Pharmacological Discrimination of Extinction and Reconsolidation of Contextual Fear Memory by a Potentiator of AMPA Receptors

Abstract

Conditioned fear memory, once formed through fear conditioning, is modulated by reexposure of individuals to a conditioned stimulus. The reexposure reactivates the fear memory, which induces reconsolidation of the memory first, and then extinction of the fear response. Both attenuating the former and facilitating the latter are effective in reducing the fear response, and these findings are potentially translatable to the enhancement of exposure therapy for complex anxiety disorders. Currently, there is no drug that is established to modulate either reconsolidation or extinction selectively, which are thought to be independent processes. Here, we report that an extinction-facilitating AMPA potentiator, 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide (PEPA), does not act on the reconsolidation of fear memory formed by contextual fear conditioning in mice. The freezing rates observed in contextually conditioned mice following short reexposure (3 min) to the context were not influenced by intraperitoneal or intra-amygdala administration of PEPA. The same short reexposure to the context enhanced freezing responses in mice that were similarly administered D-cycloserine (DCS), a drug that facilitates both extinction and reconsolidation, and this enhancement of freezing responses in mice intraperitoneally administered DCS was abolished by propranolol, a drug that suppresses reconsolidation. At the same doses used in the short reexposure experiments, PEPA and DCS facilitated extinction of the fear response induced by long reexposure to the context and suppressed reinstatement of the conditioned fear memory. PEPA and DCS did not affect reextinction. These results suggest that PEPA acts on extinction of contextual fear memory without having detectable influences on its reconsolidation.

Retrieval induces reconsolidation of fear extinction memory

“…Given the clinical relevance that reconsolidation blockade and extinction enhancement could have (7,8), research about the consequences of retrieval on LTM persistence has concentrated on the molecular, neuroanatomical, and electrophysiological requirements of reconsolidation and extinction (9)(10)(11)(12) as well as on the elucidation of the behavioral and neurochemical conditions that constrain or facilitate either process (13)(14)(15). The potential interaction of extinction and reconsolidation has been comparatively less studied, and when so, the studies produced contradictory results.…”

d-cycloserine in the basolateral amygdala prevents extinction and enhances reconsolidation of odor-reward associative learning in rats

“…The injection-to-extinction learning/reactivation interval was the same as in previous research showing a positive effect of DCS on ODT performance (Villarejo-Rodriguez et al, 2010) and similar to that used in other experiments (15 to 30 min) reporting facilitation of intra-BLA DCS on extinction (Lee et al, 2006;Mao, Hsiao, & Gean, 2006;Walker et al, 2002) and reconsolidation (Lee et al, 2009;Yamada et al, 2009). The injectors were connected by polyethylene tubing (Plastics One®) to two 10-μl syringes (SGE Analytical Science, Cromlab S.L.…”

“…Thus, intra-BLA DCS has been shown to enhance the reconsolidation of stimulus-cocaine memories as it increased cue-induced relapse in rats with an extensive drug self-administration history (Lee et al, 2009). Moreover, studies carried out in single-trial paradigms have shown that DCS, injected intraperitoneally or into the BLA, potentiates fear memory reconsolidation by increasing the animals' freezing responses during the test (Lee et al, 2006;Yamada et al, 2009). Consistent with our interpretation that a positive modulation of NMDA transmission may help to stabilize the original odor-reward memory trace when reactivated, a previous study showed that intracerebroventricular blockade of NMDARs immediately after reactivation induced amnesia for the stimuli association (Torras-Garcia et al, 2005).…”

“…Previous literature has mainly examined the effects of DCS on contextual or auditory conditioned fear, indicating that systemic and intra-BLA administrations of DCS may potentiate both extinction and reconsolidation (Ledgerwood, Richardson & Cranney, 2003;Ledgerwood et al, 2005;Lee et al, 2006;Toth et al, 2012;Walker, Ressler, Lu & Davis, 2002;Yamada, Zushida, Wada & Sekiguchi, 2009;Yamamoto et al, 2008). Also, DCS in the BLA facilitated the extinction of contextual fear with no effect on the extinction of conditioned taste aversion (Akirav, Segev, Motanis, & Maroun, 2009).…”

Prenatal Nicotine Exposure Impairs the Proliferation of Neuronal Progenitors, Leading to Fewer Glutamatergic Neurons in the Medial Prefrontal Cortex

“…DCS (5 nmol per 0.5 μl/ bilaterally) was injected into each PFC through an infusion cannula (6.0 mm, 0.35 mm in diameter; Eicom), which was connected to a microsyringe mounted on an infusion pump 10 min before the behavioral test. The doses of DCS for systemic administration and microinjection were determined according to the previous reports (Murai et al, 2007;Yamada et al, 2009). …”