Differential Effects of Nicotine and Nicotine Withdrawal on Fear Conditioning in Male Rats

Abstract

Background: Tobacco use is prevalent in individuals who are routinely exposed to stress. However, little is known about how nicotine affects responses to trauma. We examined in rats how nicotine exposure affects fear conditioning, a procedure often used to study stress-related psychiatric illness.

Methods: We examined 2 methods of nicotine exposure: self-administration, modeling voluntary use, and experimenter-programmed subcutaneous administration, modeling medicinal administration (nicotine patch). For self-administered nicotine, rats trained to self-administer nicotine i.v. were fear conditioned (via light cue preceding foot-shock) either immediately after a 12-hour self-administration session or 12 hours later during a period with somatic signs of nicotine withdrawal. For experimenter-delivered nicotine, rats were conditioned after 1-21 days of nicotine delivered by programmable (12 hours on) subcutaneous mini-pumps. Tests to evaluate acoustic startle responses to the conditioning environment (context-potentiated startle) and in the presence or absence of the light cue (fear-potentiated startle) occurred after a 10-day period.

Results: Rats fear conditioned immediately after nicotine self-administration showed reduced responses to the shock-associated context, whereas those trained during nicotine withdrawal showed exaggerated responses. Experimenter-programmed nicotine produced effects qualitatively similar to those seen with self-administered nicotine.

Conclusions: Self-administration or experimenter-programmed delivery of nicotine immediately before exposure to aversive events can reduce conditioned fear responses. In contrast, exposure to aversive events during nicotine withdrawal exacerbates fear responses. These studies raise the possibility of developing safe and effective methods to deliver nicotine or related drugs to mitigate the effects of stress while also highlighting the importance of preventing withdrawal in nicotine-dependent individuals.

Keywords: Fear conditioning; PTSD; nicotine; withdrawal.

Figure 1.

(A) Intravenous self-administration (IVSA) of nicotine in 12-hour sessions. Data reflect the mean ± SEMs for the 4 days preceding fear conditioning. (B) Average infusions per session collapsed across the entire session during the final 4 IVSA sessions. (C) Nicotine withdrawal signs 12 hours after the last 12-hour self-administration session. *P < .05, **P < .01, ***P < .001, Bonferroni’s tests.

Figure 2.

Effect of i.v. self-administration (IVSA) treatment on responsiveness to the acoustic startle stimulus and foot-shock. Data reflect mean (±SEM) platform displacement in arbitrary startle units. Neither nicotine (A) nor nicotine withdrawal (B) affected responsiveness to the acoustic startle stimulus (100-dB white noise burst) in rats before group assignment into shock or no shock conditions. Likewise, neither nicotine (C) nor nicotine withdrawal (D) affected responsiveness to foot-shock (0.5 seconds at 0.6 mA).

Figure 3.

Startle responsiveness during testing in rats that received fear conditioning immediately after i.v. self-administration (IVSA) sessions when access to nicotine was unavailable during the 10 days between training and testing. (A) Context-potentiated startle (CPS) was reduced in rats fear conditioned immediately following the final nicotine IVSA session compared with saline controls during Test 1, but there were no differences Test 2 or Test 3. As expected, no-shock controls did not exhibit contextual fear at any time point. (B) Fear-potentiated startle (FPS) did not differ between rats fear conditioned immediately following the final nicotine IVSA session and saline controls. *P < .05, Bonferroni’s tests.

Figure 4.

Startle responsiveness during testing in rats that received fear conditioning 12 hours after i.v. self-administration (IVSA) sessions, during nicotine withdrawal, when access to nicotine was unavailable during the 10 days between training and testing. (A) There were no group differences in CPS during Test 1, but rats trained during nicotine withdrawal had persistently higher CPS during Test 2 and Test 3. As expected, no-shock controls did not exhibit contextual fear at any time point. (B) Fear-potentiated startle (FPS) did not differ between nicotine withdrawal rats and saline controls. *P < .05, **P < .01, Bonferroni’s tests.

Figure 5.

Startle responsiveness during testing in rats that received fear conditioning 12 hours after i.v. self-administration (IVSA) sessions, during nicotine withdrawal, when access to nicotine was available during the 10 days between training and testing. (A) There were no group differences in CPS during Test 1, but responsiveness in saline-treated rats diminished between Test 1 and Test 3, whereas it remained persistently high in nicotine withdrawal rats. As expected, no-shock controls did not exhibit contextual fear at any time point. (B) Fear-potentiated startle (FPS) did not differ between nicotine withdrawal rats and saline controls. *P < .05, Bonferroni’s tests.

Figure 6.

Effect of programmed s.c. treatment with nicotine at various doses and durations (1, 10, and 21 days) on responsiveness to the acoustic startle stimulus and foot-shock. There were no group differences in responsiveness to the acoustic startle stimulus (A–C) or foot-shock (D–F).

Figure 7.

Startle responsiveness during testing in rats that received fear conditioning immediately following programmed s.c. treatment with nicotine when access to nicotine was unavailable during the 10 days between training and testing. (A–C) CPS was reduced in rats that received 10 days of programmed nicotine exposure but not 1 day or 21 days of exposure. (D–F) FPS was not affected by programmed nicotine exposure at any dose or duration. *P < .05, Bonferroni’s tests.