Stress-dependent opioid and adrenergic modulation of newly retrieved fear memory

Abstract

Recent studies on the effect of stress on modulation of fear memory in our laboratory have uncovered endogenous opioid and adrenergic based modulation systems, working in concert, that limit the strengthening or weakening of newly acquired fear memory during consolidation under conditions of mild or intense stress, respectively. The present study sought to determine if similar stress-dependent modulation, mediated by endogenous opioid and adrenergic systems, occurs during reconsolidation of newly retrieved fear memory. Rats underwent contextual fear conditioning followed 24 hr later by reactivation of fear memory; a retention test was administered the next day. Stress was manipulated by varying duration of recall of fear memory during reactivation. In the first experiment, vehicle or the opioid-receptor blocker naloxone was administered immediately after varied durations (30 or 120 sec) of reactivation. The results indicate that 1) reactivation, in the absence of drug, has a marked effect on freezing behavior—as duration of reactivation increases from 30 to 120 sec, freezing behavior and presumably fearinduced stress increases and 2) naloxone, administered immediately after 30 sec (mild stress) or 120 sec (intense stress) of reactivation, enhances or impairs retention, respectively, the next day. In the second experiment, naloxone and the ß-adrenergic blocker propranolol were administered either separately or in combination immediately after 120 sec (intense stress) reactivation. The results indicate that separate administration of propranolol and naloxone impairs retention, while the combined administration fails to do so. Taken together the results of the two experiments are consistent with a protective mechanism, mediated by endogenous opioid and adrenergic systems working in concert, that limits enhancement and impairment of newly retrieved fear memory during reactivation in a stress-dependent manner.

Noradrenergic Modulation of Fear Conditioning and Extinction

“…Disrupting the reconsolidation of a fear memory can potentially have far reaching clinical implications for trauma- and stressor-related disorders. Many labs have provided compelling evidence that propranolol delivered after brief memory reactivation disrupts the reconsolidation of both cued and context fear memories in rodents (Przybyslawski et al, 1999 ; Dębiec and Ledoux, 2004 ; Abrari et al, 2008 ; Muravieva and Alberini, 2010 ; Dębiec et al, 2011 ; Pitman et al, 2011 ; Schneider et al, 2014 ; Taherian et al, 2014 ). In addition, systemic clonidine has also mirrored these effects (Gamache et al, 2012 ).…”

Post Traumatic Stress Disorder and Substance Use Disorder as Two Pathologies Affecting Memory Reactivation: Implications for New Therapeutic Approaches

“…Numerous preclinical studies have shown that treatments presumed to interfere with reconsolidation given at memory reactivation can result in a loss of the initial memory concerning either drugs of abuse (Lee et al, 2006a; Robinson and Franklin, 2007; Fricks-Gleason and Marshall, 2008) or trauma memories (Debiec and Ledoux, 2004; Muravieva and Alberini, 2010; Schneider et al, 2014). However, most of the studies, which conclusively demonstrated the possibility of inducing amnesia by the use of reconsolidation blockade, have been performed on animals, with treatments that are too toxic to be used in humans.…”

Revisiting propranolol and PTSD: Memory erasure or extinction enhancement?

“…This effect has been replicated in the rodent literature, further demonstrating that propranolol reduces fear when delivered after a brief memory reactivation (Abrari, Rashidy-Pour, Semnanian, & Fathollahi, 2008; Muravieva & Alberini, 2010). In addition to cued fear memories, propranolol effectively blocks reconsolidation of context fear in rats (Schneider et al, 2014). Collectively, these data indicate that propranolol administration immediately after brief memory retrieval dampens fear responding long term and may do so by interfering with reconsolidation.…”