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J S Fowler

Publications and source records attributed to J S Fowler.

At least 73 records · Page 4Linked to original sources
PubMed1999

Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors.

Increases in dopamine concentration in limbic brain regions have been postulated to underlie the reinforcing effects of psychostimulant drugs in laboratory animals. However, neither the qualitative nor the quantitative relationship between drug-induced increases in brain dopamine and the reinforcing effects of psychostimulant drugs have been investigated in humans. Positron emission tomograph and [(11)C]raclopride, a dopamine D(2) receptor radioligand that competes with endogenous dopamine for occupancy of the D(2) receptors, were used to measure changes in brain dopamine after different doses of i.v. methylphenidate in 14 healthy controls. In parallel, measures for self-reports of drug effects were obtained to assess their relationship to methylphenidate-induced changes in brain dopamine. The intensity of the "high" induced by methylphenidate was significantly correlated with the levels of released dopamine (r = 0.78, p <.001); subjects having the greatest increases were those who perceived the most intense high. This relationship remained significant after partialing out for dose and concentration of methylphenidate in plasma. Furthermore, subjects for whom methylphenidate did not increase dopamine did not perceive a high. These results represent the first clear demonstration that stimulant-induced high, a mood descriptor that reflects reinforcing effects of drugs in humans, is associated with increases in brain dopamine, and also that there is a quantitative relationship between levels of D(2) receptor occupancy by dopamine and the intensity of the high.

Adult↗
PubMed1999

Blockade of striatal dopamine transporters by intravenous methylphenidate is not sufficient to induce self-reports of "high".

The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Using positron emission tomography (PET), we previously showed that intravenous cocaine induced a significant level of DAT blockade, which was associated with the intensity for self-reports of "high" in cocaine abusers. In this study, we measured DAT occupancies after intravenous methylphenidate and assessed whether they also were associated with the "high". Occupation of DAT by intravenous MP was measured with PET using [11C]cocaine, as a DAT ligand, in eight normal control subjects tested with different methylphenidate doses. The ratio of the distribution volume of [11C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd + 1, was used as measure of DAT availability. In parallel, self-reports of "high" were measured. Methylphenidate produced a dose-dependent blockade of DAT with an estimated ED50 of 0.075 mg/kg. DAT occupancies were significantly correlated with the "high" (p <.03). However, four of the eight subjects, despite having significant levels of DAT blockade, did not perceive the "high". Methylphenidate is as effective as cocaine in blocking DAT in the human brain (cocaine ED50 = 0.13 mg/kg), and DAT blockade, as for cocaine, was also associated with the "high". However, the fact that there were subjects who despite significant DAT blockade did not experience the "high" suggests that DAT blockade, although necessary, is not sufficient to produce the "high".

Adult↗
PubMed1998

Differences in regional brain metabolic responses between single and repeated doses of methylphenidate.

Studies investigating the acute effects of drugs of abuse on human brain metabolism have measured single doses whereas these drugs are mostly taken repeatedly. Here we compared the brain metabolic response to intravenous methylphenidate when given after a single dose to that when given after two sequential doses. Methylphenidate-induced changes in metabolism differed; whereas single doses tended to decrease metabolism, repeated doses tended to increase it, and these differences were significant in frontal, parietal and occipital cortices and hippocampus. This indicates that methylphenidate's metabolic effects vary with acute previous exposure and highlights the importance of studying drugs after single and repeated administration.

Adult↗
PubMed1998

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.

Adult↗
PubMed1998

Long-term stability of neurotransmitter activity investigated with 11C-raclopride PET.

