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Biomedical subjects

J Logan

Publications and source records attributed to J Logan.

At least 91 records · Page 5Linked to original sources
PubMed1997

Cocaine abusers do not show loss of dopamine transporters with age.

Cocaine blocks dopamine transporters (DAT) and this effect is crucial to its reinforcing properties. To assess the effects of chronic cocaine on DAT we evaluated 20 current cocaine abusers and 20 age matched controls using PET and [C-11]cocaine as a DAT ligand. Though there were no differences in DAT availability between groups, current cocaine abusers (and 12 detoxified cocaine abusers studied previously) did not show the typical age-related decline in DAT seen in controls. Though further studies are required to rule out sampling effects and to control for confounding variables (i.e. smoking), one could speculate that chronic DAT blockade by cocaine has a protective effect on the loss of DAT with age.

Adult↗
PubMed1997

Dopamine D2 receptor availability in opiate-dependent subjects before and after naloxone-precipitated withdrawal.

Dopamine may play a role in opiate withdrawal and dependence. We measured dopamine D2 receptor availability in 11 opiate-dependent subjects using PFT and [11C]raclopride at baseline and during naloxone-precipitated withdrawal. Because [11C]raclopride is sensitive to endogenous dopamine, this strategy enabled us to test whether we could document in humans the DA reductions reported in animal models of opiate withdrawal. Results were compared with values from 11 controls, two of which also received naloxone. The ratio of the distribution volume in striatum to that in cerebellum (Bmax/Kd + 1) was used as model parameter for D2 receptor availability. Baseline measures for Bmax/Kd were lower in opiate-dependent subjects (2.44 +/- 0.4) than in controls (2.97 +/- 0.45 P < or = .009). Naloxone precipitated an intense withdrawal in the abusers but did not change the Bmax/Kd ratio. This study documents decreases in D2 receptors in opiate-dependent subjects but does not document significant changes in striatal DA concentration during acute withdrawal.

Adult↗
PubMed1997

Effects of methylphenidate on regional brain glucose metabolism in humans: relationship to dopamine D2 receptors.

OBJECTIVE: The authors' goals were to determine whether baseline dopamine activity contributes to response to methylphenidate and to assess the pattern of metabolic responses associated with enhanced dopamine activity. METHOD: They used positron emission tomography with 2-deoxy-2[18F]fluoro-D-glucose to evaluate the effects of two sequential doses of methylphenidate on brain metabolism in 15 healthy subjects. Dopamine D2 receptor availability was measured with [11C]raclopride to evaluate its relation to methylphenidate-induced metabolic changes. RESULTS: Methylphenidate increased brain metabolism in six subjects, decreased it in two, and did not change it in seven; however, it consistently increased cerebellar metabolism. Methylphenidate significantly increased "relative" (region relative to the whole brain) metabolism in the cerebellum and decreased it in the basal ganglia. Regional metabolic changes in the cerebellum and the frontal and temporal cortices were significantly correlated with D2 availability. Frontal and temporal metabolism were increased in subjects with high D2 receptors and decreased in subjects with low D2 receptors. CONCLUSIONS: Methylphenidate induced variable changes in brain metabolism, but it consistently increased cerebellar metabolism. It also induced a significant reduction in relative metabolism in the basal ganglia. The significant association between metabolic changes in the frontal and temporal cortices and in the cerebellum and D2 receptors suggests that methylphenidate's metabolic effects in these brain regions are due in part to dopamine changes and that differences in D2 receptors may be one of the mechanisms accounting for the variability in response to methylphenidate.

Adult↗
PubMed1997

Serotonergic modulation of dopamine measured with [11C]raclopride and PET in normal human subjects.

