Frontal Involvement in Methylphenidate Modulated Pavlovian Fear Conditioning

The ADHD drug methylphenidate improves long-term memory, but it is still unclear whether this is a direct effect of the drug or due to improvements in executive function. Other ADHD pharmacological treatments, such as atomoxetine, improve executive control in terms of impulse control, working memory, and attention, but not long-term memory. Moreover, methylphenidate improves long-term memory in tasks with little attentional requirements, such as tone fear conditioning. This suggests that methylphenidate improves long-term memory through a mechanism that does not necessarily require improvements in executive function. This led us to hypothesize that methylphenidate directly enhances long-term memory. Frontal cortex is required for executive function, while the medial temporal lobe, including the hippocampus, is required for long-term memory formation. Methylphenidate binds targets in both the prefrontal cortex and hippocampus, but which of these is responsible for the improvements in long-term memory has yet to be determined. This study was undertaken to determine whether the frontal areas implicated in executive function are recruited in long-term memory enhancement by methylphenidate. Executive function was disrupted by lesioning prefrontal cortex in mice. Sham lesions were performed to account for the effects of surgery. Mice were then subjected to classical Pavlovian fear conditioning following administration of either methylphenidate or saline, and tested for contextual and tone memory one week later. In this study, both frontal lesions and methylphenidate failed to influence long-term memory, which may be due to increased stress from surgery that altered the optimal dose of methylphenidate. Further studies are required to elucidate the role of frontal cortex in methylphenidate-mediated memory enhancement