There is evidence for the shift of regulatory setpoints of functionally linked neurotransmitter systems as a basis of psychiatric disorders. 11C-raclopride PET, which has been shown to be sensitive to changes in endogenous dopamine and has a high short-term test-retest reliability, can be used to investigate different regulatory states of the dopaminergic system with respect to psychiatric diseases and pharmacological influences. Prior to these studies, the reliability of the method over time has to be established. The current study was performed in order to evaluate the long-term stability of the striatal dopaminergic system. Eight normal healthy subjects (mean age: 48.1 years; range: 24-75) were studied twice with 11C-raclopride PET two times under resting conditions with a mean time interval between the scans of 11.3 months (range: 1-19). The ratio of basal ganglia (BG) to cerebellar (CB) distribution volumes (DVs) revealed a mean absolute change of 6.94 (range: 0.0-12.87%) between study A and B. BG DVs mean absolute change was 6.30% (range: 0.55-30.46%), CB DVs mean absolute change was 8.65% (range: 3.51-16.33%). The mean change of the BG/CB ratio was -0.33% (range: 12.87-12.34%). BG DVs mean change was 4.55% (range: 4.2-30.46%), CB DVs mean change was 5.10% (range: -10.71-16.33%). The intraindividual differences between the two scans in our study were not significantly different as compared to the 24 hour interval test-retest data, which have been published earlier (repeated measures ANOVA with df = 11; F = 0.49; P = 0.50) [Volkow et al. (1993) J. Nucl. Med., 34:609-613]. The intraclass correlation of the DV ratio index was r = 0.81. The binding potential in the baseline scans and repeated scans showed a non-significant correlation with age (r = -0.58, P = 0.13). Interindividually, the DV ratio index revealed a mean of 3.18 (range = 2.55-3.68, SD = 0.42 in study A and of 3.16 (range 2.37-3.57, SD = 0.41) in study B. The intrasubject stability of the 11C-raclopride binding over a long-term period in normal human subjects suggests the feasibility of study designs investigating the long-term changes of the dopaminergic responsivity after pharmacological challenges. The baseline stability will also serve as a necessary reference for further dose-response studies and investigations of subchronical pharmacological interventions.

Adult↗
PubMed1998

Measuring dopamine transporter occupancy by cocaine in vivo: radiotracer considerations.

Several recent neuroimaging studies in humans and in monkeys using different radiotracers have reported widely differing values of dopamine transporter (DAT) occupancy by doses of cocaine which are perceived as reinforcing by humans. Here we tested the hypothesis that the measurement of DAT occupancies by drugs with fast pharmacokinetics such as cocaine requires a radioligand with similar kinetics in order to effectively compete with the drug. We measured DAT occupancy by four different doses of cocaine (1.0, 0.5, 0.25, and 0.1 mg/kg) using [11C]d-threo-methylphenidate (a radiotracer which binds rapidly to the DAT in vivo) and compared them to estimates reported previously using [11C]cocaine in the same two baboons and with the same four doses of cocaine [Volkow et al. (1996b) Synapse 24:399-402). Cocaine reduced [11C]d-threo-methylphenidate binding in striatum in a dose-dependent manner, and values were significantly correlated with those obtained previously with [11C]cocaine (r = 0.9, F = 37, P < 0.001). The ED50s (50% occupancy of DAT by cocaine) were 0.27 and 0.17 mg/kg for [11C]d-threo-methylphenidate and [11C]cocaine, respectively. This is significantly lower than values obtained with labeled beta-CIT and other similar radiotracers with a slow uptake and clearance (ED50s: 3-7 mg/kg). We conclude that in vivo measurements of DAT occupancy by rapidly clearing drugs like cocaine requires the use of radiotracers having similar kinetics to the drug itself.

Animals↗
PubMed1998

A novel strategy for the treatment of cocaine addiction.

