The goal of the proposed research is to illuminate the correlation between measures of neural activation and measures of behavior during Pavlovian fear conditioning, after administration of a low dose of the widely-prescribed stimulant, amphetamine. Previous research has found that amphetamine, given at low doses, enhances the memory of Pavlovian fear learning. As attention deficit hyperactivity disorder (ADHD) diagnoses are increasing in number, it is critical for researchers to investigate the mechanisms underlying not only the cause of the disease, but also the treatments currently being prescribed to large numbers of children afflicted with it. To address this issue, the proposed studies involve the use of an innovative new transgenic mouse line that allows for the tagging of active neurons at two different time points using a doxycycline (Dox)-regulated system. While mice are given standard mouse chow, without Dox in it, the GluR1 subunits of AMPA receptors activated during this time period are tagged with GFP. During this time, the mice will be administered a low dose of amphetamine and undergo Pavlovian fear conditioned. Subjects will then be returned to a diet including Dox to prevent further labeling of neurons, thereby creating a unique picture of activity, represented by GFP tagging, during the specific time window including fear conditioning. The mice will either undergo extinction or remain in their home cages, and then will be tested for fear memory, followed by immediate sacrifice. The GFP-labeled neurons will then be compared with neurons active at a later time point, immediately before the brain tissue is analyzed, using a stain for an immediate early gene such as Zif268/Egr1. These findings will have direct relevance to ADHD research, as the low dose of amphetamine used in these studies is similar to that prescribed for ADHD. Public health statement: With the diagnosis of ADHD becoming more frequent, the prescription of stimulants to our nation's children has become virtually commonplace. However, little is known about how stimulants work in the brain to help children with ADHD remain focused throughout the school day. This set of studies will help reveal why a small dose of amphetamine is able to help with learning and recall, using a unique set of mice designed to help answer such questions.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F02A-X (20))
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Avila, Albert
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University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
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Wood, Suzanne; Sage, Jennifer R; Shuman, Tristan et al. (2014) Psychostimulants and cognition: a continuum of behavioral and cognitive activation. Pharmacol Rev 66:193-221
Wood, Suzanne C; Anagnostaras, Stephan G (2011) Interdependence of measures in pavlovian conditioned freezing. Neurosci Lett 505:134-9
Carmack, Stephanie A; Wood, Suzanne C; Anagnostaras, Stephan G (2010) Amphetamine and extinction of cued fear. Neurosci Lett 468:18-22