infusions of naloxone into the dorsal PAG did not impair fear extinction. Finally, the impairment of fear extinction produced by vlPAG infusions of naloxone was dose-dependent. These results show for the first time that the midbrain PAG contributes to fear extinction and specifically identify a role for vlPAG opioid receptors in the acquisition but not the expression of such extinction. Taken together with our previous findings, we suggest that, during fear conditioning, activation of vlPAG opioid receptors contributes to detection of the discrepancy between the actual and expected outcome of the conditioning trial. vlPAG opioid receptors regulate the learning that accrues to the CS and other stimuli present on a trial because they instantiate an associative error correction process influencing US information reaching the site of CS-US convergence in the amygdala. During nonreinforcement, this vlPAG opioid receptor contribution signals extinction.

Attachment figures activate a safety signal-related neural region and reduce pain experience

“…Thus, blocking endogenous μ-opioid neurotransmission enhances the acquisition of conditioned fear (43) and impairs the acquisition of extinction or learned safety (44)(45)(46). The implication of these findings is that μ-opioids are involved in reducing conditioned fear responses and enhancing fear extinction or learned safety.…”

Mechanisms of fear extinction

“…Brain structures Several brain structures have been implicated in fear extinction and fear inhibition more generally, including sensory cortex, [74][75][76][77][78] periaqueductal gray [79][80][81] (see below), inferior colliculus, 82 lateral septum, [83][84][85][86] bed nucleus of the stria terminalis, 87 and ventral 88 and dorsal striatum. 89 In this section, we will focus on those for which there is the most information available: the amygdala, hippocampus and prefrontal cortex.…”

“…The effect is mediated by central, not peripheral, opioid receptors and is not a consolidation or expression effect because naloxone administration immediately after extinction training or before test has no effect. Naloxone infusions directly into ventrolateral (vlPAG) but not dorsal PAG mimic the systemic effect, 81 suggesting that the vlPAG is the critical locus of extinction-related endogenous opioid release. Intra-vlPAG infusion of the m opioid receptor antagonist CTAP, but not the k receptor antagonist nor-binaltorphimine or the receptor antagonist naltrindole, also mimics the systemic effect of naloxone, suggesting that binding of endogenous opioids to m receptors specifically is involved in extinction.…”

Acquisition of Fear Extinction Requires Activation of NR2B-Containing NMDA Receptors in the Lateral Amygdala

“…Thus, our data are consistent with a neural model for fear extinction that involves a distributed network, where the lateral amygdala plays a central role. Other likely candidate sites are the medial prefrontal cortex (Morgan et al, 1993;Quirk et al, 2000;Milad and Quirk, 2002;Santini et al, 2004), the periaqueductal gray matter (McNally et al, 2004), and the hippocampus (Corcoran et al, 2005).…”