Distribution of nitrogen-13 from labeled nitrate (13No3-) in humans and rats.

The body distribution of gavaged or intravenously administered nitrate labeled with nitrogen-13 was studied in humans and rats with the following results: (i) the labeled compound is not quickly absorbed from the stomach; (ii) the concentration of the label increases inside the lower intestinal tract (cercum and large intestine) when ingested or intravenously injected; and (iii) humans and rats have the capacity to store a portion of the label in their bodies. These observation indicate that depletion of body stores, the passage of nitrate down the gut, or the secretion of nitrate into the intestinal lumen may be a better explanation of the urinary, ileal, and fecal concentrations of nitrate and nitrite recently measured in humans that a bacterial nitrification reaction in the intestines, as suggested by Tannenbbaum et al.

Evaluation of nitrate synthesis by intestinal microorganisms in vivo.

The nitrate balance of germfree and conventional rats was assessed to determine whether the intestinal flora produces nitrate in vivo. The results indicate that there can be excess nitrate in the urine of germfree as well as conventional rats. This nitrate is apparently of host origin, and the presence of intestinal flora decreases the output of nitrate in urine.

Origin of excess urinary nitrate in the rat.

The ability of intestinal microorganisms to N-oxidize nitrogenous compounds to nitrite or nitrate was evaluated both in vivo and in vitro. Nitrate balance studies with germ-free and conventional rats indicated that the host and not the microbial flora is responsible for excess urinary nitrate. In vitro studies showed that most intestinal microorganisms are not able to N-oxidize nitrogenous compounds to nitrite. Although the metabolic pathway for endogenous nitrate formation remains unknown, the capacity of the rats to N-oxidize acetohydroxamate and hydroxylamine to nitrate indicates that such compounds could be intermediates in nitrate synthesis.

Bromine-80m radiotoxicity and the potential for estrogen receptor-directed therapy with auger electrons.

While theoretically feasible, estrogen receptor (ER)-directed radiotherapy of hormone-dependent cancers has not been realized because no ER-seeking ligand with an appropriate radiotoxic potential has been identified. Since an appropriate nuclide is a key component we studied the 4.4-h half-life, Auger electron-emitting nuclide bromine-80m. When incorporated into DNA this nuclide was radiotoxic to cells in culture and caused substantial chromosomal damage, while similar concentrations of bromine-80m as bromide or bromoantipyrine were without effect. The mean lethal dose for bromine-80m was 45 atoms per nucleus which is consistent with use in receptor-positive cancers with limited numbers of ER.

Loss of dopamine transporters in methamphetamine abusers recovers with protracted abstinence.

Methamphetamine is a popular drug of abuse that is neurotoxic to dopamine (DA) terminals when administered to laboratory animals. Studies in methamphetamine abusers have also documented significant loss of DA transporters (used as markers of the DA terminal) that are associated with slower motor function and decreased memory. The extent to which the loss of DA transporters predisposes methamphetamine abusers to neurodegenerative disorders such as Parkinsonism is unclear and may depend in part on the degree of recovery. Here we assessed the effects of protracted abstinence on the loss of DA transporters in striatum, in methamphetamine abusers using positron emission tomography and [(11)C]d-threo-methylphenidate (DA transporter radioligand). Brain DA transporters in five methamphetamine abusers evaluated during short abstinence (<6 months) and then retested during protracted abstinence (12-17 months) showed significant increases with protracted abstinence (caudate, +19%; putamen, +16%). Although performance in some of the tests for which we observed an association with DA transporters showed some improvement, this effect was not significant. The DA transporter increases with abstinence could indicate that methamphetamine-induced DA transporter loss reflects temporary adaptive changes (i.e., downregulation), that the loss reflects DA terminal damage but that terminals can recover, or that remaining viable terminals increase synaptic arborization. Because neuropsychological tests did not improve to the same extent, this suggests that the increase of the DA transporters was not sufficient for complete function recovery. These findings have treatment implications because they suggest that protracted abstinence may reverse some of methamphetamine-induced alterations in brain DA terminals.

Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain.

