The CB1 receptor antagonist AM251 impairs reconsolidation of pavlovian fear memory in the rat basolateral amygdala

Abstract

We have investigated the requirement for signaling at CB1 receptors in the reconsolidation of a previously consolidated auditory fear memory, by infusing the CB1 receptor antagonist AM251, or the FAAH inhibitor URB597, directly into the basolateral amygdala (BLA) in conjunction with memory reactivation. AM251 disrupted memory restabilization, but only when administered after reactivation. URB597 produced a small, transient enhancement of memory restabilization when administered after reactivation. The amnestic effect of AM251 was rescued by coadministration of the GABAA receptor antagonist bicuculline at reactivation, indicating that the disruption of reconsolidation was mediated by altered GABAergic transmission in the BLA. These data show that the endocannabinoid system in the BLA is an important modulator of fear memory reconsolidation and that its effects on memory are mediated by an interaction with the GABAergic system. Thus, targeting the endocannabinoid system may have therapeutic potential to reduce the impact of maladaptive memories in neuropsychiatric disorders such as posttraumatic stress disorder.

Figure 1

Representation of cannulae placements within the BLA. The placements for individual experiments are shown separately, and coordinates are from bregma. For each experiment ((a), administration before reactivation, (b) administration after reactivation, (c) administration without reactivation, and (d) combined endocannabinoid and GABAergic signaling manipulations), the white circles represent the vehicle group and the dark circles represent the AM251 group. The gray circles represent URB597 group (a–c), the gray squares represents the bicuculline group (d), and the dark squares represent AM+BIC group (d). This figure was modified, with permission, from Paxinos and Watson (2004).

Figure 2

Effects of the FAAH inhibitor URB597 and the CB1 receptor antagonist AM251 on CS-fear memory reconsolidation. Administration of URB597 or AM251 before memory reactivation had no effect on the retrieval of the CS-fear memory at reactivation and did not alter expression of freezing response at tests conducted 24 h or 8 days later. Group sizes were VEH, n=9; URB597, n=10; and AM251, n=9.

Figure 3

Effects of the FAAH inhibitor URB597 (30 ng per 0.5 μl) and the CB1 receptor antagonist AM251 (300 ng per 0.5 μl) on CS-fear memory reconsolidation. Administration of URB597 immediately after the reactivation session produced a small, transient enhancement of CS-fear memory reconsolidation at 24 h, but not 8 days, after reactivation. AM251 persistently impaired memory reconsolidation when compared with vehicle and URB597-treated rats after both 24 h and 8 days after the reactivation session. Data are presented as means±SEM. Group sizes were VEH, n=10; URB597, n=12; and AM251, n=10.

Figure 4

Effects of the FAAH inhibitor URB597 (30 ng per 0.5 μl) and the CB1 receptor antagonist AM251 (300 ng per 0.5 μl) on CS-fear memory reconsolidation in rats not exposed to the memory reactivation session. Administration of URB597 or AM251 in the absence of memory reactivation had no effect on the retrieval of the CS-fear memory both 24 h and 8 days after administration. Data are presented as means±SEM. Group sizes were VEH, n=8; URB597, n=8; and AM251, n=8.

Figure 5

Effects of the CB1 receptor antagonist AM251 (300 ng per 0.5 μl) or the GABA_A receptor antagonist bicuculline (BIC 50 ng per 0.5 μl) on CS-fear memory reconsolidation. Administration of AM251 immediately after the reactivation session persistently impaired the CS-fear memory both 24 h and 8 days after the reactivation session. Data are presented as means±SEM. Group sizes were VEH, n=10; AM251, n=10; BIC, n=10; and AM251+BIC, n=8.