UC San Diego

The psychostimulants methylphenidate and amphetamine enhance monoaminergic neurotransmission by acting on reuptake transporters. Together, they form the cornerstone of treatment for attention-deficit hyperactivity disorder, the most common psychiatric disorder in children, because of their ability to improve learning at low doses. At high doses, they are subject to abuse that can lead to addiction and cognitive dysfunction. Current theories posit that methylphenidate and amphetamine exert their therapeutic effects by acting on the norepinephrine transporter (NET) and produce their reinforcing effects by acting on the dopamine transporter (DAT). The studies in this dissertation were specifically aimed at identifying the contributions of NET and DAT to stimulant-induced memory enhancement. While stimulant effects on memory have typically been interpreted as the result of changes in high-level functions like impulsivity and executive function, here we present evidence that stimulants can also improve memory directly (Chapters 2-4). Furthermore, memory enhancement is independent of effects on locomotion, reinforcement, and anxiety (Chapter 3). In comparing the effects of agonists with varying affinities for DAT and NET on memory, we conclude that action at DAT and perhaps NET is required for these memory enhancements (Chapter 3). To clarify this mechanism, we used triple point mutant knockin mice of the gene coding DAT or NET that hinder the binding of methylphenidate and reduce the efficiency of the transporters (Chapter 5). We found that the mutations in DAT, but not NET, produced severe learning and memory defects across multiple memory domains. Together, these results indicate that stimulants enhance memory and we propose that DAT plays an obligatory role in memory