The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects.

BACKGROUND: (2S,3S)-2-(3-Chlorophenyl)-3,5,5,-trimethyl-2-morpholinol hydrochloride (radafaxine) is a new antidepressant that blocks dopamine transporters (DAT). A concern with drugs that block (DAT) is their potential reinforcing effects and abuse liability. Using positron emission tomography (PET) we have shown that for DAT-blocking drugs to produce reinforcing effects they must induce >50% DAT blockade and the blockade has to be fast (within 15 minutes). This study measures the potency and kinetics for DAT blockade by radafaxine in human brain. METHODS: PET and [11C]cocaine were used to estimate DAT blockade at 1, 4, 8, and 24 hours after radafaxine (40 mg p.o.) in 8 controls. Plasma pharmacokinetics and behavioral and cardiovascular effects were measured in parallel. RESULTS: DAT blockade by radafaxine was slow, and at 1 hour, it was 11%. Peak blockade occurred at about 4 hours and was 22%. Blockade was long lasting: at 8 hours 17%, and at 24 hours 15%. Peak plasma concentration occurred about 4 to 8 hours. No behavioral or cardiovascular effects were observed. CONCLUSIONS: The relatively low potency of radafaxine in blocking DAT and its slow blockade suggests that it is unlikely to have reinforcing effects. This is consistent with preclinical studies showing no self-administration. This is the first utilization of PET to predict abuse liability of a new antidepressant in humans based on DAT occupancy and pharmacokinetics.

Evidence that methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain.

OBJECTIVE: Methylphenidate is the most commonly prescribed drug for attention deficit hyperactivity disorder (ADHD), yet its therapeutic mechanisms are poorly understood. The objective of this study was to assess if methylphenidate, by increasing dopamine (neurotransmitter involved in motivation) in brain, would enhance the saliency of an academic task, making it more interesting. METHOD: Healthy subjects (N=16) underwent positron emission tomography with [(11)C]raclopride (dopamine D(2) receptor radioligand that competes with endogenous dopamine for binding) to assess the effects of oral methylphenidate (20 mg) on extracellular dopamine in the striatum. The authors compared the effects of methylphenidate during an academic task (solving mathematical problems with monetary reinforcement) and a neutral task (passively viewing cards with no remuneration). In parallel, the effects of methylphenidate on the interest that the academic task elicited were also evaluated. RESULTS: Methylphenidate, when coupled with the mathematical task, significantly increased extracellular dopamine, but this did not occur when coupled with the neutral task. The mathematical task did not increase dopamine when coupled with placebo. Subjective reports about interest and motivation in the mathematical task were greater with methylphenidate than with placebo and were associated with dopamine increases. CONCLUSIONS: The significant association between methylphenidate-induced dopamine increases and the interest and motivation for the task confirms the prediction that methylphenidate enhances the saliency of an event by increasing dopamine. The enhanced interest for the task could increase attention and improve performance and could be one of the mechanisms underlying methylphenidate's therapeutic effects. These findings support educational strategies that make schoolwork more interesting as nonpharmacological interventions to treat ADHD.

Exposure to appetitive food stimuli markedly activates the human brain.

OBJECTIVE: The increased incidence of obesity most likely reflects changes in the environment that had made food more available and palatable. Here we assess the response of the human brain to the presentation of appetitive food stimuli during food presentation using PET and FDG. METHOD: Metabolic changes in response to food presentation were done in 12 healthy normal body weight subjects who were food deprived before the study. RESULTS: Food presentation significantly increased metabolism in the whole brain (24%, P < 0.01) and these changes were largest in superior temporal, anterior insula, and orbitofrontal cortices. The increases in the right orbitofrontal cortex were the ones that correlated significantly with the increases in self-reports of hunger and desire for food. DISCUSSION: The marked increase in brain metabolism by the presentation of food provides evidence of the high sensitivity of the human brain to food stimuli. This high sensitivity coupled with the ubiquitousness of food stimuli in the environment is likely to contribute to the epidemic of obesity. In particular, the activation of the right orbitofrontal cortex, a brain region involved with drive, may underlie the motivation to procure food, which may be subjectively experienced as "desire for food" and "hunger" when exposed to food stimuli.

Low monoamine oxidase B in peripheral organs in smokers.

