Systemic propranolol acts centrally to reduce conditioned fear in rats without impairing extinction

Abstract

Background: Previous work has implicated noradrenergic beta-receptors in the consolidation and reconsolidation of conditioned fear. Less is known, however, about their role in fear expression and extinction. The beta-receptor blocker propranolol has been used clinically to reduce anxiety. With an auditory fear conditioning task in rats, we assessed the effects of systemic propranolol on the expression and extinction of two measures of conditioned fear: freezing and suppression of bar-pressing.

Methods: One day after receiving auditory fear conditioning, rats were injected with saline, propranolol, or peripheral beta-receptor blocker sotalol (both 10 mg/kg, IP). Twenty minutes after injection, rats were given either 6 or 12 extinction trials and were tested for extinction retention the following day. The effect of propranolol on the firing rate of neurons in prelimbic (PL) prefrontal cortex was also assessed.

Results: Propranolol reduced freezing by more than 50%, an effect that was evident from the first extinction trial. Suppression was also significantly reduced. Despite this, propranolol had no effect on the acquisition or retention of extinction. Unlike propranolol, sotalol did not affect fear expression, although both drugs significantly reduced heart rate. This suggests that propranolol acts centrally to reduce fear. Consistent with this, propranolol reduced the firing rate of PL neurons.

Conclusion: Propranolol reduced the expression of conditioned fear, without interfering with extinction learning. Reduced fear with intact extinction suggests a possible use for propranolol in reducing anxiety during extinction-based exposure therapies, without interfering with long-term clinical response.

Figure 1

Propranolol reduces fear expression but does not impair extinction learning. Systemic injections of propranolol (arrow) prior to complete extinction on day 2 led to a significant decrease in fear expression as measured by (A) percent freezing and (B) bar-press suppression. On day 3 both groups recalled extinction similarly. Data shown in blocks of 2 trials. (conditioning: Cond)

Figure 2

Propranolol does not facilitate extinction learning or erase fear memory. Injection of propranolol (arrow) prior to partial extinction on day 2 led to a significant decrease in fear expression as measured by (A) percent freezing and (B) bar-press suppression. There were no differences between groups in further extinction sessions on day 3 and day 5. Two unpaired shocks on day 5 reinstated fear on day 6 equally in both groups. Data shown in blocks of 2 trials. (conditioning: Cond; extinction: Ext; reinstatement: Reinst; day 2: D2)

Figure 3

(A) Propranolol does not alter spontaneous locomotion (left), anxiety in an open field (center), or rate of bar-pressing for food reward (right).

Figure 4

Peripheral beta blocker sotalol does not reduce fear expression or impair extinction learning. Systemic injections of sotalol (arrow) prior to complete extinction on day 2 did not decrease fear expression as measured by (A) percent freezing and (B) bar-press suppression. On day 3, both groups recalled extinction similarly. Data shown in blocks of 2 trials. (C) Propranolol and sotalol both reduced heart rate from baseline levels in anesthetized rats. Rates were assessed prior to, and 10 min after, injection of drugs. Propranolol significantly reduced heart rate below baseline (94%, *p<0.05). Similarly, sotalol significantly reduced heart rate below baseline (87%, **p<0.01). (conditioning: Cond; heart rate: HR)

Figure 5

Propranolol reduces spontaneous firing rate of prelimbic (PL) neurons in awake rats. (A) Unit recording sites in PL (IL: infralimbic cortex; ACd: dorsal anterior cingulate cortex). (B) Systemic propranolol decreased spontaneous firing rate (**p<0.01), but not bursting, in PL neurons. (C) The firing rates of individual neurons before and after injection are shown. Unlike saline, injection of propranolol decreased the firing rate of the majority of neurons (p<0.05). Solid lines in each plot represent the linear regression; dotted line in the propranolol plot represents the linear regression of the saline results. (propranolol: Prop; injection: inj.)