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S J Gatley

Publications and source records attributed to S J Gatley.

At least 19 recordsLinked to original sources
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

Evaluation of the importance of rebinding to receptors in slowing the approach to equilibrium of high-affinity PET and SPECT radiotracers.

The importance of rebinding to receptors in influencing the kinetics of in vivo binding of PET and SPECT radiotracers was evaluated by examining the binding of a high-affinity D1 receptor radiotracer, [3H]SCH 23390, in tissue homogenates, living brain slices, and in vivo. In rat striatal homogenates, [3H]SCH 23390 binding reached equilibrium with a half-time of 6 min. By contrast, in striatal brain slices incubated in [3H] SCH 23390, the radioactivity levels in the slice increased in a linear fashion over the 4-h incubation, with no indication of an approach to equilibrium at the termination of the experiment. In in vivo experiments, [3H]SCH 23390 was given as a slow intravenous infusion to mice, using a paradigm that kept the plasma concentration at a constant level. Under these conditions, striatal [3H] SCH 23390 levels increased in a linear fashion over the 4-h infusion period, similar to what was observed in the brain slices, and as in the slices there was no indication of approach to a steady state. However, when given instead as a single-bolus intravenous dose, the striatal [3H]SCH 23390 levels reached a peak only 15 min after injection. Calculations based on the slice experiments, in which the blood-brain barrier is absent, suggested that the rate-limiting step accounting for the failure of [3H]SCH 23390 levels to reach equilibrium was its hindered diffusion as a result of repeated rebinding to receptors. This phenomenon may also be important in vivo and should be considered as a factor in determining the time-course of binding of radiotracers in PET and SPECT experiments where either the receptor density or radiotracer affinity is high.

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

Imaging the brain marijuana receptor: development of a radioligand that binds to cannabinoid CB1 receptors in vivo.

The major active ingredient of marijuana, (-)-delta9-tetrahydrocannabinol, exerts its psychoactive effects via binding to cannabinoid CB1 receptors, which are widely distributed in the brain. Radionuclide imaging of CB1 receptors in living human subjects would help explore the presently unknown physiological roles of this receptor system, as well as the neurochemical consequences of marijuana dependence. Currently available cannabinoid receptor radioligands are exceedingly lipophilic and unsuitable for in vivo use. We report the development of a novel radioligand, [123I]AM281[N-(morpholin-4-yl)-5-(4-[123I]iodophenyl)-1-(2,4 -dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], that is structurally related to the CB1-selective antagonist SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide]. Baboon single photon emission computed tomography studies, mouse brain dissection studies, and ex vivo autoradiography in rat brain demonstrated rapid passage of [123I]AM281 into the brain after intravenous injection, appropriate regional brain specificity of binding, and reduction of binding after treatment with SR141716A. AM281 has an affinity in the low nanomolar range for cerebellar binding sites labeled with [3H]SR141716A in vitro, and binding of [123I]AM281 is inhibited by several structurally distinct cannabinoid receptor ligands. We conclude that [123I]AM281 has appropriate properties for in vivo studies of cannabinoid CB1 receptors and is suitable for imaging these receptors 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↗
PubMed1997

Effect of the cannabinoid receptor SPECT agent, AM 281, on hippocampal acetylcholine release from rat brain slices.

The SPECT ligand AM 281, a less lipophilic analog of the cannabinoid receptor antagonist SR 141716A, robustly potentiated electrically-evoked release of acetylcholine from superfused hippocampal slices and prevented the inhibition of acetylcholine release by the cannabimimetic drug WIN 55212-2. These results, similar to earlier observations with SR 141716A, indicate that AM 281 is either a cannabinoid receptor antagonist or inverse agonist. Despite showing lower affinity than SR 141716A in hippocampal membrane binding experiments, AM 281 had slightly greater potency than SR 141716A in the hippocampal slice experiments, perhaps because of reduced drug absorption to slice membranes and to the apparatus.

