Nicotine reduces discrimination between threat and safety in the hippocampus, nucleus accumbens and amygdala

Abstract

Nicotine intake is linked to the maintenance and development of anxiety disorders and impairs adaptive discrimination of threat and safety in rodents and humans. Yet, it is unclear if nicotine exerts a causal pharmacological effect on the affective and neural mechanisms that underlie aversive learning. We conducted a pre-registered, pseudo-randomly and double-blinded pharmacological fMRI study to investigate the effect of acute nicotine on Fear Acquisition and Extinction in non-smokers (n = 88). Our results show that nicotine administration led to decreased discrimination between threat and safety in subjective fear. Nicotine furthermore decreased differential (threat vs. safety) activation in the hippocampus, which was functionally coupled with Nucleus Accumbens and amygdala, compared to placebo controls. Additionally, nicotine led to enhanced physiological arousal to learned threats and overactivation of the ventral tegmental area. This study provides mechanistic evidence that single doses of nicotine impair neural substrates of adaptive aversive learning in line with the risk for the development of pathological anxiety.

Fig. 1. Experimental procedure.

The group Nic1 received nicotine before the fear acquisition on day 1 (ACQ), all remaining subjects received placebo. After 24 h the group Nic2 received nicotine and the remaining subjects received Placebo. Following that, subjects performed the Extinction training (EXT) with a subsequent Return of Fear (RoF) manipulation in form of a Reinstatement. CS colours were counterbalanced.

Fig. 2. Fear ratings.

Weaker stimulus discrimination in the groups that received nicotine when compared to the Placebo group in fear ratings, (a) after Fear Acquisition (day 1), (b) before Extinction (day 2). No group differences in the differential fear ratings were found pre ACQ, post EXT or post RoF. Single subject responses are shown as scatterpoints, mean differential fear ratings are depicted as lines with standard errors. Dashed lines represent the mean differential fear ratings per group post ACQ/pre EXT.

Fig. 3. Hippocampal activity.

a Acquisition: Acute nicotine administration, compared to placebo, reduces differential responses to the CS+ and the CS- during the last block of ACQ in the left hippocampus (similar to fear rating results). This effect is robust over all three blocks of the ACQ in the left HC. b Psycho-physiological interaction (PPI) during the last block of ACQ with left hippocampus as seed region. Nicotine administration before ACQ leads to increased connectivity towards the bilateral AMY and the right NAcc, compared to placebo controls. c Extinction: Weaker stimulus discrimination during late EXT in the left HC in the group that received nicotine before ACQ (Nic1), when compared to placebo controls. No group differences in hippocampal activity during EXT or RoF were found between Nic2 and Pla. Scatterpoints represent single subject parameter estimates to each CS. Bars represent means across each group with standard error. d Psycho-physiological interaction (PPI) during the last block of EXT with left hippocampus as seed region. Nicotine administration before EXT leads to decreased connectivity towards the vmPFC, compared to placebo controls.

Fig. 4. Stimulus discrimination during Fear Acquisition.

fMRI results over all blocks in the (a) left Amygdala and (b) left Ncl. Accumbens. The group that received nicotine (Nic1) shows a lower activity in the ROIs over time, when compared to the Placebo group (contrast: CS + > CS-, Pla>Nic1).

Fig. 5. Parametric Modulation of US expectancy in SN/VTA.

Stronger activation in the SN/VTA in the Nicotine group, when subjects expected the US, when compared to the placebo group over the whole fear acquisition. Scatterpoints represent single subject contrast estimates in the SN/VTA, bars represent means with standard errors.