Despite a wealth of preclinical information on stimulant-induced adaptations (plasticity or toxicity) in the CNS, the translation of that knowledge to clinical neuroscience has been hampered by the inability to accurately assess human brain function in vivo. The advent of magnetic resonance (MR) neuroimaging techniques, with increasingly high-resolution and sensitivity, has revolutionized research strategies in studies of human substance abusers. However the physiological significance of MR-derived measures in humans is not yet fully understood. In fact, preclinical MR studies of CNS function lag far behind the number of MR studies with humans, despite the fact that preclinical studies are amenable to controlled pharmacological manipulation and independent verification. With an emphasis on stimulant abuse, the present proposal addresses the physiological significance of several neurochemicals that can be measured with proton MR spectroscopy (1H-MRS). By applying state-of-the-art MR techniques (at 11.7 T) to proven paradigms of drug study, the results should provide 1) novel insight into the neurobiology and neurotoxicology of acute and repeated exposure to stimulants, and 2) interpretations and hypotheses that can be directly translated into clinical utility. In an effort to validate the physiological significance of MR-visible compounds, a major objective of the research plan is to use high-resolution magic angle spinning (HR-MAS) 1H-MRS to determine ex vivo the basic neuropharmacology of the MR-visible neurochemical profile in rat brain. Thus, in discrete monoamine-related areas of the rat brain, we plan to determine the effect of in vivo pretreatment with 1) specific neurotoxins, 2) three psychostimulants with distinct mechanisms of action (MDMA, cocaine, and methamphetamine), and 3) D1 and 5HT2 receptor ligands on the MR-visible neurochemical profile. In each case, direct comparisons will be made between the 1H-MRS observations and those determined with HPLC-EC. Neurochemicals that are readily measured by HR-MAS 1H-MRS reflect several key cellular functions including neuronal viability (Nacetylaspartate), neurotransmission (glutamate, glutamine, GABA), energy status (lactate, creatine), 2 nd-messenger pathways (myo-inositol), and membrane phospholipid metabolism (phosphocholine and glycerophosphocholine). After establishing the pharmacological and physiological parameters that modulate the MR-visible neurochemical profile, a series of experiments will use in vivo 1H-MRS and MRI (at 11.7 T) to determine the longitudinal effects of stimulant exposure. A critical component of validating the in vivo observations will be a direct comparison to the results obtained with HR-MAS 1H-MRS. MRI T2 images, water diffusion maps, and in vivo neurochemistry obtained in a longitudinal design in vivo, are expected to define regionally selective lesions following drug exposure. MDMA abuse has increased unabated in adolescents, despite convincing evidence that street doses are toxic to both 5HT and DA neurons in rodents and monkeys, up to 7 yrs after drug cessation. The potential loss of 5HT innervation subsequent to MDMA exposure may have profound effects on the emergence of mood disorders in the relatively young cohort of MDMA users. Increased use, combined with preclinical toxicity, speaks to the necessity to resolve the question of MDMA toxicity in humans. MR neuroimaging, especially 1H-MRS, provides a non-invasive window into human brain function. Development of a neurochemical fingerprint describing the effects of 3 stimulants will provide a solid basis for hypothesis-driven investigations of stimulant-induced plasticity and/or toxicity in the CNS.
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