Faculty Bibliography

Cocaine and alcohol are frequently used simultaneously and this combination is associated with enhanced toxicity. We recently showed that active cocaine abusers have a markedly enhanced sensitivity to benzodiazepines. Because both benzodiazepines and alcohol facilitate GABAergic neurotransmission we questioned whether cocaine abusers would also have an enhanced sensitivity to alcohol that could contribute to the toxicity. In this study we compared the effects of alcohol (0.75 g/kg) on regional brain glucose metabolism between cocaine abusers (n = 9) and controls (n = 10) using PET and FDG. Alcohol significantly decreased whole brain metabolism and this effect was greater in controls (26+/-6%) than in abusers (17+/-10%) even though they had equivalent levels of alcohol in plasma. Analysis of the regional measures showed that cocaine abusers had a blunted response to alcohol in limbic regions, cingulate gyrus, medial frontal and orbitofrontal cortices. CONCLUSIONS: The blunted response to alcohol in cocaine abusers contrasts with their enhanced sensitivity to benzodiazepines suggesting that targets other than GABA-benzodiazepine receptors are involved in the blunted sensitivity to alcohol and that the toxicity from combined cocaine-alcohol use is not due to an enhanced sensitivity to alcohol in cocaine abusers. The blunted response to alcohol in limbic regions and in cortical regions connected to limbic areas could result from a decreased sensitivity of reward circuits in cocaine abusers

Extracts of Ginkgo biloba have been reported to reversibly inhibit both monoamine oxidase (MAO) A and B in rat brain in vitro leading to speculation that MAO inhibition may contribute to some of its central nervous system effects. Here we have used positron emission tomography (PET) to measure the effects of Ginkgo biloba on human brain MAO A and B in 10 subjects treated for 1 month with 120 mg/day of the Ginkgo biloba extract EGb 761, using [11C]clorgyline and [11C]L-deprenyl-D2 to measure MAO A and B respectively. A three-compartment model was used to calculate the plasma to brain transfer constant K1 which is related to blood flow, and lambdak3, a model term which is a function of the concentration of catalytically active MAO molecules. Ginkgo biloba administration did not produce significant changes in brain MAO A or MAO B suggesting that mechanisms other than MAO inhibition need to be considered as mediating some of its CNS effects

OBJECTIVE: Despite the well-documented loss of brain dopamine activity with age, little is known about its functional consequences in healthy individuals. This study investigates the relationship between measures of brain dopamine D(2) receptors (molecules that transmit dopamine signals) and regional brain glucose metabolism (a marker of brain function) in healthy individuals. METHOD: Thirty-seven healthy volunteers aged 24-86 years underwent positron emission tomography scans after injection of [(11)C]raclopride to assess dopamine D(2) receptors and [(18)]fluorodeoxyglucose to assess regional brain glucose metabolism. Two methods used to assess the correlations between metabolism and dopamine D(2) receptors-pixel-by-pixel correlations and correlations in preselected regions of interest-were then compared. RESULTS: D(2) receptors as well as frontal and cingulate metabolism declined with age. Regardless of the method used, significant correlations between metabolism and D(2) receptors were found in the frontal cortex (Brodmann's areas 6, 7, 8, 9, 10, 11, 44, 45, 47), anterior cingulate gyrus (areas 24, 32), temporal cortex (area 21), and caudate. These correlations remained significant after removing age effects (partial correlation). CONCLUSIONS: These results provide the first link between age-related declines in brain dopamine activity and frontal and cingulate metabolism, which supports the need to investigate the therapeutic utility of interventions that enhance dopamine function in the elderly. The fact that correlations remained significant after removing age effects suggests that dopamine may influence frontal, cingulate, and temporal metabolism regardless of age

One of the most exciting methodological advances for brain research field arises in functional brain imaging, which enables us to localize and characterize neural activity and biochemical events in the living human brain. Recently developed event-related functional MRI makes it possible to visualize the brain activity associated with cognitive processes with the temporal resolution of the hemodynamic response. In addition, the high sensitivity and selectivity of positron-emission tomography allow us to probe the neurochemical processes at the molecular level. Positron-emission tomography also has been applied to investigate the effects of therapeutic drugs as well as the effects of drugs of abuse

