UC San Diego

Learning requires some form of long-lasting modification of neural activity that underlies a change in behavior. The mechanisms of long-lasting changes in the brain are likely to be conserved indicating that there is likely to be overlap in the mechanisms of memory and drug addiction. This dissertation will demonstrate how psychostimulants can modulate memory processes and create addiction-like memories in mice. First, we showed that a low dose of modafinil, a psychomotor stimulant, selectively enhances contextual fear memories, while a high dose disrupts this memory. This high dose can, however, enhance water maze learning. Second, we demonstrated that modafinil can induce a conditioned place preference and can elicit locomotor sensitization in cocaine-trained animals. These results indicate that modafinil can induce and modulate both contextual and addiction-related memory processes. To further explore the action of modafinil and other psychostimulants, we conducted a literature review to identify regions of the brain involved in the induction and expression of addiction-related memories. We found a diverse range of brain areas implicated in drug addiction but also a lack of consistency perhaps due to limitations of classical techniques. In order to localize the neural correlate of addiction-related memories, we used a histone -GFP mouse that expresses a long-term tag of neuronal activity within a specified tagging window. We tagged neurons active during initial drug exposure and compared them to a marker of neurons active during place preference testing, using the immediate early gene zif. When cocaine was paired with the conditioning context rather than the home cage neurons in the dorsal striatum were more likely to be activated during both time points. This indicates that the dorsal striatum is one site of neural plasticity that underlies conditioned place preference to cocaine. Finally, to localize the neural correlate of locomotor sensitization we tagged initial exposure to cocaine and compared these neurons to immediate early gene expression after a subsequent exposure to cocaine. The medial prefrontal cortex and nucleus accumbens shell appear to store a memory of the drug experience, but are unlikely to be involved in the contextual control of sensitization