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Biomedical subjects

J S Fowler

Publications and source records attributed to J S Fowler.

At least 109 records · Page 6Linked to original sources
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

Displacement of RTI-55 from the dopamine transporter by cocaine.

The cocaine analog 3 beta-(4-iodophenyl)tropane-2 beta-carboxylic acid methyl ester (RTI-55 or beta CIT) has a higher affinity for the dopamine transporter and may be potentially useful in interfering with cocaine's actions in brain. However, imaging studies have demonstrated displacement of tracer doses of [123I]RTI-55 by a subsequent dose of cocaine. Similar displacement of pharmacological doses of RTI-55 might compromize therapy with RTI-55 in cocaine abuse. The reduction in dopamine transporter availability, assessed in vivo in mouse striatum using [3H]cocaine, caused by pretreatment with RTI-55 was significantly mitigated by subsequent administration of cocaine. In a similar experiment using a tracer dose of [123I]RTI-55 significant reductions of striatal radioligand binding by pretreatment with cocaine or RTI-55 were not observed. These results suggest that: (1) cocaine can displace pharmacological doses of RTI-55 from striatum, and (2) radioligands used to assess binding site occupancy should have a lower affinity than the occupying drug.

Animals↗
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

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↗
PubMed1996

Opioid receptor imaging and displacement studies with [6-O-[11C] methyl]buprenorphine in baboon brain.

Buprenorphine (BPN) is a mixed opiate agonist-antagonist used as an analgesic and in the treatment of opiate addiction. We have used [6-O-[11C]methyl]buprenorphine ([11C]BPN) to measure the regional distribution in baboon brain, the test-retest stability of repeated studies in the same animal, the displacement of the labeled drug by naloxone in vivo, and the tissue distribution in mice. The regional distribution of radioactivity in baboon brain determined with PET was striatum > thalamus > cingulate gyrus > frontal cortex > parietal cortex > occipital cortex > cerebellum. This distribution corresponded to opiate receptor density and to previously published data (37). The tracer uptake in adult female baboons showed no significant variation in serial scans in the same baboon with no intervention in the same scanning session. HPLC analysis of baboon plasma showed the presence of labeled metabolites with 92% +/- 2.2% and 43% +/- 14.4% of the intact tracer remaining at 5 and 30 min, respectively. Naloxone, an opiate receptor antagonist, administered 30-40 min after tracer injection at a dose of 1.0 mg/kg i.v., reduced [11C]BPN binding in thalamus, striatum, cingulate gyrus, and frontal cortex to values 0.25 to 0.60 of that with no intervention. There were minimal (< 15%) effects on cerebellum. Naloxone treatment significantly reduced the slope of the Patlak plot in receptor-containing regions. These results demonstrate that [11C]BPN can be displaced by naloxone in vivo, and they affirm the feasibility of using this tracer and displacement methodology for short-term kinetics studies with PET. Mouse tissue distribution data were used to estimate the radiation dosimetry to humans. The critical organ was the small intestine, with a radiation dose estimate to humans of 117 nrad/mCi.

Animals↗
PubMed1996

Distribution volume ratios without blood sampling from graphical analysis of PET data.

The distribution volume ratio (DVR), which is a linear function of receptor availability, is widely used as a model parameter in imaging studies. The DVR corresponds to the ratio of the DV of a receptor-containing region to a nonreceptor region and generally requires the measurement of an arterial input function. Here we propose a graphical method for determining the DVR that does not require blood sampling. This method uses data from a nonreceptor region with an average tissue-to-plasma efflux constant k2 to approximate the plasma integral. Data from positron emission tomography studies with [11C]raclopride (n = 20) and [11C]d-threo-methylphenidate ([11C]dMP) (n = 8) in which plasma data were taken and used to compare results from two graphical methods, one that uses plasma data and one that does not. k2 was 0.163 and 0.051 min-1 for [11C]raclopride and [11C]dMP, respectively. Results from both methods were very similar, and the average percentage difference between the methods was -0.11% for [11C]raclopride and 0.46% for [11C]dMP for DVR of basal ganglia (BG) to cerebellum (CB). Good agreement between the two methods was also achieved for DVR images created by both methods. This technique provides an alternative method of analysis not requiring blood sampling that gives equivalent results for the two ligands studied. It requires initial studies with blood sampling to determine the average kinetic constant and to test applicability. In some cases, it may be possible to neglect the k2 term if the BG/CB ratio becomes reasonably constant for a sufficiently long period of time over the course of the experiment.