OBJECTIVES: Recent studies using positron emission tomography (PET) have established the relationship between an intravenous dose of cocaine and the percentage occupancy of the dopamine transporter in humans, and have documented the requirement of more than 50% occupancy for perception of the 'high'. The present experiments were conducted to examine dose-occupancy and dose-effect relationships in mice for cocaine and also for methylphenidate, a dopamine uptake blocker used in pediatric psychiatry. METHODS: Percentage occupancies of the dopamine transporter by cocaine and methylphenidate were estimated after intravenous injection in mice from the displacement of in vivo binding of [(3)H]cocaine from the striatum. Locomotor activity was measured in a photocell apparatus. RESULTS: The relationship between drug doses (milligrams of hydrochloride salt per kilogram body weight) and percentage occupancy of the dopamine transporter was indistinguishable for cocaine and methylphenidate, and corresponded to about 50% occupancy at 0.25 mg/kg and about 80% at 1 mg/kg. This was similar to the relationship between drug dose and transporter occupancy, previously measured in human and baboons using [(11)C]cocaine or [(11)C]d-threo-methylphenidate and PET. Methylphenidate increased locomotor activity in the mice substantially more than cocaine at the same dose and the same degree of dopamine-transporter receptor occupancy. CONCLUSIONS: The range of dopamine-transporter occupancy required for behavioral activation in the mice was thus similar to that previously reported for experience of a cocaine- or methylphenidate-induced 'high' in human subjects. Our results are consistent with other studies in which both cocaine and methylphenidate were evaluated in animal behavioral assays and were found to have very similar psychopharmacological properties

OBJECTIVE: This study assessed whether brain dopamine D2 receptor levels, which show significant intersubject variability, predict reinforcing responses to psychostimulants in humans. METHOD: [11C]Raclopride and positron emission tomography were used to measure D2 receptor levels in 23 healthy men (mean age = 34 years, SD = 7) who had no drug abuse histories in order to assess if there were differences between the subjects who liked and those who disliked the effects of intravenous methylphenidate (0.5 mg/kg). RESULTS: Subjects who liked the effects of methylphenidate had significantly lower D2 receptor levels (mean = 2.72 Bmax/Kd, SD = 0.3) than subjects who disliked its effects (mean = 3.16, SD = 0.3). Moreover, the higher the D2 levels found, the more intense were methylphenidate's unpleasant effects. CONCLUSIONS: These results provide preliminary evidence that D2 receptor levels predict response to psychostimulants in humans and that low D2 receptors may contribute to psychostimulant abuse by favoring pleasant response

Although PET is technologically complex because the restricted time scale requires that radioisotope production, radiotracer synthesis, and PET imaging be carried out in the same place, the payoff is that compounds labeled with these isotopes can be used to track the distribution and movement of drugs in the brain and also measure drug effects on specific molecular targets in the human brain. Provided that appropriate radiotracers are available, one can determine the amount of a drug that gets into the brain, the minimum effective dose, the duration of action, or the binding site occupancy required to elicit a particular therapeutic or behavioral effect with a relatively small number of PET studies. Because studies are carried out directly in humans, the relationship of these parameters to behavior and to therapeutic efficacy can be evaluated. The possibilities are enormous and are largely driven by advances in PET technology (including radiotracer chemistry and instrumentation) that synergize with advances in neuropharmacology

The use of PET to examine the behavioral, therapeutic and toxic properties of drugs and substances of abuse is emerging as a powerful new scientific tool. PET provides a new perspective on drug research by virtue of its ability to directly assess both pharmacokinetic and pharmacodynamic events in humans and in animals. These parameters can be assessed directly in the human body both in healthy volunteers and in patients. Moreover, the new generation of high-resolution, small-animal cameras hold the promise of introducing imaging in the early stages of drug development and make it possible to carry out longitudinal studies in animals and to study genetically altered animals. This places PET in a unique position to contribute significantly to the process of drug development through understanding the molecular mechanisms underlying drug action while addressing some very practical questions such as determining effective drug doses for clinical trials for new drugs, determining the duration of drug action and examining potential drug interactions