Limited efficacy of propranolol on the reconsolidation of fear memories

Abstract

Previous studies suggested that the beta-adrenergic receptor antagonist propranolol might be a novel, potential treatment for post-traumatic stress disorder (PTSD). This hypothesis stemmed mainly from rodent studies showing that propranolol interferes with the reconsolidation of Pavlovian fear conditioning (FC). However, subsequent investigations in humans have produced controversial evidence about the effect of propranolol on fear memories and an effect on PTSD symptomatology has yet to be reported. Thus, it remains to be established whether propranolol interferes with the reconsolidation of fear memories at large. To address this question, we tested the effect of systemic injections of propranolol administered before or after the retrieval of an inhibitory avoidance (IA) memory elicited with different footshock intensities. In parallel, the same treatment was tested on the reconsolidation of Pavlovian FC. Propranolol showed no effect on the reconsolidation of IA, although the pre-retrieval administration resulted in a significant retrieval impairment. This impairment was transient, and memory returned to control levels at later times. In agreement with previous studies, we found that systemic administration of propranolol disrupts the reconsolidation of Pavlovian FC and that its injection following a retrieval elicited by cue exposure also interferes with the reconsolidation of contextual FC. Hence, propranolol disrupts the reconsolidation of Pavlovian FC, but has no effect on the reconsolidation of IA. The results indicate that the efficacy of systemic administration of propranolol in disrupting the reconsolidation of fear memories is limited.

Figure 1.

Propranolol administered systemically impairs IA retrieval but has no effect on reconsolidation. Experimental timelines are shown above each experiment. Values of latencies are expressed in seconds (s) and shown as means ± SEM. (A) Animals were trained in IA with 0.9 mA footshock intensity, 48 h later they were tested (Test 1), and immediately after, they were injected i.p. with propranolol or saline. Rats were tested again 48 h later (Test 2). No significant effect of treatment was found among groups. (B) Animals underwent the same experimental protocol as in A, except that 0.6 mA footshock intensity was used during training. No significant effect of treatment was found among groups. (C) Animals underwent the same experimental protocol as in A, except that 0.25 mA footshock intensity was used during training. No significant effect of treatment was found among groups. (D) Animals underwent the same experimental protocol as in B, except that they received an i.p. injection of propranolol 30 min before reactivation (Test 1). Compared with saline, propranolol significantly disrupted IA retention at Test 1 (**, P < 0.01), but not at Test 2.

Figure 2.

Propranolol administered systemically after reactivation disrupts both cue- and contextual-FC reconsolidation. Cue reactivation influences contextual memory. Experimental timelines are shown above each experiment. Freezing scores are expressed as percent of the total time of testing and shown as means ± SEM. (A) Rats were trained in FC. Forty-eight hours later, they were presented with the tone in a different context and immediately after, received an i.p. injection of either propranolol or saline. Forty-eight hours and 96 h later, the animals were tested for cue and contextual freezing, respectively. Propranolol significantly disrupted FC in both cue and context tests (***, P < 0.001). (B) Rats were trained in FC and exposed to the training context 48 h later. Immediately after context exposure, rats received an i.p. injection of either propranolol or saline. Forty-eight hours and 96 h later, the animals were tested for contextual and cue freezing, respectively. Propranolol significantly disrupted contextual fear memory but did not affect cued fear memory (***, P < 0.001). (C) Rats were trained and received propranolol or saline injections as in A in the absence of reactivation. Forty-eight hours and 96 h after the injection, the animals were tested for cue and contextual freezing, respectively. No significant differences were found among groups. (D) Rats were trained in FC and 48 h later were exposed to a novel context without any cue presentation and immediately after were injected with propranolol or saline i.p. Forty-eight hours and 96 h later, the animals were tested for cue and contextual freezing, respectively. No significant differences were found among groups.

Figure 3.

Propranolol disrupts freezing but not IA memory. Experimental timelines are shown above each experiment. Values of latencies are expressed in seconds and shown as means ± SEM. Freezing scores are expressed as percent of the total time of testing and shown as means ± SEM. (A) Rats were trained in IA with 0.6 mA footshock intensity and, during training, presented with a tone. Forty-eight hours later, they were tested in IA, and immediately after, received an i.p. injection of propranolol or saline. Forty-eight hours and 96 h later, the animals were tested in IA and cue fear memory, respectively. Compared with saline, propranolol had no effect on IA retention, but significantly disrupted freezing (Student's t-test, [**] P < 0.01). (B) Rats underwent the same protocol as in A, except that a footshock of 0.9 mA was used during training. Compared with saline, propranolol had no effect on IA retention, but significantly disrupted freezing (Student's t-test, [*] P < 0.05).