Nicotine enhances context learning but not context-shock associative learning

Abstract

Nicotine has been found to enhance learning in a variety of tasks, including contextual fear conditioning. During contextual fear conditioning animals have to learn the context and associate the context with an unconditioned stimulus (footshock). As both of these types of learning co-occur during fear conditioning, it is not clear whether nicotine enhances one or both of these types of learning. To tease these two forms of learning apart, the authors made use of the context preexposure facilitation effect (CPFE). Acquisition of the CPFE requires that contextual and context-shock learning occurs on separate days, allowing for their individual manipulation. Nicotine (0.09 mg/kg) administered prior to contextual learning and retrieval enhanced the CPFE whereas administration prior to context-shock learning and retrieval had no effect. Thus, nicotine enhances contextual learning but not context-shock associative learning. Finally, the results are discussed in terms of a theory of how nicotine could alter hippocampal-cortical-amygdala interactions to facilitate contextual learning.

Figure 1

Pre-exposure to the context for ten minutes, but not two minutes, is sufficient to produce the context pre-exposure facilitation effect. *p < 0.05 compared to the 2 or 10 minute non pre-exposed and 2 minute pre-exposed groups (n = 6–7). PE – Pre-exposed, NPE – Not pre-exposed. Error bars represent SEM.

Figure 2

Nicotine administration prior to one of the three days that comprise the CPFE. A) Nicotine administered prior to pre-exposure only had no effect on the CPFE (n = 9). B) Nicotine administered prior to immediate shock only had no effect on the CPFE (n = 8). C) Nicotine administered prior to testing only had no effect on the CPFE (n = 10). PE – Pre-exposed, NPE –Not pre-exposed, IS – Immediate shock. Error bars represent SEM.

Figure 3

Nicotine administration prior to two of three days that comprise the CPFE. A) Nicotine administered prior to pre-exposure and testing enhanced the CPFE (n = 9–10). B) Nicotine administered prior to immediate shock and testing had no effect on the CPFE (n = 13–14). C) Nicotine administered prior to pre-exposure and immediate shock had no effect on the CPFE (n = 8–9). * − p < 0.05 compared to both NPE groups and the PE group that received nicotine. PE –Pre-exposed, NPE – Not pre-exposed, IS – Immediate shock. Error bars represent SEM.

Figure 4

Testing whether nicotine can induce an internal state that can enter into an association with the US (footshock). Pairing nicotine with a footshock in context B and then testing in the presence of nicotine in a previously conditioned context A or a novel context C had no effect on freezing (n = 7). Error bars represent SEM.

Figure 5

A model of hippocampal-cortical-amygdala interaction hypothesized to underlie the enhancement of contextual fear conditioning by nicotine. C_1,2,3 represent different cortical regions; A is the amygdala; red lines represent inhibitory connections; green arrows represent strengthened connections formed/exist at each stage; glowing green indicates connections further strengthened due to nicotine administration. A) The connections between hippocampus-cortex-amygdala thought to be important for contextual fear conditioning. Both the hippocampus and cortex are able to support contextual fear conditioning using configural and feature strategies respectively (Rudy et al, 2004). Further, the hippocampus has two functions in this model: (1) to bind together disparate cortical regions into a configural representation of the context that can then enter into an association with the shock via connections to the amygdala (double headed black arrows), and (2) to inhibit the connections between the cortex and amygdala (red lines). B) Two mechanisms by which nicotine is hypothesized to alter hippocampal-cortical-amygdala connectivity: (i) by strengthening hippocampal-cortical connections and (ii) by disinhibiting cortical-amygdala connections. C) The mechanisms hypothesized to underlie the enhancement of the CPFE by nicotine. Nicotine at pre-exposure enhances hippocampal-cortical associative strength that normally forms at this stage (PE + Nicotine). During the immediate shock the context-shock association is formed by a strengthening of hippocampal-amygdala connectivity. During testing in the absence of nicotine only the hippocampal-amygdala connection drives the conditioned response to the context. Nicotine administration at testing activates the previously strengthened hippocampal-cortical pathway and disinhibits the cortical-amygdala connections resulting in an increased conditioned response via greater amygdala activation.