Methylphenidate (Ritalin) is the most commonly prescribed psychoactive drug in children for the treatment of attention deficit hyperactivity disorder (ADHD), yet the mechanisms responsible for its therapeutic effects are poorly understood. Whereas methylphenidate blocks the dopamine transporter (main mechanism for removal of extracellular dopamine), it is unclear whether at doses used therapeutically it significantly changes extracellular dopamine (DA) concentration. Here we used positron emission tomography and [(11)C]raclopride (D2 receptor radioligand that competes with endogenous DA for binding to the receptor) to evaluate whether oral methylphenidate changes extracellular DA in the human brain in 11 healthy controls. We showed that oral methylphenidate (average dose 0.8 +/- 0.11 mg/kg) significantly increased extracellular DA in brain, as evidenced by a significant reduction in B(max)/K(d) (measure of D2 receptor availability) in striatum (20 +/- 12%; p < 0.0005). These results provide direct evidence that oral methylphenidate at doses within the therapeutic range significantly increases extracellular DA in human brain. This result coupled with recent findings of increased dopamine transporters in ADHD patients (which is expected to result in reductions in extracellular DA) provides a mechanistic framework for the therapeutic efficacy of methylphenidate. The increase in DA caused by the blockade of dopamine transporters by methylphenidate predominantly reflects an amplification of spontaneously released DA, which in turn is responsive to environmental stimulation. Because DA decreases background firing rates and increases signal-to-noise in target neurons, we postulate that the amplification of weak DA signals in subjects with ADHD by methylphenidate would enhance task-specific signaling, improving attention and decreasing distractibility. Alternatively methylphenidate-induced increases in DA, a neurotransmitter involved with motivation and reward, could enhance the salience of the task facilitating the "interest that it elicits" and thus improving performance.

Imaging of the brain cannabinoid system.

This review covers two major strategies for imaging of the brain cannabinoid system: autoradiography and in vivo neuroimaging. Cannabinoid receptors can be imaged directly with autoradiography in brain slices using radiolabeled cannabinoid receptor ligands. In addition, the effects of pharmacologic doses of unlabeled cannabinoid drugs can be autoradiographically imaged using indicators of blood flow or indicators of metabolism such as glucose analogs. Although cannabinoid imaging is a relatively new topic of research compared to imaging of other drugs of abuse, autoradiographic strategies have produced high-quality information about the distribution of brain cannabinoid receptors and the effects of cannabinoid drugs on brain metabolism. In vivo neuroimaging, in contrast to autoradiography, utilizes noninvasive techniques such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) to image both the binding and the effects of drugs within living brain. These techniques are well developed; however, in vivo imaging of cannabinoid systems is in a very preliminary state. Early results have been promising yet hard to generalize. Definitive answers to some of the most important questions about cannabinoid drugs and their effects await development of suitable in vivo neuroimaging ligands for cannabinoid systems.

Imaging brain cholinergic activity with positron emission tomography: its role in the evaluation of cholinergic treatments in Alzheimer's dementia.

One of the strategies in the treatment of Alzheimer's disease is the use of drugs that enhance cholinergic brain function, since it is believed that cholinergic dysfunction is one of the factors that contributes to cognitive deterioration. Positron emission tomography is a medical imaging method that can be used to measure the concentration, kinetics, and distribution of cholinergic-enhancing drugs directly in the human brain and assess the effects of the drugs at markers of cholinergic cell viability (vesicular transporters, acetylcholinesterase), at muscarininc and nicotinic receptors, at extracellular acetylcholine, at markers of brain function (glucose metabolism and blood flow), and on amyloid plaque burden in vivo in the brains of patients with Alzheimer's disease. In addition, these measures can be applied to assess the drugs' pharmacokinetic and pharmacodynamic properties in the human brain. Since the studies are done in living human subjects, positron emission tomography can evaluate the relationship between the drugs' biological, behavioral, and cognitive effects; monitor changes in brain function in response to chronic treatment; and determine if pharmacologic interventions are neuroprotective. Moreover, because positron emission tomography has the potential to identify Alzheimer's disease during early disease, it can be used to establish whether early interventions can prevent or delay further development.

Effects of blood flow on [11C]raclopride binding in the brain: model simulations and kinetic analysis of PET data.

