ACUTE ALCOHOL INTOXICATION DECREASES GLUCOSE METABOLISM BUT INCREASES ACETATE UPTAKE IN THE HUMAN BRAIN. Alcohol intoxication results in marked reductions in brain glucose metabolism, which we hypothesized reflects metabolism of acetate. METHODS: To test this hypothesis we used to PET to measure the effects of alcohol intoxication on brain glucose metabolism in 15 social drinkers (using FDG) and on acetate brain uptake (marker of metabolism) in 16 social drinkers and 15 alcohol abusers (using 11Cacetate). RESULTS: Alcohol intoxication significantly decreased brain glucose metabolism (largest decreases in cerebellum and occipital cortex and least in thalamus) whereas it increased 1-11Cacetate metabolism (largest increases in cerebellum least in thalamus). 1-11Cacetate brain metabolism was higher in alcohol abusers than in occasional drinkers (p <0.06) and increases in 1-11Cacetate metabolism in cerebellum with alcohol were associated with alcohol doses consumed (r=0.66, p<0.01). CONCLUSIONS: Our findings support the hypothesis that during intoxication the brain may relies on acetate as an energy source and provides preliminary evidence that heavy alcohol exposures may facilitate its use. DISRUPTED DOPAMINERGIC REGULATION OF STRIATAL ACTIVITY IN ALCOHOLICS. Alcohol triggers craving and compulsive intake in alcoholics presumably though neuroadaptations in DA regulated regions. METHODS: We used PET to compare the regional brain metabolic responses to methylphenidate (MP) using FDG to measure brain metabolic responses (marker of brain function) in alcoholics (n=20) and controls (n=19) and measured the correlations between MP-induced DA increases and MP-induced changes in metabolism (11Craclopride). RESULTS: Alcoholics had relative decreases in striatal metabolism (controls did not change) with MP and lower striatal reductions in DVR (presumably from blunted DA increases) than controls. In alcoholics MP-induced DVR changes in putamen and VS were positively correlated with MP-induced changes in metabolism in putamen and VS (larger DA increases associated with greater decreases). CONCLUSION: The regional differences in striatal metabolic responses to MP (accentuated decreases in metabolism in alcoholics in whom they were associated with DA increases corroborates impaired DA regulation of striatal activity. DRD4 GENOTYPE PREDICTS LONGEVITY IN MOUSE AND HUMAN. The brains DA system may be relevant in modulating longevity since it modulates traits (e.g., incentive motivation, sustained effort), which impact behavioral responses to the environment. The DA D4 receptor (DRD4) has been shown to moderate the impact of environments on behavior and here we test the hypothesis that it influences longevity through environmental effects. METHODS: Surviving participants of a 30 year-old population-based health survey (N=310, age range 90-109;the 90+ Study) were genotyped at the DRD4 gene, and compared to a European ancestry-matched younger population (N=2902, age range 7-45)( done in collaboration with the Dr Robert Moyzes). In parallel we compared longevity between D2R4 KO, heterozygous and wild type mice when reared in isolation versus when reared in an enriched environment. RESULTS: The oldest-old population had a 66% increase in individuals carrying the DRD4 7R allele relative to the younger sample (p=3.5 x 10-9), and this genotype was strongly correlated with increased levels of physical activity (p=6.7 x 10-7). Consistent with these results, DRD4 KO mice, when compared to wild-type and heterozygous mice, displayed a 7-9.7% decrease in lifespan and no lifespan increase when reared in an enriched environment. CONCLUSION: These results support the hypothesis that DRD4 gene variants contribute to longevity and suggest that this effect is mediated by shaping behavioral responses to the environment. DOPAMINE D4 RECEPTOR POLYMORPHISM MODULATES AGE ASSOCIATED REDUCTIONS IN BRAIN GLUCOSE METABOLISM. Brain glucose metabolism decreases with aging but the rate of decrease varies significantly between individuals. Here we test the hypothesis that variants of the dopamine receptor D4 (DRD4) gene that are associated with sensitivity to environmental stimuli (negative and positive) influence the effects of aging on the human brain. METHODS: We used PET and FDG to measure brain glucose metabolism under baseline conditions in 82 healthy individuals (age range 22-55 years of age). We determined their DRD4 genotype. RESULTS: We found an interaction between DRD4 genotype and age: individuals without the 7-repeat allele (7R-, n=53) had significant decreases with age (p <0.0001) in frontal (r= -0.52), temporal (r= -0.51) and striatal metabolism (r= -0.47, p<0.001);but in carriers of the 7R allele (7R+ n=29;mostly 4/7), the decreases with age were not significant. The regression slopes with age differed significantly between the 7R+ and 7R- groups in cerebellum, inferior temporal and striatum. CONCLUSION: These results provide evidence that the DRD4 genotype modulates the decline in brain metabolism associated with age. ABNORMAL FUNCTIONAL CONNECTIVITY IN CHILDREN WITH ATTENTION DEFICIT HYPERACTIVITY DISORDER. The neuropathology of ADHD may reflect dysfunction of both attention and reward-motivation networks. METHODS: To test this hypothesis we compared the functional connectivity density (FCD) between 255 ADHD and 304 typically developing control children from a public magnetic resonance imaging database. We quantified short- and long-range FCD in the brain. RESULTS: Children with ADHD had lower connectivity (short- and long-range) in regions of the dorsal attention (superior parietal cortex, SPC) and default-mode (precuneus) networks and in cerebellum and higher connectivity (short-range) in reward-motivation regions (ventral striatum and orbitofrontal cortex) than controls. In ADHD children the lateral orbitofrontal cortex (region involved in salience attribution) had higher connectivity with reward-motivation regions (striatum and anterior cingulate) and lower connectivity with SPC (region involved in attention processing). CONCLUSION: The enhanced connectivity within reward-motivation regions and their decreased connectivity with regions from the default-mode and the attention networks suggest impaired interactions between control and reward pathways in ADHD. RADIOTRACER DEVELOPMENT FOR EPIGENTIC BIOMARKERS: WHOLE-BODY PHARMACOKINETICS OF HDAC INHIBITOR DRUGS, BUTYRIC ACID, VALPROIC ACID AND 4-PHENYLBUTYRIC ACID MEASURED WITH PET. The fatty acids, n-butyric acid (BA), 4-phenylbutyric acid (PBA) and valproic acid (VPA, 2-propylpentanoic acid) are used to treat CNS and peripheral diseases. These drugs alter epigenetic processes through inhibition of histone deacetylases (HDACs) has renewed interest in their biodistribution and PK. METHODS: To determine their PK and biodistribution we synthesized their carbon-11 labeled analogues and performed dynamic PET studies in baboons over 90 min. RESULTS: 11CBA was metabolized rapidly (only 20% in plasma as parent compound at 5 min post injection) whereas VPA and PBA 98% and 85% of the radioactivity was unmetabolized compound at 30 minutes. The brain uptake of all three carboxylic acids was very low (<0.006%ID/cc, BA>VPA>PBA) and most radioactivity was excreted through kidneys and accumulated in bladder. Organ biodistribution between the drugs differed: 11CBA showed high uptake in spleen and pancreas, 11CPBA showed high uptake in liver and heart and 11CVPA showed exceptionally high heart uptake. CONCLUSION: The unique biodistribution of each of these drugs may be of relevance to their therapeutic and side effects including teratogenicity.
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