OBJECTIVE: This study was undertaken to measure serotonergic modulation of dopamine in vivo by using positron emission tomography (PET), a radiotracer for the striatal dopamine D2 receptor ([11C]raclopride), and a pharmacologic challenge of the serotonin system (d,l-fenfluramine). METHOD: Two PET studies using [11C]raclopride were performed in 11 normal male subjects before administration of the serotonin-releasing agent and reuptake inhibitor fenfluramine (60 mg p.o.) and 3 hours afterward. A graphical analysis method was used with the [11C]raclopride data to derive the distribution volume of D2 receptors. Plasma levels of fenfluramine, norfenfluramine, homovanillic acid (HVA), cortisol, and prolactin were determined. RESULTS: Levels of fenfluramine and prolactin were elevated 2 hours after fenfluramine administration and remained significantly elevated during the second scan, while levels of HVA and cortisol were not altered significantly during the time of scanning. A significant decrease in the specific binding (striatum) and the nonspecific binding subtracted from the specific binding (striatum minus cerebellum) of [11C]raclopride was observed. The rate of metabolism of [11C]raclopride and the nonspecific binding (cerebellum) were not significantly altered by the fenfluramine intervention. CONCLUSIONS: The observed decrease in [11C]raclopride binding is consistent with an increase in dopamine concentrations and with the ability of serotonin to stimulate dopamine activity. The ability to measure serotonergic modulation of dopamine in vivo may have implications for the study of etiologic and therapeutic mechanisms in schizophrenia, major depressive disorder, obsessive-compulsive disorder, and substance abuse.

Aged↗
PubMed1997

The 'new' VA.

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Humans↗
PubMed1996

Brain monoamine oxidase A inhibition in cigarette smokers.

Several studies have documented a strong association between smoking and depression. Because cigarette smoke has been reported to inhibit monoamine oxidase (MAO) A in vitro and in animals and because MAO A inhibitors are effective antidepressants, we tested the hypothesis that MAO A would be reduced in the brain of cigarette smokers. We compared brain MAO A in 15 nonsmokers and 16 current smokers with [11C]clorgyline and positron emission tomography (PET). Four of the nonsmokers were also treated with the antidepressant MAO inhibitor drug, tranylcypromine (10 mg/day for 3 days) after the baseline PET scan and then rescanned to assess the sensitivity of [11C]clorgyline binding to MAO inhibition. MAO A levels were quantified by using the model term lambda k3 which is a function of brain MAO A concentration. Smokers had significantly lower brain MAO A than nonsmokers in all brain regions examined (average reduction, 28%). The mean lambda k3 values for the whole brain were 0.18 +/- 0.04 and 0.13 +/- 0.03 ccbrain (mlplasma)-1 min-1 for nonsmokers and smokers, respectively; P < 0.0003). Tranyl-cypromine treatment reduced lambda k3 by an average of 58% for the different brain regions. Our results show that tobacco smoke exposure is associated with a marked reduction in brain MAO A, and this reduction is about half of that produced by a brief treatment with tranylcypromine. This suggests that MAO A inhibition needs to be considered as a potential contributing variable in the high rate of smoking in depression and in the development of more effective strategies for smoking cessation.

Adolescent↗
PubMed1996

Relationship between psychostimulant-induced "high" and dopamine transporter occupancy.

The ability of cocaine to inhibit the dopamine transporter (DAT) appears to be crucial for its reinforcing properties. The potential use of drugs that produce long-lasting inhibition of the DAT as a mean of preventing the "high" and reducing drug-seeking behavior has become a major strategy in medication development. However, neither the relation between the high and DAT inhibition nor the ability to block the high by prior DAT blockade have ever been demonstrated. To evaluate if DAT could prevent the high induced by methylphenidate (MP), a drug which like cocaine inhibits the DAT, we compared the responses in eight non-drug-abusing subjects between the first and the second of two MP doses (0.375 mg/kg, i.v.) given 60 min apart. At 60 min the high from MP has returned to baseline, but 75-80% of the drug remains in brain. Positron-emission tomography and [11C]d-threo-MP were used to estimate DAT occupancies at different times after MP. DAT inhibition by MP did not block or attenuate the high from a second dose of MP given 60 min later, despite a 80% residual transporter occupancy from the first dose. Furthermore some subjects did not perceive a high after single or repeated administration despite significant DAT blockade. These results indicate that DAT occupancy is not sufficient to account for the high, and that for DAT inhibitors to be therapeutically effective, occupancies > 80% may be required.