Cocaine's addictive liability has been linked to its pharmacologic actions on mesotelencephalic dopamine (DA) reinforcement/reward pathways in the central nervous system (CNS). Dopaminergic transmission within these pathways is modulated by gamma-aminobutyric acid (GABA). With this knowledge, we examined the utility of gamma vinylGABA (GVG), a selective and irreversible inhibitor of GABA-transaminase (GABA-T) known to potentiate GABAergic inhibition, to alter cocaine's biochemical effects as well as its effects on behaviors associated with these biochemical changes. GVG significantly attenuated cocaine-induced increases in neostriatal synaptic DA in the non-human primate (baboon) brain as assessed by positron emission tomography (PET) and abolished both the expression and acquisition of cocaine-induced conditioned place preference (CPP). It had no effect on CPP for a food reward, the delivery of cocaine to the brain or locomotor activity. These findings suggest the possible therapeutic utility in cocaine addiction of a pharmacologic strategy targeted at the GABAergic neurotransmitter system, a system distinct from but functionally linked to the DA mesotelencephalic reward/reinforcement system. However, rather than targeting the GABA receptor complex with a direct GABA agonist, this novel approach with GVG takes advantage of the prolonged effects of an irreversible enzyme inhibitor that raises endogenous GABA levels without the addictive liability associated with GABA agonists acting directly at the receptor itself. Human trials with GVG are currently being developed to directly examine the utility of this novel strategy for the treatment of cocaine addiction.

4-Aminobutyrate Transaminase↗
PubMed1998

Parallel loss of presynaptic and postsynaptic dopamine markers in normal aging.

Aging of the human brain is associated with a decline in dopamine (DA) function, generally interpreted as reflecting DA cell loss. Positron emission tomography studies revealed that in healthy individuals, the age-related losses in DA transporters (presynaptic marker) were associated with losses in D2 receptors (postsynaptic marker) rather than with increases as is known to occur with DA cell loss. This association was specific for DA synaptic markers, because they were not correlated with striatal metabolism. Furthermore, the association was independent of age, suggesting that a common mechanism regulates the expression of receptors and transporters irrespective of age.

Adult↗
PubMed1998

PET studies of peripheral catechol-O-methyltransferase in non-human primates using [18F]Ro41-0960.

We previously reported the results of PET (positron emission tomography) studies of [18F]Ro41-0960, a potent COMT inhibitor, in baboon brain. Here we report an evaluation of the pharmacokinetics and specificity of binding of [18F]Ro41-0960 in the peripheral organs of baboon. We observed a rapid clearance of the tracer from the heart and no significant uptake in the lung. In contrast, there was a high uptake and slow clearance in both kidney and liver, consistent with a high level of COMT in these peripheral organs. We also observed a dose-dependent inhibition of [18F]Ro41-0960 uptake by unlabeled Ro41-0960 (ED50 was 0.5 mg/kg in liver, and <0.01 mg/kg in kidney), with a halftime for recovery of COMT of about 25 h at the dose of 2 mg/kg of unlabeled Ro41-0960. This indicates a reversible tight binding interaction between COMT and Ro41-0960 in both liver and kidney and suggests that [18F]Ro41-0960 may be a useful radiotracer for future examination of the functional activity of COMT in the human body.

Animals↗
PubMed1998

An acute dose of nicotine does not inhibit MAO B in baboon brain in vivo.

Tobacco smoke exposure has been shown to inhibit brain and platelet MAO B in animals and in humans. Though the mechanism(s) responsible for MAO B inhibition are not known, studies in rodents have shown that nicotine administration does not inhibit brain MAO B. In this study we investigated whether brain MAO B is also unaffected by nicotine in the living primate. Brain MAO B was measured with positron emission tomography (PET) and deuterium substituted [11C]L-deprenyl ([11C]L-deprenyl-D2) in three baboons at baseline and 5 minutes after the injection of (-)-nicotine (0.3 mg administered intravenously). A three-compartment model was used to calculate the plasma to brain transfer constant K1 which is related to blood flow, and lambda k3, which is a function of the concentration of catalytically active MAO B molecules. Nicotine administration did not produce significant changes in either of these parameters. This study in living baboons confirms previous studies in rodents and solidifies the notion that other mechanisms for MAO B inhibition observed in smokers need to be considered.

Animals↗
PubMed1998

In vitro and ex vivo autoradiographic studies of nicotinic acetylcholine receptors using [18F]fluoronochloroepibatidine in rodent and human brain.