Acetylcholine↗
PubMed1997

Relationship between subjective effects of cocaine and dopamine transporter occupancy.

Cocaine is believed to work by blocking the dopamine transporter (DAT) and thereby increasing the availability of free dopamine within the brain. Although this concept is central to current cocaine research and to treatment development, a direct relationship between DAT blockade and the subjective effects of cocaine has not been demonstrated in humans. We have used positron emission tomography to determine what level of DAT occupancy is required to produce a subjective 'high' in human volunteers who regularly abuse cocaine. We report here that intravenous cocaine at doses commonly abused by humans (0.3-0.6 mg kg(-1)) blocked between 60 and 77% of DAT sites in these subjects. The magnitude of the self-reported high was correlated with the degree of DAT occupancy, and at least 47% of the transporters had to be blocked for subjects to perceive cocaine's effects. Furthermore, the time course for the high paralleled that of cocaine concentration within the striatum, a brain region implicated in the control of motivation and reward. This is the first demonstration in humans that the doses used by cocaine abusers lead to significant blockade of DAT, and that this blockade is associated with the subjective effects of cocaine. Although these findings provide justification to target the DAT for medication development they suggest that for drugs to be effective in blocking cocaine's effects they would have to be given at doses that achieve almost complete DAT occupancy.

Adult↗
PubMed1997

Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects.

Cocaine blocks the reuptake of dopamine, a neurotransmitter involved in the control of movement, cognition, motivation and reward. This leads to an increase in extracellular dopamine; the reinforcing effect of cocaine is associated with elevated dopamine levels in the nucleus accumbens. But addiction to cocaine involves other effects, such as craving, loss of control and compulsive drug intake; the role of the dopamine system in these effects is less well-understood. We therefore used positron emission tomography (PET) to compare the responses of cocaine addicts and normal controls to intravenous methylphenidate, a drug that, like cocaine, causes an increase in synaptic dopamine. Addicts showed reduced dopamine release in the striatum, the brain region where the nucleus accumbens is located, and also had a reduced 'high' relative to controls. In contrast, addicts showed an increased response to methylphenidate in the thalamus (a region that conveys sensory input to the cortex). This thalamic response was associated with cocaine craving and was not seen in control subjects. Thus, our findings challenge the notion that addiction involves an enhanced striatal dopamine response to cocaine and/or an enhanced induction of euphoria. Moreover, they suggest a participation of thalamic dopamine pathways in cocaine addiction, a possibility that merits further investigation.

Adult↗
PubMed1997

Examination of the effect of the cannabinoid receptor agonist, CP 55,940, on electrically evoked transmitter release from rat brain slices.

In the present study we examined the effect of the cannabinoid receptor agonist, [[1 a,2-(R)-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyc lohexyl]-phenol; CP 55,940] on [14C]acetylcholine and [3H]norepinephrine release from hippocampal slices and on [14C]acetylcholine release from striatal slices. CP 55,940 potently inhibited electrically evoked [14C]acetylcholine release from hippocampal slices, with an EC50 of 0.02 microM and a maximal inhibition of 61% at 1 microM. The inhibition of acetylcholine release by CP 55,940 was partially antagonized (60%) by the cannabinoid receptor antagonist, [[N-piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide hydrochloride; SR 141716A]. Alone, SR 141716A significantly enhanced stimulated [14C]acetylcholine release. In contrast to the effects of CP 55,940 on [14C]acetylcholine release, electrically evoked [3H]norepinephrine release from hippocampal slices and [14C]acetylcholine release from striatal slices were both unaffected by this compound. Similarly, hippocampal [3H]norepinephrine release and striatal [14C]acetylcholine release were not affected by SR 141716A. In conclusion, the results of this study extend our previous data indicating that cannabinoid receptors modulate acetylcholine release in the hippocampus. The effects of cannabinoid receptor activation on [3H]acetylcholine release in the hippocampus does not appear to extend to [3H]norepinephrine release from this region or to acetylcholine release from the striatum.

