Faculty Bibliography

We had shown that striatal DA D2 receptors levels predicted the reinforcing responses to the psychostimulant drug methylphenidate in nondrug-abusing subjects. Here, we assessed the replicability of this finding. We measured D2 receptors with PET and [(11)C]raclopride (twice to determine stability) in seven nondrug-abusing subjects to assess if they predicted the self-reports of 'drug-liking' to intravenous methylphenidate (0.5 mg/kg). DA D2 measures were significantly correlated with 'drug-liking' in both evaluations (r = 0.82 and r = 0.78); subjects with the lowest levels reported the higher ratings of 'drug-liking' and vice versa. These results replicate our previous findings and provide further evidence that striatal DA D2 receptors modulate reinforcing responses to stimulants in humans and may underlie predisposition for drug self-administration

Monoamine oxidase (MAO) regulates neurotransmitter concentration in the brain and is also an important detoxifying enzyme in peripheral organs. It occurs in 2 subtypes, MAO A and MAO B. Their relative ratios in different organs are variable, depending on the particular organ and species, making it difficult to extrapolate measures from animals to humans. The purpose of this study was to investigate the feasibility of imaging MAO B in peripheral organs in humans with PET. METHODS: Nine healthy subjects (7 males, 2 females; mean age +/- SD, 37 +/- 7 y) received 2 dynamic PET studies of the torso area 2 h apart with 11C-L-deprenyl and deuterium-substituted 11C-L-deprenyl (11C-L-deprenyl-D2). Time-activity curves for heart, lungs, liver, kidneys, and spleen and arterial plasma input were measured for each study. The uptake at plateau and the incorporation quotient (IQ = uptake/plasma input) as well as model terms K1 (which is a function of blood flow) and k3 and lambdak3 (which are kinetic terms proportional to MAO B) were compared to identify organs that showed reduced values with deuterium substitution (deuterium isotope effect) characteristic of MAO B. In addition, a sensitivity analysis compared the 2 tracers with respect to their ability to quantify MAO B. RESULTS: Heart, lungs, kidneys, and spleen showed a robust deuterium isotope effect on uptake, IQ, k3, and lambdak3. The arterial plasma input function was significantly larger for 11C-L-deprenyl-D2 than for 11C-L-deprenyl. Liver time-activity curves were not affected by deuterium substitution and model terms could not be estimated. In organs showing an isotope effect, lambdak3 showed the rank order: kidneys >or= heart > lungs = spleen. A sensitivity analysis showed that 11C-L-deprenyl-D2 is a better index of MAO activity than 11C-L-deprenyl. CONCLUSION: This study demonstrates that (a) the deuterium isotope effect is useful in assessing the binding specificity of labeled deprenyl to peripheral MAO B; (b) MAO B can be visualized and quantified in the heart, lungs, kidneys, and spleen but not in the liver; (c) with the exception of the liver, which cannot be measured, MAO B activity is highest in the kidneys and heart; and (d) quantitation in organs having high levels of MAO B is improved by the use of 11C-L-deprenyl-D2, similar to prior studies on the brain. This study indicates that 11C-L-deprenyl-D2 will be useful for measuring the effects of different variables, including tobacco smoke exposure on MAO B activity in peripheral organs in humans

Monoamine oxidase (MAO) is an integral protein of outer mitochondrial membranes and occurs in neuronal and nonneuronal cells in the brain and in peripheral organs. It oxidizes amines from both endogenous and exogenous sources, thereby influencing the concentration of neurotransmitter amines as well as many xenobiotics. It occurs in two subtypes, MAO A and MAO B, which are different gene products and have different substrate and inhibitor specificities. Both MAO A and B can be imaged and quantified in the living human brain using positron emission tomography (PET) and radiotracers labeled with carbon-11. PET studies have been carried out to measure the effects of age, MAO inhibitor drugs, tobacco smoke exposure, and other factors on MAO activity in the human brain

