Evidence that L-deprenyl treatment for one week does not inhibit MAO A or the dopamine transporter in the human brain.

In this study, we investigated whether treatment with L-deprenyl, a selective monoamine oxidase B (MAO B) inhibitor, also inhibits MAO A or the dopamine transporter in the human brain. Six normal volunteers (age 46+/-6 yrs) had two PET sessions, one at baseline and one following L-deprenyl (10 mg/day) for 1 week. Each session included one scan with [11C]clorgyline (to assess MAO A) and one scan 2 hours later with [11C]cocaine (to assess dopamine transporter availability). A 3-compartment model was used to compare the plasma-to-brain transfer constant, K1 (a function of blood flow) and lambdak3 (a kinetic term proportional to brain MAO A) before and after treatment. Dopamine transporter availability was measured as the ratio of distribution volumes of the striatum to cerebellum (DVR) which is equal to Bmax/KD +1. L-Deprenyl treatment for 1 week did not affect either brain MAO A activity or dopamine transporter availability. There was a non-significant trend for an increase in K1 after L-deprenyl. These results confirm that L-deprenyl after one week of treatment at doses typically used clinically is selective for MAO B and that it does not produce a measurable affect on the dopamine transporter, suggesting that MAO A inhibition and dopamine transporter blockade do not contribute to its pharmacological effects.

Transaction costs and sequential bargaining in transferable discharge permit markets.

Market-type mechanisms have been introduced and are being explored for various environmental programs. Several existing programs, however, have not attained the cost savings that were initially projected. Modeling that acknowledges the role of transactions costs and the discrete, bilateral, and sequential manner in which trades are executed should provide a more realistic basis for calculating potential cost savings. This paper presents empirical evidence on potential cost savings by examining a market for the abatement of sediment from farmland. Empirical results based on a market simulation model find no statistically significant change in mean abatement costs under several transaction cost levels when contracts are randomly executed. An alternative method of contract execution, gain-ranked, yields similar results. At the highest transaction cost level studied, trading reduces the total cost of compliance relative to a uniform standard that reflects current regulations.

Brain dopamine and obesity.

BACKGROUND: The cerebral mechanisms underlying the behaviours that lead to pathological overeating and obesity are poorly understood. Dopamine, a neurotransmitter that modulates rewarding properties of food, is likely to be involved. To test the hypothesis that obese individuals have abnormalities in brain dopamine activity we measured the availability of dopamine D2 receptors in brain. METHODS: Brain dopamine D2 receptor availability was measured with positron emission tomography (PET) and [C-11]raclopride (a radioligand for the dopamine D2 receptor). Bmax/Kd (ratio of the distribution volumes in striatum to that in cerebellum minus 1) was used as a measure of dopamine D2 receptor availability. Brain glucose metabolism was also assessed with 2-deoxy-2[18F]fluoro-D-glucose (FDG). FINDINGS: Striatal dopamine D2 receptor availability was significantly lower in the ten obese individuals (2.47 [SD 0.36]) than in controls (2.99 [0.41]; p < or = 0.0075). In the obese individuals body mass index (BMI) correlated negatively with the measures of D2 receptors (r=0.84; p < or = 0.002); the individuals with the lowest D2 values had the largest BMI. By contrast, neither whole brain nor striatal metabolism differed between obese individuals and controls, indicating that striatal reductions in D2 receptors were not due to a systematic reduction in radiotracer delivery. INTERPRETATION: The availability of dopamine D2 receptor was decreased in obese individuals in proportion to their BMI. Dopamine modulates motivation and reward circuits and hence dopamine deficiency in obese individuals may perpetuate pathological eating as a means to compensate for decreased activation of these circuits. Strategies aimed at improving dopamine function may be beneficial in the treatment of obese individuals.

PET studies of the effects of aerobic exercise on human striatal dopamine release.

UNLABELLED: In vivo microdialysis studies have shown that exercise increases the concentration of dopamine (DA) in the striatum of the rat brain. It has also been shown that PET with [11C]raclopride can be used to assess changes in brain DA induced by drugs and by performance tasks such as playing a video game. The purpose of this study was to evaluate the effects of exercise (treadmill running) on striatal DA release in the human brain. METHODS: Twelve healthy volunteers (5 women, 7 men; mean age, 32 +/- 5 y; age range, 25-40 y) with a history of regular exercise received 2 PET scans with [11C]raclopride on 2 separate days, 1 at baseline and 1 at 5-10 min after running on a treadmill for 30 min. The speed and inclination of the treadmill were increased gradually to reach a maximal speed of 9.7 km/h (6 mph) and a maximal inclination of 10degrees. Data were acquired on a Siemens HR+ scanner in 3-dimensional mode for 60 min. Heart rates and electrocardiograms were monitored. DA D2 receptor availability was measured using the ratio of the distribution volume in the putamen to that in the cerebellum, which is a function of the number of available binding sites/dissociation constant. RESULTS: The subjects ran at an average speed of 8.7 +/- 0.5 km/h (5.4 +/- 0.3 mph) and at an inclination of 3.3degrees +/- 2degrees. The maximum effort of running was maintained for 10-15 min. The heart rates of the subjects were increased by 143% +/- 47%. DA D2 receptor availability in the putamen after treadmill running (4.22 +/- 0.34) was no different from that of baseline (4.17 +/- 0.29; P < 0.6). CONCLUSION: No significant changes in synaptic DA concentration were detected, although the subjects exercised vigorously for 30 min.