To assess the stability of different measures of receptor occupancy from [11C]raclopride (a D2 antagonist) studies with positron emission tomography, we analyze data from five test/retest studies in normal volunteers in terms of individual model parameters from a three-compartment model, the distribution volume (DV) and the ratio of DVs from a receptor-containing region of interest to a non-receptor-containing region. Large variations were found in the individual model parameters, limiting their usefulness as an indicator of change in receptor systems. The DV ratio showed the smallest variation. Individual differences were reflected in the greater intersubject variation in DV than intrasubject variation. The potential effects of blood flow on these measurements were addressed both experimentally and by simulation studies using three models that explicitly incorporate blood flow into a compartmental model that also includes receptor-ligand binding. None of the models showed any variation in the DV with changes in blood flow as long as flow was held constant during the simulation. Experimentally, blood flow was significantly reduced by hyperventilation in a human subject. The DV was found to be reduced relative to baseline in the hyperventilation study, but the DV ratio remained unchanged. The effect of elevated and reduced flow was also tested in two baboon experiments in which PCO2 was varied. Some variability in the DV ratio was observed but was not correlated with changes in blood flow. This raises the possibility that other factors indirectly related to changes in blood flow (or PCO2) may cause changes in DV, and these effects need to be considered when evaluating experimental results.

Alternative approach to single-scan estimation of cerebral glucose metabolic rate using glucose analogs, with particular application to ischemia.

In the glucose analog method for determining local glucose utilization rates, time courses of tissue and plasma radioactivity are measured and then analyzed in terms of first-order exchange of label between tissue compartments. The rate of glucose utilization is assumed to have a fixed, linear relationship to the analog phosphorylation rate calculated from the fitted rate constants. Accurate estimation of the rate constants requires many hours of dynamic data acquisition. Therefore, techniques assuming a linear relationship between analog phosphorylation rate and total tissue concentration of label were developed to predict glucose utilization rates from a single scan. Previously reported linearizations differ in their sensitivity to differences between current and average kinetic rate constants, and thus in their accuracy. We have developed a method that is insensitive to the presumed value of the blood flow-capillary wall transport parameter k1. This new single-scan approach has been validated by comparison of the single-scan metabolic rate values with the values calculated from the dynamic measurements.

Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects.

A graphical method of analysis applicable to ligands that bind reversibly to receptors or enzymes requiring the simultaneous measurement of plasma and tissue radioactivities for multiple times after the injection of a radiolabeled tracer is presented. It is shown that there is a time t after which a plot of integral of t0ROI(t')dt'/ROI(t) versus integral of t0Cp(t')dt'/ROI(t) (where ROI and Cp are functions of time describing the variation of tissue radioactivity and plasma radioactivity, respectively) is linear with a slope that corresponds to the steady-state space of the ligand plus the plasma volume,.Vp. For a two-compartment model, the slope is given by lambda + Vp, where lambda is the partition coefficient and the intercept is -1/[kappa 2(1 + Vp/lambda)]. For a three-compartment model, the slope is lambda(1 + Bmax/Kd) + Vp and the intercept is -[1 + Bmax/Kd)/k2 + [koff(1 + Kd/Bmax)]-1) [1 + Vp/lambda(1 + Bmax/Kd)]-1 (where Bmax represents the concentration of ligand binding sites and Kd the equilibrium dissociation constant of the ligand-binding site complex, koff (k4) the ligand-binding site dissociation constant, and k2 is the transfer constant from tissue to plasma). This graphical method provides the ratio Bmax/Kd from the slope for comparison with in vitro measures of the same parameter. It also provides an easy, rapid method for comparison of the reproducibility of repeated measures in a single subject, for longitudinal or drug intervention protocols, or for comparing experimental results between subjects. Although the linearity of this plot holds when ROI/Cp is constant, it can be shown that, for many systems, linearity is effectively reached some time before this. This analysis has been applied to data from [N-methyl-11C]-(-)-cocaine ([11C]cocaine) studies in normal human volunteers and the results are compared to the standard nonlinear least-squares analysis. The calculated value of Bmax/Kd for the high-affinity binding site for cocaine is 0.62 +/- 0.20, in agreement with literature values.

Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels.