Adult↗
PubMed1996

Measuring age-related changes in dopamine D2 receptors with 11C-raclopride and 18F-N-methylspiroperidol.

This study investigates the rate of age-related dopamine D2 receptor loss as determined by positron emission tomography (PET) and 11C-raclopride and compares it with D2 loss previously estimated with 18F-N-methylspiroperidol (NMS). Dopamine D2 receptors were measured with 11C-raclopride in 24 healthy volunteers (24-73 years of age) using the ratio of the distribution volume in striatum to that in cerebellum (Bmax/Kd + 1). The results were compared with those obtained in 20 healthy male volunteers (20-49 years of age) in whom D2 receptors were measured with NMS using the ratio index (slope of the striatum-to-cerebellum ratio as a function of time). Findings of correlational analysis between age and dopamine D2 receptor availability were significant for both ligands. Estimates of dopamine D2 receptor loss per decade corresponded to 7.9% for the 11C-raclopride study and 7.8% for the NMS study. Both ligands documented significant age-related decreases in dopamine D2 receptors that occurred relatively early in life (40 years of age).

Adult↗
PubMed1996

Inhibition of monoamine oxidase B in the brains of smokers.

The massive health problem associated with cigarette smoking is exacerbated by the addictive properties of tobacco smoke and the limited success of current approaches to cessation of smoking. Yet little is known about the neuropharmacological actions of cigarette smoke that contribute to smoking behaviour, or why smoking is so prevalent in psychiatric disorders and is associated with a decreased risk of Parkinson's disease. Here we report that brains of living smokers show a 40% decrease in the level of monoamine oxidase B (MAO B; EC 1.4.3.4) relative to non-smokers or former smokers. MAO B is involved in the breakdown of dopamine, a neurotransmitter implicated in reinforcing and motivating behaviours as well as movement. MAO B inhibition is therefore associated with enhanced activity of dopamine, as well as with decreased production of hydrogen peroxide, a source of reactive oxygen species. We propose that reduction of MAO B activity may synergize with nicotine to produce the diverse behavioural and epidemiological effects of smoking.

Adult↗
PubMed1996

Temporal relationships between the pharmacokinetics of methylphenidate in the human brain and its behavioral and cardiovascular effects.

Positron emission tomography was used to compare the pharmacokinetics of [11C]methylphenidate in the human brain with the temporal course of the subjective and cardiovascular effects observed after intravenous methylphenidate (0.5 mg/kg). Four subjects were tested twice with [11C]methylphenidate, at baseline and after methylphenidate. All subjects showed almost identical uptake of 11C labeled drug in brain, as well as a very similar decrease in binding of [11C]methylphenidate in basal ganglia, after pretreatment with methylphenidate. In contrast, the magnitude of the behavioral and cardiovascular changes induced by methylphenidate varied among the subjects. The temporal course for methylphenidate effects paralleled closely the pharmacokinetics of [11C]methylphenidate in brain for the perception of "restlessness" and for changes in systolic blood pressure and heart rate. In contrast, methylphenidate induced "high", "anxiety" and changes in diastolic blood pressure decreased rapidly despite long lasting binding of the drug in brain. These results indicate that binding of methylphenidate in brain does not appear to predict individual responses to the drug and that more than one neurotransmitter and/or adaptation process are likely to be involved in the behavioral and cardiovascular effects of methylphenidate.

Adult↗
PubMed1996

Who gives advice about postpartum contraception?