A fluorine-18-labeled analog of the potent nicotinic agonist epibatidine is a candidate radioligand for positron emission tomographic (PET) studies of nicotinic acetylcholine receptors (nAcChR). Following intravenous administration of [18F]exo-2-(2'-fluoro-5'-pyridinyl)-7-azabicyclo[2.2.1]heptane (NFEP), high uptake in thalamus was visualized in sections of mouse and rat brain by autoradiography using a phosphor imaging device. Binding of [18F]NFEP to rat thalamic homogenate was consistent with a single class of binding site with a Kd value of 71 pM. In vitro autoradiography of thaw-mounted sections of human thalamus revealed a heterogeneous pattern of binding; Bmax values for ventrolateral nucleus, insular cortex and dorsomedial nucleus, and internal capsule were 20, 8, and 3 pmol/cc of tissue, respectively. However, similar Kd values close to 50 pM were calculated for all regions. These studies support the suitability of [18F]NFEP as a radioligand for PET studies of nAcChR in the living human brain.

Animals↗
PubMed1998

Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate.

OBJECTIVE: The therapeutic effects of methylphenidate in the treatment of attention deficit disorder have been attributed to its ability to increase the synaptic concentration of dopamine by blocking the dopamine transporters. However, the levels of dopamine transporter blockade achieved by therapeutic doses of methylphenidate are not known. This study measured, for the first time, dopamine transporter occupancy by orally administered methylphenidate in the human brain and its rate of uptake in the brain. METHOD: Positron emission tomography (PET) and [11C]cocaine were used to estimate dopamine transporter occupancies after different doses of oral methylphenidate in seven normal subjects (mean age=24 years, SD=7). In addition, the pharmacokinetics of oral methylphenidate were measured in the baboon brain through use of PET and [11C]methylphenidate administered through an orogastric tube. RESULTS: At 120 minutes after administration, oral methylphenidate produced a dose-dependent blockade of dopamine transporter; means=12% (SD= 4%) for 5 mg, 40% (SD=12%) for 10 mg, 54% (SD=5%) for 20 mg, 72% (SD=3%) for 40 mg, and 74% (SD=2%) for 60 mg. The estimated dose of oral methylphenidate required to block 50% of the dopamine transporter corresponded to 0.25 mg/kg. Oral methylphenidate did not reach peak concentration in brain until 60 minutes after its administration. CONCLUSIONS: Oral methylphenidate is very effective in blocking dopamine transporters, and at the weight-adjusted doses used therapeutically (0.3 to 0.6 mg/kg), it is likely to occupy more than 50% of the dopamine transporters. The time to reach peak brain uptake for oral methylphenidate in brain corresponds well with the reported time course to reach peak behavioral effects.

Administration, Oral↗
PubMed1998

Enhanced sensitivity to benzodiazepines in active cocaine-abusing subjects: a PET study.

OBJECTIVE: Because cocaine enhances dopamine brain activity and dopamine signals are transferred through gamma-aminobutyric acid pathways, the authors hypothesized GABA-ergic disruption in cocaine-abusing subjects. This study tests this hypothesis. METHOD: GABA brain function was assessed indirectly by measuring the brain metabolic responses to lorazepam, a drug that facilitates GABA neurotransmission. Thirteen current cocaine-abusing subjects and 14 comparison subjects were scanned twice with positron emission tomography and [18F]fluorodeoxyglucose; the first scan was obtained after placebo administration and the second after lorazepam administration (30 micrograms/kg). RESULTS: Despite significantly higher plasma lorazepam concentrations in comparison subjects than in cocaine-abusing subjects, lorazepam-induced decrements in whole brain metabolism were significantly greater in cocaine-abusing (mean = 21%, SD = 13%) than in comparison (mean = 13%, SD = 7%) subjects. These differences were largest in striatum, thalamus, and parietal cortex. Lorazepam-induced sleepiness in cocaine-abusing subjects was intense and was significantly greater than in comparison subjects, and it was correlated with lorazepam-induced changes in thalamic metabolism. Whereas regional metabolic measures during placebo administration were significantly higher in cocaine-abusing subjects than in comparison subjects, the measures during lorazepam administration were equivalent for both groups. CONCLUSIONS: The enhanced sensitivity to lorazepam in cocaine-abusing subjects suggests disruption of GABA pathways that may reflect, in part, cocaine withdrawal. The intense sleepiness induced by lorazepam in some of the abusers, despite their significantly lower plasma concentrations, should alert clinicians of the potential toxicity from accentuated responses to sedative hypnotics in active cocaine-abusing subjects.