The drive for food is one of the most powerful of human and animal behaviors. Dopamine, a neurotransmitter involved with motivation and reward, its believed to regulate food intake in laboratory animals by modulating its rewarding effects through the nucleus accumbens (NA). Here we assess the involvement of dopamine in 'nonhedonic' food motivation in humans. Changes in extracellular dopamine in striatum in response to nonhedonic food stimulation (display of food without consumption) were evaluated in 10 food-deprived subjects (16-20 h) using positron emission tomography (PET) and [11C]raclopride (a D2 receptor radioligand that competes with endogenous dopamine for binding to the receptor). To amplify the dopamine changes we pretreated subjects with methylphenidate (20 mg p.o.), a drug that blocks dopamine transporters (mechanism for removal of extracellular dopamine). Although the food stimulation when preceded by placebo did not increase dopamine or the desire for food, the food stimulation when preceded by methylphenidate (20 mg p.o.) did. The increases in extracellular dopamine were significant in dorsal (P < 0.005) but not in ventral striatum (area that included NA) and were significantly correlated with the increases in self-reports of hunger and desire for food (P < 0.01). These results provide the first evidence that dopamine in the dorsal striatum is involved in food motivation in humans that is distinct from its role in regulating reward through the NA. In addition it demonstrates the ability of methylphenidate to amplify weak dopamine signals

Methylphenidate (Ritalin) is an effective drug in the treatment of attention deficit hyperactivity disorder. However, the doses required therapeutically vary significantly between subjects and it is not understood what determines these differences. Since methylphenidate's therapeutic effects are in part due to increases in extracellular DA secondary to blockade of dopamine transporters (DAT), the variability could reflect differences in levels of DAT blockade. Here we used PET to assess if for a given dose of methylphenidate the differences in DAT blockade account for the variability in methylphenidate-induced increases in extracellular DA. Ten healthy adult subjects were tested before and 60 min after oral methylphenidate (60 mg) with PET to estimate DAT occupancy (with [(11)C]cocaine as the radioligand) and levels of extracellular DA (with [(11)C]raclopride as the D2 receptor radioligand that competes with endogenous DA for binding to the receptor). Methylphenidate significantly blocked DAT (60 +/- 11%) and increased extracellular DA in brain (16 +/- 8% reduction in [(11)C]raclopride binding in striatum). However, the correlation between methylphenidate-induced DAT blockade and DA increases was not significant. These results indicate that for a given dose of methylphenidate, individual differences in DAT blockade are not the main source for the intersubject variability in MP-induced increases in DA. This finding suggests that individual differences in response to MP are due in part to individual differences in DA release, so that for an equivalent level of DAT blockade, MP would induce smaller DA changes in subjects with low than with high DA cell activity

Methylphenidate (MPH) is the most commonly prescribed drug for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). We have used Positron Emission Tomography (PET) to investigate the mechanism of action of MPH in the human brain. We have shown (a) that oral MPH reaches peak concentration in the brain 60-90 minutes after its administration, (b) that therapeutic doses of MPH block more than 50% of the dopamine transporters (DAT), and (c) that of the two enantiomers that compose MPH, it is d-threo-methylphenidate (d-MPH) and not l-threo-methylphenidate (l-MPH) that binds to the DAT. We have also shown that therapeutic doses of MPH significantly enhance extracellular dopamine (DA) in the basal ganglia, which is an effect that appears to be modulated by the rate of DA release and that is affected by age (older subjects show less effect). Thus, we postulate (a) that MPH's therapeutic effects are in part due to amplification of DA signals, (b) that variability in responses is in part due to differences in DA tone between subjects, and (c) that MPH's effects are context dependent. Because DA enhances task specific neuronal signaling and decreases noise, we also postulate that MPH-induced increases in DA could improve attention and decrease distractibility; and that since DA modulates motivation, the increases in DA would also enhance the saliency of the task facilitating the 'interest it elicits' and thus improving performance