Acetylcholine↗
PubMed1997

Model for estimating dopamine transporter occupancy and subsequent increases in synaptic dopamine using positron emission tomography and carbon-11-labeled cocaine.

Although increases in dopamine secondary to the inhibition of the dopamine transporter appear to underlie the reinforcing properties of cocaine, there is presently no model that relates the elevation of synaptic dopamine to the transporter occupancy by cocaine. We propose such a model based on positron emission tomographic (PET) measurements of the brain concentration of cocaine and the assumption of rapid equilibrium between free cocaine and cocaine bound to the dopamine transporter. A euphorigenic dose of cocaine (about 40 mg) is predicted to occupy 80-90% of the transporters, while a perceptible dose (about 5 mg) occupies about 40% of the transporters. If reuptake of dopamine is reduced in proportion to the fraction of transporters occupied by cocaine, our model indicates that synaptic dopamine rises supra-linearly with occupancy, so that 5 and 40 mg doses of cocaine give about 2- and 10-fold increases, respectively. A consequence is that a given dose of cocaine produces a similar degree of elevation of dopamine regardless of the prior level of occupation of the transporters by cocaine. This prediction is supported by recent PET/neuropsychological studies in our laboratory where dopamine transporter occupancy was measured after giving methylphenidate intravenously to volunteers; similarly intense "highs" were reported whether the initial occupancy was zero or 75-85%. It could also explain why attempts to block the psychostimulant-induced "high" by pretreating subjects with drugs that block the dopamine transporter have been unsuccessful, and why the use of methylphenidate to treat cocaine addicts led to increased cocaine consumption.

Animals↗
PubMed1997

Concentration and occupancy of dopamine transporters in cocaine abusers with [11C]cocaine and PET.

The concentration (Bmax) of the dopamine transporter (DAT) and the maximum and effective occupancies by cocaine doses of 0.1 mg/kg or 0.05 mg/kg were measured in the striatum of cocaine abusers (n = 12) by using [11C]cocaine as a radiotracer for the DAT and positron emission tomography (PET). Two methods based on a three-compartment model with one binding site (the nonlinear least squares (NLSQ) and the Farde pseudoequilibrium method) were used to estimate Bmax. Effective occupancies and maximum occupancies were calculated from the distribution volume ratios (DVR) and a three-compartment model, respectively. The NLSQ and Farde methods gave similar values of Bmax (average, 650 +/- 350 pmol/ml and 776 +/- 400 pmol/ml, respectively), but the individual estimates of Bmax were found to be very sensitive to small variations in other model parameters and were not correlated with the parameter Bmax/Kd (r = .07). The average maximum (and effective) occupancies were found to be 67% (50%) and 52% (39%) for the 0.1-mg/kg and the 0.05-mg/kg studies, respectively. The ED50 based on the effective occupancy corresponds to 0.1 mg/kg, which is significantly smaller than the ED50 of 3 mg/kg calculated from studies in which [123]beta-CIT is displaced by cocaine. The effect on the Bmax estimate of two binding sites with different Kd's is also considered by simulation. We conclude (1) that the lack of robustness in the Bmax estimate limits the usefulness of any one subject's Bmax and suggests that the combination parameter Bmax/Kd (or the DVR), which has been used extensively, is a more stable measure of free receptor/transporter concentration. The average Bmax may, however, provide an estimate of the expected concentration in humans. (2) The DVR can be used as a measure of DAT occupancy without applying an explicit model.

Adult↗
PubMed1997

Chiral drugs: comparison of the pharmacokinetics of [11C]d-threo and L-threo-methylphenidate in the human and baboon brain.