Reproducibility of repeated measures of endogenous dopamine competition with [11C]raclopride in the human brain in response to methylphenidate.

UNLABELLED: The measure of changes in synaptic dopamine (DA) concentration in response to the psychostimulant drug methylphenidate (MP) has been used as an indicator of responsiveness of the DA system. The purpose of this study was to assess the reproducibility of these measures. METHODS: Seven healthy subjects were scanned with PET and [11C]raclopride twice in the same day: 7 min after placebo or methylphenidate (0.5 mg/kg) administration. In parallel we also measured the physiologic and behavioral responses to placebo and to methylphenidate. The same procedures were repeated 1-2 wk later to assess test-retest reproducibility. RESULTS: Measures of plasma to brain transfer constant (K1), striatal distribution volume (DVstr) and DA D2 receptor availability (Bmax/Kd), for the placebo condition were similar for the first (E1) and second (E2) evaluations (Bmax/Kd, E1: 2.77+/-0.44; E2: 2.97+/-0.44). MP administration did not change K1, but it significantly decreased DVstr (E1: -25.9%+/-8.7%, P < or = 0.0002; E2: -20.7%+/-11.7%, P < or = 0.007) and Bmax/Kd (E1: -18.4%+/-8.7%, P < or = 0.002; E2: -13.4%+/-9.2%, P < or = 0.008), and the magnitude of these changes, though lower for E2, did not differ significantly. MP increased pulse rate (E1: +64%+/-43%, P < or = 0.002; E2: +69%+/-33%, P < or = 0.001), systolic pressure (E1: +37%+/-19%, P < or = 0.0006; E2: +29%+/-15%, P < or = 0.0009), self reports for drug effects (0: nothing to 10: extreme) of "rush" (E1: +8+/-3, P < or = 0.0004; E2: +6+/-4, P < or = 0.01) and "high" (E1: +8+/-3, P < or = 0.0001, E2: +8+/-3, P < or = 0.0003), anxiety (E1: +5+/-4, P < or = 0.02; E2: +4+/-4, P = 0.1) and restlessness (E1: +4+/-4, P < or = 0.04; E2: +4+/-5, P = 0.1). The magnitude of the cardiovascular and behavioral effects did not differ between E1 and E2. CONCLUSION: MP-induced changes in striatal DV and in Bmax/Kd, as well as the behavioral and cardiovascular effects, were reproducible with repeated administration.

Evaluation of gender difference in regional brain metabolic responses to lorazepam.

Women are prescribed benzodiazepines twice as frequently as men and there is evidence of differences in therapeutic responsiveness to benzodiazepines between genders. In this study we compared the regional brain metabolic response to benzodiazepines between male and female subjects. Sixteen healthy men and 12 healthy women were scanned with positron emission tomography (PET) and [F-18] fluorodeoxyglucose (FDG) twice: prior to placebo and prior to lorazepam (30 microg/kg) on separate days. Lorazepam significantly and consistently decreased whole brain metabolism and the magnitude as well as the regional pattern of the changes was comparable for both genders (M = -4.7+/- 3 and F = -3.9 +/- 3.8 micromol/100 g/min). Lorazepam effects were largest in thalamus (- 12.5 +/- 6.2 and -8.6 +/- 7.1 micromol/100 g/min) and occipital cortex (-10.5 +/- 5.5 and -10.1 +/- 6.6 micromol/100 g/min). Lorazepam-induced changes in 'relative' metabolism were also similar for both genders except for trend differences (0.01 < P < 0.05) in rectal gyrus, where lorazepam increased relative metabolism in women (+4.4 +/- 9.9%) whereas it decreased in men (-3.2 +/- 8.8%, P < 0.04) and in cerebellum, where lorazepam-induced decrements were larger in women (-5.9 +/- 6%) than in men (-1.1% +/- 6.6%, P < 0.05). There were no differences between genders for any of the behavioral effects of lorazepam. In summary, this study does not show differences in the response to lorazepam between the genders as assessed by its behavioral effects and the changes in absolute metabolism; the trend toward a difference in the relative changes in rectal gyrus and cerebellum merits further investigation.

Age associated decrements in dopamine D2 receptors in thalamus and in temporal insula of human subjects.

This study evaluates the effects of age on DA D2 receptors in extrastriatal regions. DA D2 receptor availability was evaluated in 42 healthy male subjects (mean age 41 +/- 16, range 21 - 86 year old) with positron emission tomography (PET) and [11C]raclopride. Estimates of Bmax/Kd were obtained using the ratio of the distribution volume in the region of interest (caudate, putamen, thalamus, frontal, occipital cortices, temporal insula, cingulate and orbitofrontal gyri) to that in cerebellum. Correlations between age and D2 receptors were significant in putamen (r = -0.58, p < or = 0.0001), caudate (r = -0.54, p < or = 0.0002), thalamus (r = -0.33, p < or = 0.03) and temporal insula (r = -0.39, p < or = 0.01) but not in any of the frontal regions. The decrease in DA D2 receptor availability was 6.6% per decade in caudate, 8.2% in putamen, 7.6% in thalamus and 13% in temporal insula. This study indicates that D2 losses with age are not limited to striatum and involve also thalamic as well as temporal cortical regions.