Extracellular signal-regulated kinase 1/2 involvement in the enhancement of contextual fear conditioning by nicotine

Abstract

Contextual fear conditioning is enhanced by nicotine, but the cellular mechanisms underlying this effect are unknown. Extracellular signal regulated kinase 1/2 (ERK 1/2) has been shown to play an integral role in the formation of contextual fear memories. As such, it is possible that ERK 1/2 is involved in the enhancement of contextual fear conditioning by nicotine. To determine whether ERK 1/2 plays a role in this enhancement, a dose of SL327 (a selective, systemic ERK 1/2 inhibitor) that is subthreshold for inhibiting contextual fear conditioning was coadministered with nicotine prior to training, testing, or both training and testing of contextual fear conditioning in C57BL/6 mice. When administered prior to training, this subthreshold dose of SL327 attenuated the enhancement of contextual fear conditioning by nicotine to levels similar to those of vehicle-treated animals. When administered prior to testing, the subthreshold dose of SL327 did not significantly alter conditioning. These results suggest that activation of ERK 1/2 by nicotine during acquisition leads to an enhancement of contextual fear conditioning.

Figure 1. Effects of SL327 on nicotine-enhanced contextual fear conditioning

(A) Administration of SL327, a selective inhibitor of extracellular signal-regulated kinase (ERK) 1/2, blocks contextual fear conditioning at a dose of 10 mg/kg but not at a dose of 5 mg/kg. Therefore, SL327 is subthreshold for the disruption of contextual fear conditioning at a dose of 5 mg/kg. (B) Subthreshold inhibition of ERK 1/2 at training of contextual fear conditioning blocks the enhancement of contextual fear conditioning by nicotine (0.09 mg/kg). SL327 (5 mg/kg) was administered only prior to training; prior to testing, mice received a matched vehicle injection. (C) Subthreshold inhibition of ERK 1/2 at training and testing of contextual fear conditioning blocks the enhancement of contextual fear conditioning by nicotine (0.09 mg/kg). (D) Subthreshold inhibition of ERK 1/2 at testing has no significant effect on nicotine-enhanced contextual fear conditioning. SL327 (5 mg/kg) administered only prior to testing; prior to training, mice received a matched vehicle injection. Asterisk (*) indicates significant difference from vehicle control groups. Data are mean (± SEM).