Acute nicotine delays extinction of contextual fear in mice

Abstract

Smoking is linked to post-traumatic stress disorder (PTSD) which suggests smoking is either a risk factor or an attempt at self-medication. The ability to reduce or extinguish fear-related memories may be altered in patients with PTSD and it is possible that nicotine modulates this. Although there are numerous studies examining the effects of nicotine on acquisition of fear learning, the effects of nicotine on extinction of contextual fear are not well understood. In the present study, we examined the effects of acute nicotine (0.18 mg/kg) on extinction of contextual fear in C57BL/6J mice. Animals were first trained in a background contextual fear conditioning paradigm using a white noise as a conditioned stimulus (CS), which co-terminated with a 2 s 0.57 mA unconditioned foot-shock stimulus (US). Animals were then administered either nicotine or saline and exposed to either the training context or a novel context in order to measure freezing to the context during extinction. Our results demonstrate that nicotine administration during extinction delays extinction of contextual freezing while nicotine did not affect cued freezing or freezing to the novel context.

Keywords: Anxiety; Context; Extinction; Fear Conditioning; Nicotine; PTSD.

Figure 1

The schematic experimental designs of Experiment 1 and 2. While each box represents a phase of the experiment, the syringes represent nicotine or saline injections and the thunder bolt symbol indicates the presentations of the foot-shocks (FC = Fear Conditioning).

Figure 2

The effects of acute nicotine injections prior to the retest phase. Extinction of contextual fear conditioning was impaired in the nicotine group (n=8) comparing to the saline group (n=7) while pre-CS freezing and cued extinction was unaffected (CX: context). Error bars indicate Standard Error of the Mean (SEM) and asterisks represent differences at the p < 0.05 level.

Figure 3

The effects of acute nicotine injections on contextual freezing prior to the retest phase within the test and retest sessions. Each point represents an averaged freezing level over a 100 sec bin. Error bars indicate Standard Error of the Mean (SEM) and asterisks represent differences at the p < 0.05 level.

Figure 4

The effects of acute nicotine administration prior to 5 retest sessions. Extinction of contextual fear conditioning was delayed in the nicotine group (n=8) comparing to the saline group (n=7) whereas nicotine did not have any effect on the freezing response to a novel context (CX: context). Error bars indicate Standard Error of the Mean (SEM) and asterisks represent differences at the p < 0.05 level.

Figure 5

Data from Elias et al. (2010) within the first extinction session in Context A (AAA) or in Context B (ABA). Extinction of contextual freezing was delayed in the AAA design but not in the ABA design. A t-test showed that freezing to the context during the 3^rd 120 s bin was significant (t(16)=2.136, p=0.048). Error bars indicate Standard Error of the Mean (SEM) and asterisks represent differences at the p < 0.05 level.