INVESTIGATE THE MECHANISMS UNDERLYING THE REINFORCING AND THERAPEUTIC EFFECTS OF STIMULANT DRUGS Studies on DA and Saliency -- Methylphenidate (MP) is the most commonly prescribed drug for ADHD yet its therapeutic mechanisms are poorly understood. The objective of this study was to assess if MP, by increasing dopamine (DA) (neurotransmitter involved in motivation), would enhance the saliency of an academic task thus making it more interesting. Studies were done in 16 controls using PET and [11]C-raclopride (i.e., D2 receptor radioligand that competes with DA for binding) to assess the effects of oral MP (20 mg) on DA in striatum. We compared the effects of MP during an academic task (working mathematical problems with monetary reinforcement) and a neutral task (passively viewing cards with no remuneration). MP, when coupled with the mathematical task, significantly increased DA but this did not occur when coupled with the neutral task. The mathematical task did not increase DA when coupled with placebo. Subjective reports about interest and motivation in the mathematical task were greater with MP than with placebo and were associated with DA increases. The significant association between MP-induced DA increases and the interest and motivation for the task confirms the prediction that MP enhances the saliency of an event by increasing DA. This could be one of the mechanisms underlying MP?s therapeutic effects. Investigating the Role that Expectation has on the Effects of Drug -- We have shown that in cocaine addicted subjects expectation markedly enhances the effects of MP, a drug with effects similar to cocaine, on regional brain metabolism (used as marker of brain function) (Volkow et al, J Neuroscience 23:11461-8, 2003). We hypothesized that the expectation effects reflected conditioned responses from previous learned drug experiences and would therefore not be observed in non-drug abusing subjects. Here we assessed the effects of expectation on the regional brain metabolic responses to MP in non-drug abusing subjects. Eleven healthy controls with minimal prior drug experiences were tested with positron emission tomography (PET) and fluorodeoxyglucose (FDG) under four conditions: (1) subjects told they will receive placebo and received placebo, this scan was used as baseline; (2) told they will receive placebo but received MP; (3) told they will receive MP and received MP; (4) told they will receive MP but received placebo. The order was randomized and MP (0.5 mg IV) was given 5 min prior to FDG. SPM was used to assess significant differences on the normalized images (p<0.005) with respect to the baseline condition. The regional brain metabolic responses to expected and unexpected MP were very similar and included significant increases in cerebellum (vermis) and in right frontal cortex (BRD 10). In contrast, expectation of receiving MP and receiving placebo induced significant increases in orbitofrontal cortex (BRD 25, BRD 47). The expectation of receiving MP in controls had a minimal influence on MP?s effects in brain. These results differed markedly to those in cocaine-addicted subjects in whom expectation enhanced MP?s effects in brain thus corroborating the relevance of learned experiences on the brain responses to drugs of abuse. The activation of the orbitofrontal cortex by expectation alone suggests an involvement of this region in processing unexpected stimuli (not just that of processing unexpected reward). INVESTIGATE THE EFFECTS OF ALCOHOL ON THE HUMAN BRAIN -- The depressant action of moderate and high doses of alcohol in the brain is well known. In this study we measured brain glucose metabolism response to different doses of alcohol. We analyzed the results obtained over the past 3 years that measured the effects of different doses of alcohol (0.25, 0.5 and 0.75 mg/kg) in brain glucose metabolism. Studies were done in normal healthy voolunteers using positron emission tomography (PET) and [F-18]FDG at baseline, after placebo, and following alcohol. Eight Regional analyses were performed using a template of 423 ROIs compressed into 10 composite regions and measurement of global brain metabolism was obtained by averaging the values from all of the ROIs. Also, relative regional measures were computed by normalizing activity to the global metabolic rate. We found acute alcohol administration induced marked decreases in glucose metabolism throughout the human brain for all alcohol doses. Even the low dose of alcohol (0.25 mg/kg) induced significant decreases in whole brain metabolism (20% reduction, p=0.005). In contrast this low dose of alcohol had minimal behavioral effects. There was no correlation between the decrements in metabolism and the behavioral measures of intoxication. These results indicate that acute intoxication of alcohol significantly decreases the whole and regional brain glucose metabolic rate. The decreases are significantly greater than those observed with lorazepam (12% reductions) at a dose that induced significant sedation (30 microgram). This raises the possibility that during intoxication the decreases in metabolism may not just reflect decreases in brain activity but changes in energy utilization by the brain. INVESTIGATE THE NEUROBIOLOGICAL MECHANISM UNDERLYING ADDICTIVE BEHAVIORS -- Comparison of the regional brain responses to drugs of abuse between addicted vs non-addicted subjects provides a strategy to identify brain regions that may underlie addictive behaviors. Here we compared the pattern of brain responses to intravenous MP, a drug that cocaine abusers report to have effects similar to cocaine, between addicted and non-addicted subjects. Brain metabolism was measured in 21 cocaine-addicted male subjects and 15 male controls using PET and FDG. Subjects underwent two PET-FDG scans; one after two sequential placebos (given 90 min apart) and the other after two sequential MP doses (0.5 and 0.25 mg/kg IV given 90 min apart). Statistical parametric analysis was done on the normalized images to assess differences between controls and cocaine abusers in response to MP (significance was p<0.005). Individual ROIs were obtained to assess the correlation between regions showing metabolic differences and self-reports of drug effects. We found that MP induced significant increases in self-reports of ?high? and these effects were significantly larger in controls than in abusers, whereas in abusers but not in controls, MP induced significant drug craving (p<0.001). Overall, regional brain changes induced by MP were similar between abusers and controls and included significant increases in cerebellum and occipital cortex and decreases in striatum and temporal insula. However, MP increased metabolism in orbitofrontal cortex in abusers but significantly decreased it in controls. Metabolic increases in orbitofrontal cortex in the abusers were associated with self-reports of cocaine craving. Differential activation of the orbitofrontal cortex (region involved with salience attribution, motivation and drive) by MP in abusers but not in controls provides evidence of a differential sensitivity of this region in addicted subjects. Moreover, the significant association between metabolic activation and drug craving suggests that its activation during drug intoxication may underlie the strong drive and the compulsion to repeatedly administer the drug that characterizes addiction.
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