This R21 application is in response to NIDA RFA #DA-04-011 """"""""Animal Models of Adolescent Drug Abuse: Integrative Studies of Brain and Behavioral Development."""""""" Inhalant abuse is a significant public health problem throughout the U.S. and the world. Adolescents are by far the largest population of solvent abusers, particularly of toluene-based products. Consequently, there is special concern about the negative impact that adolescent inhalant abuse can have on life-long behavioral and cognitive maturation. Yet, there is a relative paucity of systematic studies of the developmental consequences of adolescent binge exposure to inhaled organic solvents. The clinical picture of adolescent inhalant abuse may be confounded by use of multiple solvents, exposure to other drugs, and maturational and environmental variables. An initial goal of the proposed research is to develop a rodent model of adolescent inhalant abuse, using our established model of clinically relevant abuse patterns of inhalant exposure, to assess behavioral and neurochemical effects. A key strength of this proposal is the use of our preclinical model of inhalant administration that mimics the repeated, brief, episodic, high-dose exposure pattern in humans who abuse toluene and other solvents. We will characterize, in rats, behavioral, neurobiological, and psychopharmacological consequences of adolescent binge exposure to inhaled organic solvents during defined """"""""critical periods"""""""" of postnatal development that mirror maturational stages of human development: juveniles, adolescents, young adults and adults. We will examine the developmental profiles of behavioral and neurochemical sensitivity to toluene. The proposed study will include behavioral assessments (e.g., motor function and learning) and state-of-the-art brain imaging techniques. These include T-2 weighted magnetic resonance imaging (MRI) scans to measure regional changes in brain size, and high-resolution """"""""magic-angle"""""""" -spin proton magnetic resonance spectroscopy (HR-MAS 1H-MRS) at 11.7 Tesla (T), i.e., a very powerful magnetic field, to examine the age-dependent effects of toluene exposure on neurochemistry. Finally, this research will generate a clinically relevant model with which neuroanatomical and biochemical outcomes, along with the mechanisms of adolescent inhalant abuse may be studied. The model also has the potential to assist in devising effective treatments and prevention strategies for adolescent inhalant abuse.