Methamphetamine is a popular drug of abuse that is neurotoxic to dopamine (DA) terminals when administered to laboratory animals. Studies in methamphetamine abusers have also documented significant loss of DA transporters (used as markers of the DA terminal) that are associated with slower motor function and decreased memory. The extent to which the loss of DA transporters predisposes methamphetamine abusers to neurodegenerative disorders such as Parkinsonism is unclear and may depend in part on the degree of recovery. Here we assessed the effects of protracted abstinence on the loss of DA transporters in striatum, in methamphetamine abusers using positron emission tomography and [(11)C]d-threo-methylphenidate (DA transporter radioligand). Brain DA transporters in five methamphetamine abusers evaluated during short abstinence (<6 months) and then retested during protracted abstinence (12-17 months) showed significant increases with protracted abstinence (caudate, +19%; putamen, +16%). Although performance in some of the tests for which we observed an association with DA transporters showed some improvement, this effect was not significant. The DA transporter increases with abstinence could indicate that methamphetamine-induced DA transporter loss reflects temporary adaptive changes (i.e., downregulation), that the loss reflects DA terminal damage but that terminals can recover, or that remaining viable terminals increase synaptic arborization. Because neuropsychological tests did not improve to the same extent, this suggests that the increase of the DA transporters was not sufficient for complete function recovery. These findings have treatment implications because they suggest that protracted abstinence may reverse some of methamphetamine-induced alterations in brain DA terminals

OBJECTIVE: The role of dopamine in the addictive process (loss of control and compulsive drug intake) is poorly understood. A consistent finding in drug-addicted subjects is a lower level of dopamine D2 receptors. In cocaine abusers, low levels of D2 receptors are associated with a lower level of metabolism in the orbitofrontal cortex. Because the orbitofrontal cortex is associated with compulsive behaviors, its disruption may contribute to compulsive drug intake in addicted subjects. This study explored whether a similar association occurs in methamphetamine abusers. METHOD: Fifteen methamphetamine abusers and 20 non-drug-abusing comparison subjects were studied with positron emission tomography (PET) and [11C]raclopride to assess the availability of dopamine D2 receptors and with [18F]fluorodeoxyglucose to assess regional brain glucose metabolism, a marker of brain function. RESULTS: Methamphetamine abusers had a significantly lower level of D2 receptor availability than comparison subjects (a difference of 16% in the caudate and 10% in the putamen). D2 receptor availability was associated with metabolic rate in the orbitofrontal cortex in abusers and in comparison subjects. CONCLUSIONS: Lower levels of dopamine D2 receptor availability have been previously reported in cocaine abusers, alcoholics, and heroine abusers. This study extends this finding to methamphetamine abusers. The association between level of dopamine D2 receptors and metabolism in the orbitofrontal cortex in methamphetamine abusers, which replicates previous findings in cocaine abusers, suggests that D2 receptor-mediated dysregulation of the orbitofrontal cortex could underlie a common mechanism for loss of control and compulsive drug intake in drug-addicted subjects

Clorgyline is an irreversible inhibitor of monoamine oxidase (MAO A) which has been labeled with carbon-11 (C-11) and used to measure human brain MAO A with positron emission tomography (PET). In this study we compared [11C]clorgyline and deuterium-substituted [11C]clorgyline ([11C]clorgyline-D2) to better understand the molecular link between [11C]clorgyline binding and MAO A. In PET studies of five normal healthy volunteers scanned with [11C]clorgyline and [11C]clorgyline-D2 2 h apart, deuterium substitution generally produced the expected reductions in the brain uptake of [11C]clorgyline. However, the reduction was not uniform with the C-11 binding in white matter being significantly less sensitive to deuterium substitution than other brain regions. The percentages of the total binding attributable to MAO A is largest for the thalamus and smallest for the white matter and this is clearly seen in PET images with [11C]clorgyline-D2. Thus deuterium-substituted [11C]clorgyline selectively reduces the MAO A binding component of clorgyline in the human brain revealing non-MAO A binding which is most apparent in the white matter. The characterization of the non-MAO A binding component of this widely used MAO A inhibitor merits further investigation