Basal Ganglia↗
PubMed1996

Decreases in dopamine receptors but not in dopamine transporters in alcoholics.

It has been hypothesized that ethanol's actions on the dopamine (DA) system may participate in addiction. The purpose of this study was to evaluate the DA system in the brain of alcoholics. We evaluated 10 alcoholics and 17 nonalcoholics using positron emission tomography and [11C]raclopride to measure DA D2 receptors. In addition, in 5 of the alcoholics and 16 of the nonalcoholics, we also measured DA transporters with [11C]d-threo methylphenidate. The ratio of the distribution volumes in striatum to that in cerebellum, which corresponds to Bmax/Kd + 1, was used as model parameter of DA D2 receptor and transporter availability. Dopamine D2 receptor availability (Bmax/Kd) was significantly lower in alcoholics (2.1 +/- 0.5) than in nonalcoholics (2.7 +/- 0.6) (p < 0.05) and was not correlated with days since last alcohol use. Alcoholics showed DA transporter values similar to those in nonalcoholics. The ratio of DA D2 receptor to transporter availability was significantly higher in nonalcoholics (1.4 +/- 0.1) than in alcoholics (1.1 +/- 0.1) (p < 0.005). Alcoholics showed significant reductions in D2 receptors (postsynaptic marker) but not in DA transporter availability (presynaptic marker) when compared with nonalcoholics. Because D2 receptors in striatum are mainly localized in gamma-aminobutyric acid (GABA) cells these results provide evidence of GABAergic involvement in the dopaminergic abnormalities seen in alcoholics.

Adult↗
PubMed1996

Cocaine addiction: hypothesis derived from imaging studies with PET.

Analysis of the behavior of cocaine in the human brain with Positron Emission Tomography reveals that it is not only its affinity for the dopamine transporter that gives it its unique properties but also its fast pharmacokinetics. Its very fast uptake and clearance from the brain contrast with that of methylphenidate, another drug that inhibits the DA transporter. Methylephenidate clears from the brain at a much slower rate and is less addictive than cocaine. We postulate that periodic and frequent stimulation of the dopaminergic system secondary to chronic use of cocaine favors activation of a circuit that involves the orbitofrontal cortex, cingulate gyrus, thalamus and striatum. This circuit is abnormal in cocaine abusers and we postulate that is activation by cocaine perpetuates the compulsive administration of the drug and is perceived by the cocaine abuser as a intense desire resulting in the loss of control over the drive to take more cocaine.

Animals↗
PubMed1996

Dopamine transporters decrease with age.

UNLABELLED: Postmortem studies have documented degeneration of dopamine cells with age, but the changes that occur in healthy aging individuals is less clear. The purpose of this study was to evaluate the extent to which age-induced changes in dopamine transporters occur in subjects with no evidence of motor impairment. METHODS: We evaluated 23 right-handed healthy volunteers (age range 20-74 yr) using PET and [11C]d-threo-methylphenidate. The ratio of the distribution volume for [11C]d-threo-methylphenidate in striatum to that in cerebellum was used as model parameter for dopamine transporter availability (Bmax/Kd + 1). RESULTS: Dopamine transporter availability was significantly lower in subjects > 40 yr of age than in those < 40 yr. Estimates of dopamine transporter availability showed a significant negative correlation with age both for the putamen (r = -0.72, p < 0.0001) and the caudate (r = -0.74, p < 0.0001). Dopamine transporter availability was higher in the left than in the right putamen but did not differ between the left and right caudate. CONCLUSION: This study documents a 6.6% decrease per decade of life in striatal dopamine transporters of healthy volunteers.

Adult↗
PubMed1996

Cardiotoxic properties of cocaine: studies with positron emission tomography.

This study documented marked accumulation of cocaine in the human and baboon heart, which was not inhibited by desipramine pretreatment. However, cocaine inhibited 6-[18F]fluoronorepinephrine uptake in heart to the same degree as did desipramine (Fowler et al. 1994). Since uptake of [18F]norepinephrine in the heart is a function of its uptake by the NE transporter (Fowler et al. 1994), its inhibition by cocaine corroborates in vivo a significant interaction of cocaine with this transporter.

Adult↗