One of the major mechanisms for terminating the actions of catecholamines and vasoactive dietary amines is oxidation by monoamine oxidase (MAO). Smokers have been shown to have reduced levels of brain MAO, leading to speculation that MAO inhibition by tobacco smoke may underlie some of the behavioral and epidemiological features of smoking. Because smoking exposes peripheral organs as well as the brain to MAO-inhibitory compounds, we questioned whether smokers would also have reduced MAO levels in peripheral organs. Here we compared MAO B in peripheral organs in nonsmokers and smokers by using positron emission tomography and serial scans with the MAO B-specific radiotracers,l-[11C]deprenyl and deuterium-substituted l-[11C]deprenyl (l-[11C]deprenyl-D2). Binding specificity was assessed by using the deuterium isotope effect. We found that smokers have significantly reduced MAO B in peripheral organs, particularly in the heart, lungs, and kidneys, when compared with nonsmokers. Reductions ranged from 33% to 46%. Because MAO B breaks down catecholamines and other physiologically active amines, including those released by nicotine, its inhibition may alter sympathetic tone as well as central neurotransmitter activity, which could contribute to the medical consequences of smoking. In addition, although most of the emphases on the carcinogenic properties of smoke have been placed on the lungs and the upper airways, this finding highlights the fact that multiple organs in the body are also exposed to pharmacologically significant quantities of chemical compounds in tobacco smoke.

Alcohol intoxication induces greater reductions in brain metabolism in male than in female subjects.

BACKGROUND: The mechanisms underlying the gender differences in alcohol drinking behavior and alcohol's effects are poorly understood and may reflect gender differences in brain neurochemistry. Alcohol decreases glucose metabolism in the human brain in a pattern that is consistent with its facilitation of GABAergic neurotransmission. We compared the regional changes in brain glucose metabolism during alcohol intoxication between female and male subjects. METHODS: Ten female and 10 male healthy controls were scanned with positron emission tomography and 2-deoxy-2[18F]fluoro-D-glucose twice: 40 min after placebo (diet soda) or alcohol (0.75 g/kg mixed with diet soda). RESULTS: Alcohol significantly and consistently decreased whole-brain metabolism. The magnitude of these changes was significantly larger in male (-25 +/- 6%) than in female (-14 +/- 11%; p < 0.005) subjects. Half of the female subjects had reductions in metabolism during intoxication that were significantly lower than those in male subjects. This blunted response in the female subjects was not due to differences in alcohol concentration in plasma, because these did not differ between the genders. In contrast, the self-reports for the perception of intoxication were significantly greater in female than in male subjects. The cognitive deterioration during alcohol intoxication, although not significant, tended to be worse in female subjects. CONCLUSIONS: This study shows a markedly blunted sensitivity to the effects of acute alcohol on brain glucose metabolism in female subjects that may reflect gender differences in alcohol's modulation of GABAergic neurotransmission. The greater behavioral effects of alcohol in female subjects despite the blunted metabolic responses could reflect other effects of alcohol, for which the regional metabolic signal may be hidden within the large decrements in metabolism that occur during alcohol intoxication.

Monoamine oxidase A imaging in peripheral organs in healthy human subjects.

Monoamine oxidase (MAO) catalyzes the oxidative deamination of many biogenic and dietary amines. Though studies of MAO have focused mainly on its regulatory role in the brain, MAO in peripheral organs also represents a vast mechanism for detoxifying vasoactive compounds as well as for terminating the action of physiologically active amines, which can cross the blood brain barrier. Indeed, robust central and peripheral MAO activity is a major requirement in the safe use of many CNS drugs, particularly antidepressants, and thus an awareness of the MAO inhibitory potential of drugs is essential in therapeutics. In this study, we examined the feasibility of quantifying MAO A in peripheral organs in healthy human subjects using comparative positron emission tomography (PET) imaging with carbon-11 (t(1/2): 20.4 min) labeled clorgyline ([(11)C]clorgyline) a suicide inactivator of MAO A and its deuterium labeled counterpart ([(11)C]clorgyline-D2). Heart, lungs, kidneys, thyroid, and spleen showed a robust deuterium isotope effect characteristic of MAO and the magnitude of the effect was similar to that of trancylcypromine, an irreversible MAO inhibitor used in the treatment of depression. Liver time-activity curves were not affected by deuterium substitution precluding the estimation of liver MAO in vivo. In organs showing an isotope effect, MAO A is greatest in the lungs and kidneys followed by the thyroid and heart. This method, which has been previously applied in the human brain, opens the possibility to also directly assess the effects of different variables including smoking, dietary substances, drugs, disease, and genetics on peripheral MAO A in humans.

Brain dopamine is associated with eating behaviors in humans.