Adult↗
PubMed1998

Association between decline in brain dopamine activity with age and cognitive and motor impairment in healthy individuals.

OBJECTIVE: Although it is documented that brain dopamine activity declines with age, the functional significance of this is not known. This study assessed the relation between measures of brain dopamine activity and indexes of motor and cognitive function in healthy individuals. METHOD: Thirty healthy volunteers aged 24-86 years were studied with positron emission tomography and [11C]raclopride to assess dopamine D2 receptors. All subjects underwent a neuropsychological test battery that included tasks found to be sensitive to dopamine alterations in patients with neurodegenerative disease and control tasks. RESULTS: Transfer of [11C]raclopride from plasma to brain in the striatum and cerebellum was not affected by age. In contrast, D2 receptor availability in the caudate and putamen declined with age. Correlations between D2 receptors and neuropsychological test performance were strongest for the motor task (Finger Tapping Test) and were also significant for most tasks involving frontal brain regions, including measures of abstraction and mental flexibility (Wisconsin Card Sorting Test) and attention and response inhibition (Stroop Color-Word Test, interference score). These relationships remained significant after control for age effects. CONCLUSIONS: Age-related decreases in brain dopamine activity are associated with a decline in motor function and may also contribute to impaired performance on tasks that involve frontal brain regions. Interventions that enhance dopamine activity may improve performance and quality of life for the elderly. The fact that correlations remained significant after age effects were partialed out suggests that dopamine activity may influence motor and cognitive performance irrespective of age.

Adult↗
PubMed1998

Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAO B) inhibition.

We measured the concentration of brain monoamine oxidase B (MAO B; EC 1.4.3.4) in 8 smokers and compared it with that in 8 non-smokers and in 4 former smokers using positron emission tomography (PET) and deuterium substituted [11C]L-deprenyl ([11C]L-deprenyl-D2) as a radiotracer for MAO B. Smokers had significantly lower brain MAO B than non-smokers as measured by the model term lambda k3 which is a function of MAO B activity. Reductions were observed in all brain regions. Low brain MAO B in the cigarette smoker appears to be a pharmacological rather than a genetic effect since former smokers did not differ from non-smokers. Brain MAO B inhibition by cigarette smoke is of relevance in light of the inverse association between smoking and Parkinson's disease and a high prevalence of smoking in psychiatric disorders and in substance abuse. Though nicotine is at the core of the neuropharmacological actions of tobacco smoke, MAO B inhibition may also be an important variable in understanding and treating tobacco smoke addiction.

Adult↗
PubMed1998

PET imaging studies in drug abuse.

UNLABELLED: In spite of the massive public health problem associated with drug abuse, effective treatments remain elusive. This is due in part to a relatively poor understanding of the neurochemical changes which drugs of abuse produce in the human brain and the relationship of these changes to the behavioral and addictive properties of drugs. With the development of modern imaging methods and a variety of labeled drugs and radiotracers, it has now become possible to track many aspects of drug pharmacokinetics and pharmacodynamics directly in the human brain and to relate these parameters to the behavioral and toxic properties of drugs. REVIEW: In this article, we will highlight some examples of the use of Positron Emission Tomography to measure drug pharmacokinetics and pharmacodynamics and their relationship to addiction and to toxicity.

Brain↗