OBJECTIVE: This study assessed whether brain dopamine D2 receptor levels, which show significant intersubject variability, predict reinforcing responses to psychostimulants in humans. METHOD: [11C]Raclopride and positron emission tomography were used to measure D2 receptor levels in 23 healthy men (mean age = 34 years, SD = 7) who had no drug abuse histories in order to assess if there were differences between the subjects who liked and those who disliked the effects of intravenous methylphenidate (0.5 mg/kg). RESULTS: Subjects who liked the effects of methylphenidate had significantly lower D2 receptor levels (mean = 2.72 Bmax/Kd, SD = 0.3) than subjects who disliked its effects (mean = 3.16, SD = 0.3). Moreover, the higher the D2 levels found, the more intense were methylphenidate's unpleasant effects. CONCLUSIONS: These results provide preliminary evidence that D2 receptor levels predict response to psychostimulants in humans and that low D2 receptors may contribute to psychostimulant abuse by favoring pleasant response.

Association of methylphenidate-induced craving with changes in right striato-orbitofrontal metabolism in cocaine abusers: implications in addiction.

OBJECTIVE: The authors have shown that decreases in dopamine D2 receptors in cocaine abusers were associated with decreased metabolism in the cingulate and prefrontal and orbitofrontal cortices. To assess whether increasing dopamine would reverse these metabolic decrements, they measured the effects of methylphenidate, a drug that increases dopamine, on brain glucose metabolism in 20 cocaine abusers. METHOD: The subjects underwent two [18F]fluorodeoxyglucose positron emission tomography scans, one after two sequential placebo injections and one after two intravenous doses of methylphenidate. D2 receptors were measured with [11C]raclopride to evaluate their relation to methylphenidate-induced metabolic changes. RESULTS: Methylphenidate induced variable changes in brain metabolism: subjects with the higher D2 measures tended to increase metabolism, whereas those with the lower D2 measures tended to decrease metabolism. Methylphenidate's effects were significant for increases in metabolism in the superior cingulate, right thalamus, and cerebellum. Methylphenidate-induced changes in the right orbitofrontal cortex and right striatum were associated with craving, and those in the prefrontal cortex were associated with mood. CONCLUSIONS: Although methylphenidate increased metabolism in the superior cingulate, it only increased metabolism in orbitofrontal or prefrontal cortices in the subjects in whom it enhanced craving and mood, respectively. This indicates that dopamine enhancement is not sufficient per se to increase metabolism in these frontal regions. Activation of the right orbitofrontal cortex and right striatum (brain regions found to be abnormal in compulsive disorders) in the subjects reporting craving may be one of the mechanisms underlying compulsive drug administration in addicted persons. The predominant correlation of craving with right but not left brain regions suggests laterality of reinforcing and/or conditioned responses.

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.

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.

Higher cortical and lower subcortical metabolism in detoxified methamphetamine abusers.

OBJECTIVE: Methamphetamine has raised concerns because it may be neurotoxic to the human brain. Although prior work has focused primarily on the effects of methamphetamine on dopamine cells, there is evidence that other neuronal types are affected. The authors measured regional brain glucose metabolism, which serves as a marker of brain function, to assess if there is evidence of functional changes in methamphetamine abusers in regions other than those innervated by dopamine cells. METHOD: Fifteen detoxified methamphetamine abusers and 21 comparison subjects underwent positron emission tomography following administration of [(18)F]fluorodeoxyglucose. RESULTS: Whole brain metabolism in the methamphetamine abusers was 14% higher than that of comparison subjects; the differences were most accentuated in the parietal cortex (20%). After normalization for whole brain metabolism, methamphetamine abusers exhibited significantly lower metabolism in the thalamus (17% difference) and striatum (where the differences were larger for the caudate [12%] than for the putamen [6%]). Statistical parametric mapping analyses corroborated these findings, revealing higher metabolism in the parietal cortex and lower metabolism in the thalamus and striatum of methamphetamine abusers. CONCLUSIONS: The fact that the parietal cortex is a region devoid of any significant dopaminergic innervation suggests that the higher metabolism seen in this region in the methamphetamine abusers is the result of methamphetamine effects in circuits other than those modulated by dopamine. In addition, the lower metabolism in the striatum and thalamus (major outputs of dopamine signals into the cortex) is likely to reflect the functional consequence of methamphetamine in dopaminergic circuits. These results provide evidence that, in humans, methamphetamine abuse results in changes in function of dopamine- and nondopamine-innervated brain regions.

Association between age-related decline in brain dopamine activity and impairment in frontal and cingulate metabolism.