OBJECTIVE: Eating behavior in humans is influenced by variables other than just hunger-satiety including cognitive restraint, emotional distress, and sensitivity to food stimuli. We investigate the role of dopamine (DA), a neurotransmitter involved with food motivation, in these variables. METHODS: We used the Dutch Eating Behavior Questionnaire (DEBQ) to measure Restraint, Emotionality, and Externality in 10 subjects. We correlated DEBQ scores with brain DA levels. Positron emission tomography and [(11)C]raclopride uptake were used to measure baseline D(2) receptors (neutral stimulation) and to assess changes in extracellular DA to food stimulation (display of food). RESULTS: Restraint was correlated with DA changes with food stimulation (higher restraint, greater responsivity), emotionality was negatively correlated with baseline D(2) receptors (higher emotionality, lower D(2) receptors), whereas externality was not. These correlations were significant in the dorsal but not in the ventral striatum. DISCUSSION: These results provide evidence that DA in the dorsal striatum is involved with the restraint and emotionality components regulating eating behavior and that these two dimensions reflect different neurobiologic processes.

Cardiovascular effects of methylphenidate in humans are associated with increases of dopamine in brain and of epinephrine in plasma.

RATIONALE: The cardiovascular effects of psychostimulant drugs (methylphenidate, amphetamine, cocaine) have been mostly associated with their noradrenergic effects. However, there is some evidence that dopaminergic effects are involved in the cardiovascular actions of these drugs. Here, we evaluated this association in humans. METHODS: Positron emission tomography (PET) and [(11)C]raclopride, a dopamine (DA) D2 receptor radioligand that competes with endogenous DA for occupancy of the D2 receptors, were used to measure changes in brain DA after different doses of intravenous methylphenidate in 14 healthy subjects. Cardiovascular (heart rate and blood pressure) and catecholamine (plasma epinephrine and norepineprhine) responses were determined in parallel to assess their relationships to methylphenidate-induced changes in brain DA. RESULTS: Methylphenidate administration significantly increased heart rate, systolic and diastolic blood pressures and epinephrine concentration in plasma. The increases in blood pressure were significantly correlated with methylphenidate-induced increases of DA in striatum (r>0.78, P<0.001) and of plasma epinephrine levels (r>0.82, P<0.0005). In turn methylphenidate-induced DA increases in striatum were correlated with increases of epinephrine in plasma (r=0.85, P<0.0001). Subjects in whom methylphenidate did not increase DA had no change in blood pressure or in plasma epinephrine concentration. DISCUSSION: These results are consistent with the hypothesis that methylphenidate-induced increases in blood pressure are in part due to its central dopaminergic effects. They also suggest that methylphenidate's pressor effects may be in part mediated by DA-induced increases in peripheral epinephrine.

PET imaging of monoamine oxidase B in peripheral organs in humans.

UNLABELLED: 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.

Brain DA D2 receptors predict reinforcing effects of stimulants in humans: replication study.

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.

Enhanced resting activity of the oral somatosensory cortex in obese subjects.

The cerebral mechanisms underlying excess food intake in obese subjects are poorly understood. We used PET and 2-deoxy-2[18F]fluoro-D-glucose to assess differences in regional brain metabolism between obese and lean subjects at rest. Brain metabolic images were analyzed using statistical parameter maps. We found that obese subjects have significantly higher metabolic activity in the bilateral parietal somatosensory cortex in the regions where sensation to the mouth, lips and tongue are located. The enhanced activity in somatosensory regions involved with sensory processing of food in the obese subjects could make them more sensitive to the rewarding properties of food related to palatability and could be one of the variables contributing to their excess food consumption.

"Nonhedonic" food motivation in humans involves dopamine in the dorsal striatum and methylphenidate amplifies this effect.

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.

PET Studies of the Effect of the Antidepressant Drugs Nefazodone or Paroxetine on [11C]Raclopride Binding in Human Brain.

Serotonin modulates dopamine release in the striatum. In this study we set out to determine whether nefazodone and paroxetine, two antidepressant drugs that interact with the brain serotonin system, produce detectable changes in synaptic dopamine in vivo in the human brain using positron emission tomography (PET) and [11C]raclopride, a dopamine D-2 receptor specific radiotracer that is sensitive to changes in synaptic dopamine. Three normal healthy human volunteers had 4 PET/[11C]raclopride scans each in 2 sessions. In the first session, subjects had a baseline [11C]raclopride scan and a second scan 1 hour following the oral administration of either nefazodone (200 mg PO) or paroxetine (20 mg PO). Four to 6 weeks later, in a second PET/[11C]raclopride session, the same subjects received the other drug for comparison. Neither nefazodone nor paroxetine produced significant changes in [11C]raclopride binding. This and other reports in the literature indicate that different drugs that affect the serotonin system do not produce consistent and predictable changes in [11C]raclopride binding and that a full understanding of their actions on serotonin and the associated changes in dopamine requires further investigation.