MEMORY PROCESSES GOVERNING PSYCHOSTIMULANT SENSITIZATION

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DESCRIPTION (provided by applicant): Behavioral sensitization results from repeated intermittent use of stimulant drugs, and may contribute to addiction. Prior studies investigating the influence of associative pairing of contextual stimuli with psychostimulant administration on the expression of psychomotor sensitization in rodents have shown that under certain circumstances, sensitization can be context-specific. Based on these and other findings, we proposed that three memory mechanisms regulate the context-specificity of stimulant sensitization: (1) Repeated drug administration induces sensitization of the neural substrate that mediates the unconditional response (UR) to the drug, a form of non-associative learning. (2) An inhibitory process can block the expression of neural sensitization in contexts where the drug is not expected, a process involving inhibitory occasion-setting. (3) An excitatory conditioned response (CR) can amplify the sensitized response in a context where the drug is expected, and produces a CR, which may contribute to craving, in the absence of the drug. The ability of drug-associated contexts to modulate the expression of neural sensitization via occasion-setting may combine with the ability of a drug-associated context to produce conditioned responses, together providing powerful associative control over not only behavioral sensitization, but in addicts, over craving and relapse. In the current proposal, we will investigate if distinct neural memory systems selectively mediate memory processes involved in behavioral sensitization. First, we will use mice to optimize the behavioral paradigm for studying memory processes underlying stimulant sensitization, developing a procedure which produces robust sensitization, rapid acquisition (so that distinct memory phases may be examined), and measuring sensitization, context-specificity, and conditioned responses. Following establishment of this paradigm, we will attempt to identify critical neural substrates of these processes by examining the impact of lesions of memory-related brain structures, including the hippocampus and amygdala. Finally, using this novel mouse paradigm, we will investigate the molecular neurobiology of these processes, examining mice with targeted genetic mutations known to disrupt memory. This approach, using systems and molecular methods, should elucidate whether structures and genes known to be important for learning and memory are similarly crucial for the expression of stimulant sensitization.