Blocking, Unblocking, and Overexpectation of Fear: A Role for Opioid Receptors in the Regulation of Pavlovian Association Formation.

Abstract

Injection of the opioid receptor antagonist naloxone facilitated acquisition of fear to contextual and auditory conditioned stimuli (CSs) in Experiments 1A and 1B. Experiment 2 showed that prior conditioning to a distinctive context blocked conditioning to an auditory CS. Blocking of CS fear was prevented by administrations of naloxone or increases in footshock intensity. Blocking of CS fear was facilitated by decreases in footshock intensity in a naloxone-reversible manner. Experiment 3 showed that compound conditioning of two CSs, each previously and separately paired with shock, produced overexpectation of fear that was reversed by naloxone. These results are consistent with a role for opioid receptors controlling Pavlovian association formation by regulating the discrepancy ( Ϫ ⌺V) described by R. A. Rescorla and A. R. Wagner (1972).

The effects of FG7142 on overexpectation of Pavlovian fear conditioning.

“…These results confirm the presence of overexpectation of fear learning (Blaisdell et al, 2001;Kamin & Gaioni, 1974;Kremer, 1978;McNally et al, 2004;Rescorla, 1970). They show, that under present conditions, overexpectation is maximal after two Stage II trials and is reduced with further Stage II training.…”

Mechanisms of fear extinction

“…This prediction was borne out experimentally. 219 Altogether this line of research presents convincing evidence for a role of endogenous opioid release at the level of the vlPAG in error correction in Pavlovian fear acquisition and extinction. It remains to be seen how an error signal orchestrated at the level of the vlPAG modulates plasticity occurring elsewhere in the brain, such as the amygdala; and whether this signal specifically modulates conditioned fear responses that require PAG to be expressed, such as freezing, 221 but not those that operate independently of PAG, such as conditioned suppression.…”

“…This is exactly what happens: blocking is eliminated by naloxone. 80,210,219 This effect, like the retardation of extinction, is mimicked by infusion of naloxone or the m opioid antagonist CTAP directly into vlPAG. 80 The second additional phenomenon examined by McNally and co-workers is overexpectation, in which two CSs, C and D, are paired with the US separately in one phase of training, then are paired with the US in compound in a second phase (lower panel of Figure 4).…”

Error Correction in Latent Inhibition and its Disruption by Opioid Receptor Blockade with Naloxone

“…The opposite effects of naloxone on fear acquisition and fear extinction suggests that endogenous opioids do not simply enhance or impair associative learning; rather, they perform a computational function in fear conditioning, specifically encoding the subtractive component ( À P V) in the error term (l À P V) described by error-correction models (McNally et al, 2004(McNally et al, , 2011McNally, 2009). When prediction error is positive, blockade of this subtractive component augments the positive error signal and facilitates fear conditioning.…”

“…In Pavlovian fear conditioning, it is hypothesized that the error signal that regulates associative formation is instantiated through the endogenous opioid system (Fanselow, 1998;McNally, 2009). When an expected US is absent, that is, when prediction error is negative, systemic administration of the competitive opioid receptor antagonist naloxone impairs fear extinction (McNally and Westbrook, 2003) and the overexpectation effect (McNally et al, 2004). There is evidence that novel stimuli can activate the release of endogenous opioids (eg, Cador et al, 2002;Izquierdo et al, 1984).…”