Methylphenidate (Ritalin) is the most commonly prescribed psychoactive medication for children in the US where it is used for the treatment of attention deficit hyperactivity disorder. Methylphenidate is marketed as a racemic mixture of the d-threo and l-threo enantiomers. It is believed that the d enantiomer is responsible for the therapeutic effect of methylphenidate. In this study we labeled the individual enantiomers with carbon-11 and compared their binding and pharmacokinetics in the human and baboon brain. Microdialysis studies in the rat were performed to compare their potency in elevating striatal dopamine concentration. Positron emission tomographic (PET) studies with [11C]d-threo-methylphenidate ([11C]d-threo-MP) demonstrated highest regional uptake in basal ganglia. In contrast, [11C]l-threo-methylphenidate ([11C]l-threo-MP) displayed similar uptakes in all brain regions. The ratios of distribution volumes at the steady-state for the basal ganglia to cerebellum (DVBG/DVCB) ranged from 2.2 to 3.3 for [11C]d-threo-MP in baboon and human, and only 1.1 for [11C]l-threo-MP. Pretreatment with unlabeled methylphenidate (0.5 mg/kg) or GBR12909 (1.5 mg/kg) markedly reduced the striatal but not the cerebellar uptake of [11C]d-threo-MP, whereas there was no effect on DVBG/DVCB for [11C]l-threo-MP. In the rat, d-threo-MP increased extracellular dopamine concentration by 650% whereas l-threo-MP did not affect dopamine levels. These results indicate that pharmacological specificity of MP resides entirely in the d-threo isomer and directly show that binding of the l-isomer in human brain is mostly nonspecific.

Aged↗
PubMed1997

Binding of the non-classical cannabinoid CP 55,940, and the diarylpyrazole AM251 to rodent brain cannabinoid receptors.

The binding of [123I]AM251 (a radioiodinated analog of the cannabinoid CB1 receptor antagonist SR141716A) was compared to that of [3H]CP 55,940 in mouse and rat brain preparations. Scatchard analysis of the binding of [123I]AM251 and [3H]CP 55,940 to membranes prepared from mouse cerebellum, striatum and hippocampus yielded similar Bmax values (15-41 pmol/g wet wt tissue). Kd values were lower for [123I]AM251 (0.23-0.62 nM) than for [3H]CP 55,940 (1.3-4 nM). CP 55,940 and SR141716A increased dissociation of [123I]AM251 from binding sites in mouse cerebellar homogenates to a similar extent. The structurally dissimilar cannabinoid receptor ligands THC, methanandamide, WIN 55, 212-2, CP 55,940 and SR141716A were each able to fully compete with binding of both [123I]AM251 and [3H]CP 55,940 in mouse cerebellum. In vitro autoradiography demonstrated that the distribution of binding sites for [123I]AM251 in rat brain was very similar to published distributions of binding sites for [3H]CP 55,940. Together, these observations suggest that AM251 binds to the same site (the cannabinoid CB1 receptor) in rodent brains as CP 55,940. However, the binding site domains which interact with AM251 and CP 55,940 may not be identical, since IC50 values for cannabinoid receptor ligands depended on whether [123I]AM251 or [3H]CP 55,940 was used as radioligand.

Animals↗
PubMed1997

Fluoro-norchloroepibatidine: preclinical assessment of acute toxicity.

18Fluoro-norchloroepibatidine (exo-2-(6-fluoro-3-pyridyl)-7-azabicyclo-[2.2.1]heptane [NFEP]), a labeled derivative of epibatidine, has shown promise for imaging brain nicotinic acetylcholine receptors with PET. We determined the dose-dependent effects of NFEP in conscious rats. NFEP (1.5 microg/kg; administered intravenously) resulted in 30% mortality. Neither 0.5 microg/kg or 0.25 microg/kg NFEP resulted in any significant changes in cardiorespiratory parameters, but plasma catecholamines increased (2- to 3-fold). Further studies are needed to determine the safety of NFEP that are specifically designed to assess the catecholamine response. Our results suggest that it is not advisable to initiate human PET studies with [18F]-NFEP without further evidence supporting its safety.

Animals↗
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↗