OBJECTIVE: Despite the well-documented loss of brain dopamine activity with age, little is known about its functional consequences in healthy individuals. This study investigates the relationship between measures of brain dopamine D(2) receptors (molecules that transmit dopamine signals) and regional brain glucose metabolism (a marker of brain function) in healthy individuals. METHOD: Thirty-seven healthy volunteers aged 24-86 years underwent positron emission tomography scans after injection of [(11)C]raclopride to assess dopamine D(2) receptors and [(18)]fluorodeoxyglucose to assess regional brain glucose metabolism. Two methods used to assess the correlations between metabolism and dopamine D(2) receptors-pixel-by-pixel correlations and correlations in preselected regions of interest-were then compared. RESULTS: D(2) receptors as well as frontal and cingulate metabolism declined with age. Regardless of the method used, significant correlations between metabolism and D(2) receptors were found in the frontal cortex (Brodmann's areas 6, 7, 8, 9, 10, 11, 44, 45, 47), anterior cingulate gyrus (areas 24, 32), temporal cortex (area 21), and caudate. These correlations remained significant after removing age effects (partial correlation). CONCLUSIONS: These results provide the first link between age-related declines in brain dopamine activity and frontal and cingulate metabolism, which supports the need to investigate the therapeutic utility of interventions that enhance dopamine function in the elderly. The fact that correlations remained significant after removing age effects suggests that dopamine may influence frontal, cingulate, and temporal metabolism regardless of age.

Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers.

OBJECTIVE: Methamphetamine is a popular and highly addictive drug of abuse that has raised concerns because it has been shown in laboratory animals to be neurotoxic to dopamine terminals. The authors evaluated if similar changes occur in humans and assessed if they were functionally significant. METHOD: Positron emission tomography scans following administration of [(11)C]d-threo-methylphenidate (a dopamine transporter ligand) measured dopamine transporter levels (a marker of dopamine cell terminals) in the brains of 15 detoxified methamphetamine abusers and 18 comparison subjects. Neuropsychological tests were also performed to assess motor and cognitive function. RESULTS: Methamphetamine abusers showed significant dopamine transporter reduction in the striatum (mean differences of 27.8% in the caudate and 21.1% in the putamen) relative to the comparison subjects; this reduction was evident even in abusers who had been detoxified for at least 11 months. Dopamine transporter reduction was associated with motor slowing and memory impairment. CONCLUSIONS: These results provide evidence that methamphetamine at dose levels taken by human abusers of the drug leads to dopamine transporter reduction that is associated with motor and cognitive impairment. These results emphasize the urgency of alerting clinicians and the public of the long-term changes that methamphetamine can induce in the human brain.

Determination of regional cerebral blood flow in patients with cerebral infarction. Use of fluoromethane labeled with fluorine 18 and positron emission tomography.

Regional cerebral blood flow (rCBF) was determined using the tissue kinetic of fluoromethane labeled with fluorine 18 and positron emission tomography (PET) in 13 normal subjects and 21 patients with cerebrovascular diseases. The mean brain rCBF was 42.9 +/- 4.3 mL/100 g/min during the resting state. The highest rCBF (60 +/- 8 mL/100 g/min) was noted in the mesial occipital region corresponding to cortical area 17. All 17 cases of cerebral ischemic infarcts had depressed rCBF in the hemisphere ipsilateral to the infarct. Every area of decreased density shown in the conventional computed tomograms (CT) was detected on the PET as an area of decreased rCBF (mean rCBF of infarcted area, 14.3 +/- 6 mL/100 g/min). The PET images showed a wider area of depressed rCBF than the region of the anatomic infarct. Five types of remote effects were noted in areas without structural damage: (1) decreased flow in the thalamus and caudate ipsilateral to the infarct; (2) decreased flow in the hemisphere contralateral to the cerebral infarct; (3) decreased flow in the cerebellar hemisphere contralateral to the cerebral infarct; (4) decreased flow in the visual cortex distal to the optic radiation lesion; and (5) decreased flow in the frontal cortex ipsilateral to the infarct. The effects in the contralateral hemisphere and the cerebellum were present only in the acute postictal phase. In four cases of transient ischemic attacks, rCBF was normal. It is concluded that this technique of measuring rCBF is a reliable method of identifying cerebral ischemia and that the determination of the extent of impaired rCBF provides a more accurate assessment of the region of brain dysfunction than CTs.

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.