Women were interviewed to determine what advice they received about postpartum contraception and what they thought of it. Only 4% of women discussed postpartum contraception antenatally. Up to 84% discussed the issue with a midwife on the postnatal ward but discussion was often felt to be brief, limited and frequently held as the mother was leaving the hospital. Obstetricians appeared to have little interest in the subject and only 50% of mothers left the hospital with supplies of a contraceptive. Almost all women discussed contraception with their general practitioner at the postnatal check but a significant number felt that the choice of method was limited to condoms or pills. The postnatal check is traditionally held at six weeks--two to three weeks after the recommended time for starting contraceptive precautions. Women with short inter-pregnancy intervals were younger, less likely to be married and more likely to default from postnatal follow-up. Pregnant women should be offered the opportunity during the antenatal period to discuss postpartum contraception with someone who has a special interest in the subject. The postnatal ward is not an appropriate setting for discussion about future contraception.

Contraception↗
PubMed1996

Mapping catechol-O-methyltransferase in vivo: initial studies with [18F]Ro41-0960.

Ro41-0960 is a potent, fluorine containing COMT inhibitor which has be en reported to cross the blood brain barrier and to inhibit COMT in the brain. It is structurally similar to Ro40-7592 which is currently undergoing clinical trials in Parkinson's disease. Positron emission tomographic (PET) studies in baboon using F-18 labeled Ro41-0960 demonstrated a negligible uptake in the brain both at tracer doses and with the addition of unlabeled drug (1.5 mg/kg) at all times through a 90 min experimental interval. The brain to plasma ratios of F-18 averaged about 0.025. Region of interest analysis of the brain tissue area suggests that most of F-18 in the brain was due to the blood in the brain and not the brain tissue itself. However, high uptake was observed in the kidneys and in other organs which are known to have high COMT activity. Studies in mice showed that at 30 min after injection of tracer, F-18 in kidneys was largely as unchanged [18F]Ro41-0960 and that it could be displaced with unlabeled Ro41-0960. The fact that the average brain to blood ratio for mice (n=12) was 0.04, and that similar HPLC metabolite patterns were observed for brain and blood, provides consistent evidence that nearly all the F-18 in the brain represents F-18 in the cerebral blood vessels. These studies raise the question of whether the central pharmacological effects of Ro41-0960 are due to its presence in the brain. They also provide the first example of a positron emitter labeled radiotracer for COMT, and provide initial encouraging evidence that [18F]Ro41-0960 may be used to examine COMT in peripheral organs in vivo.

Animals↗
PubMed1996

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.

Adult↗
PubMed1996

Cocaine uptake is decreased in the brain of detoxified cocaine abusers.

Binding of [11C]cocaine in brain was measured with positron emission tomography in 12 detoxified cocaine abusers and in 20 controls to evaluate if there were changes in cocaine binding and in dopamine (DA) transporter availability associated with chronic cocaine use. Nine controls and 10 cocaine abusers had an additional scan with [18F]N-methylspiroperidol to measure dopamine D2 receptors. Cocaine abusers had significantly lower uptake of [11C]cocaine in brain (6.2 +/- 1% dose/cc tissues) than controls (7.7 +/- 2%). The distribution volumes (DV) for [11C]cocaine were reduced in basal ganglia (BG), cortex, thalamus, and cerebellum (CB) of cocaine abusers. However there were no differences in the ratio of the DV in BG to that in CB, which is an estimate of DA transporter availability. Values for DA D2 receptor availability were decreased in cocaine abusers and did not correlate with estimates of dopamine transporter availability. In summary, detoxified cocaine abusers showed decreased uptake of cocaine in brain but did not show changes in DA transporter availability.

Adult↗
PubMed1996

[18F]haloperidol binding in baboon brain in vivo.

The binding of [18F]haloperidol to dopamine D2 and to sigma recognition sites in baboon brain was examined using positron emission tomography (PET). Studies were performed at baseline and after treatment with either haloperidol (to evaluate saturability), (+)-butaclamol (which has specificity for dopamine D2 receptors) or (-)-butaclamol (which has specificity for sigma sites). Binding was widespread. Treatment with (-)-butaclamol had no effect, whereas (+)-butaclamol selectively reduced the uptake in striatum. Haloperidol increased the clearance rate from all brain regions. These results indicate that the binding profile of [18F]haloperidol does not permit the selective examination of either dopamine D2 or sigma sites using PET.

Animals↗