STUDIES ON THE EFFECTS OF METHYLPHENIDATE ON BRAIN REACTIVITY TO COCAINE CUES IN COCAINE ABUSERS Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on the brain activation induced by cocaine-cues in cocaine abusers. Methods: Brain metabolism was measured with PET and 18FDG in 24 active cocaine abusers tested four times;twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video with each video preceded once by placebo and once by methylphenidate (20 mg). Results: The Cocaine-cues video increased craving with placebo (68%) and methylphenidate (64%). SPM analysis revealed that differences between Neutral vs Cocaine-cues conditions were significantly greater with placebo than methylphenidate;with placebo there were significant decreases with Cocaine-cues (p <0.005) in left limbic regions , whereas with methylphenidate there were not. Decreases in metabolism in these regions were not associated with craving;in contrast, craving was correlated with metabolism in orbitofrontal cortex (p <0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidates attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Conclusion: Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2-5 minutes), which may reflect long lasting limbic inhibition following a short lasting activation. The clinical significance of methylphenidates blunting of cue-induced limbic inhibition merits investigation. STUDIES ON THE DISTRIBUTION AND PHARMACOKINETICS OF METHAMPHETAMINE IN THE HUMAN BODY Methamphetamine is one of the most toxic of the drugs of abuse, which may reflect its distribution and accumulation in the human body. However no studies have measured methamphetamines organ distribution and pharmacokinetics in the human body. Methods: PET was used in conjunction with 11Cd-methamphetamine to measure its whole-body distribution and bioavailability as assessed by peak uptake, rate of clearance and accumulation in healthy participants (9 Caucasians and 10 African Americans). Results: Methamphetamine distributed through most organs. Highest uptake (whole organ) occurred in lungs, liver and intermediate in brain. Kidneys also showed high uptake. Methamphetamines clearance was fastest in heart and lungs and slowest in brain, liver and stomach . Lung accumulation of 11Cd-methamphetamines was 30% higher for African Americans than Caucasians (p<0.05) but did not differ in other organs. Conclusions: The high accumulation of methamphetamine in most body organs is likely to contribute to its medical toxicity. In particular methamphetamines high pulmonary uptake could render this organ vulnerable to infections (tuberculosis) and pathology (pulmonary hypertension). The higher lung accumulation of methamphetamine in African Americans than Caucasians merits further investigation . STUDIES ON THE INVOLVEMENT OF THE DOPAMINE MESOACCUMBENS PATHWAY ON THE MOTIVATION DEFICIT IN ADHD ADHD is typically characterized as a disorder of inattention and hyperactivity/impulsivity but there is increasing evidence of deficits in motivation. Using PET we showed decreased function in the brain dopamine reward pathway in adults with ADHD, which we hypothesized could underlie the motivation deficits in this disorder. Methods: To evaluate this hypothesis we performed secondary analyses to assess the correlation between the PET measures of dopamine D2/D3 receptor and dopamine transporter availability in the dopamine reward pathway and a surrogate measure of trait motivation in 45 ADHD participants and 41 controls. Results: The Achievement scale was lower in ADHD participants than in controls and was significantly correlated with D2/D3 receptors and transporters in ADHD participants, but not in controls. ADHD participants also had lower values in the Constraint factor and higher values in the Negative Emotionality factor of the MPQ but did not differ in the Positive Emotionality factor - and none of these were correlated with the dopamine measures. In ADHD participants scores in the Achievement scale were also negatively correlated with symptoms of inattention. Conclusion: These findings provide evidence that disruption of the dopamine reward pathway is associated with motivation deficits in ADHD adults, which may contribute to attention deficits and supports the use of therapeutic interventions to enhance motivation in ADHD. STUDIES ON RESTING FUNCTIONAL CONNECTIVITY OF THE NORMAL HUMAN BRAIN To support fast communication with minimal energy cost, cortical brain networks may have few nodes with dense local clustering (hubs) and numerous nodes with low number of connections. The energy-efficient regions (densely connected nodes) are thought to serve as the interconnection hubs, and neuropsychiatric diseases have been linked to these. However, the investigation of hubs in the brain has been hindered by cumbersome computational requirements . To address this we developed an alternative data-driven method that we term functional connectivity density mapping, or FCDM, using resting-state functional connectivity datasets. This ultra-fast technique allows calculation of individual functional connectivity maps with higher spatial resolution Methods: We tested this method in 979 subjects from a large repository of MRI time series collected in resting conditions (1000 Functional Connectomes Project). Results: Consistently across research sites, a region located in the posterior cingulate/ventral precuneus (BA 23/31) was the area with the highest lFCD, which suggests that this is the most prominent functional hub in the brain. In addition regions located in the paracentral lobule, cuneus, and posterior cingulate cortices had high lFCD. Conclusion: These findings showed that the probability distribution of lFCD had a power scaling with k (number of functional connections in a cluster), and that this scaling was robust across different threshold conditions, subjects and research sites. BIODISTRIBUTION AND PHARMACOKINETICS OF EPIGENETIC DRUGS We have started to develop PET radiotracers for histone deacetylases (HDAC) inhibitors focusing on compounds that have been used in humans: butyric acid (BA), 4-phenylbutyric acid and valproic acid (VA). Method: C-11 version of these three carboxylic acids were synthesized with 11Ccarbon dioxide and their corresponding Grignard reagents and their whole body biodistribution was compared in three female baboons using PET. Complimentarily, rodent PET studies were performed to determine metabolic stability and chemical identity in brain. Result and discussion: all three carboxylic acids have low brain uptake ( - 0.006%ID/cc). The chemical identity of accumulated C-11 in brain at 20 min post iv injection of 11CBA in rodent was radiolabled metabolite. All three carboxylic acids drugs and labeled metabolites were excreted through the kidneys. Valproic acid showed exceptionally high heart uptake . We note that heart block and fetal heart deformity in humans have been reported at high doses of VA, which raises the question of whether epigenetic processes contribute to this teratogenic effects.
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