ACUTE NICOTINE-DEPENDENT ALTERATIONS IN ASSOCIATIVE LEARNING INTERFERE WITH BACKWARDS TRACE CONDITIONED SAFETY

Abstract

Organisms can form safety associations with cues that predict the absence of an aversive event. This cognitive process, learned safety, is important for modulating emotional processing, as safety cues can decrease fear in the presence of previously learned danger cues. Further, there are clinical implications in understanding learned safety, as individuals with PTSD present with deficits in learned safety. Additionally, there is a well established relationship between smoking and PTSD. The link between smoking and PTSD is unclear, however one possibility is that nicotine-associated changes in cognition could facilitate PTSD symptoms, particularly by disrupting are altering learned safety. Considering that nicotine has been shown to modulate associative learning, including hippocampus-dependent forms of fear learning, we hypothesized that nicotine administration could cause maladaptive associative learning to occur, leading to altered safety learning. In the present study, mice were administered acute nicotine and trained and tested in two forms of cued safety learning, explicitly unpaired and backwards trace conditioning. To test for conditioned inhibition of fear by safety cues we performed summation testing. Summation testing indicated that acute nicotine did not impact unpaired learned safety, but did disrupt backwards trace conditioned safety. Additionally, chronic nicotine was found to have no effect on backwards trace conditioned safety, suggesting the development of tolerance. Importantly, on a separate test in which the backwards trace conditioned stimulus was presented alone in a novel context, acute nicotine administration was found to facilitate a fear association with the backwards trace conditioned stimulus. Therefore, acute nicotine prevented backwards trace conditioned safety, by facilitating the formation of a maladaptive fear association. Finally, we found that infusion of nicotine into the dorsal hippocampus and medial prefrontal cortex resulted in similar maladaptive behavioral patterns in summation testing. These findings are discussed with respect to how nicotine can alter cognition and the role alterations in cognition may play PTSD.