Dopamine release in ventral striatum of pathological gamblers losing money.

OBJECTIVE: To investigate dopaminergic neurotransmission in relation to monetary reward and punishment in pathological gambling. Pathological gamblers (PG) often continue gambling despite losses, known as 'chasing one's losses'. We therefore hypothesized that losing money would be associated with increased dopamine release in the ventral striatum of PG compared with healthy controls (HC). METHOD: We used Positron Emission Tomography (PET) with [(11)C]raclopride to measure dopamine release in the ventral striatum of 16 PG and 15 HC playing the Iowa Gambling Task (IGT). RESULTS: PG who lost money had significantly increased dopamine release in the left ventral striatum compared with HC. PG and HC who won money did not differ in dopamine release. CONCLUSION: Our findings suggest a dopaminergic basis of monetary losses in pathological gambling, which might explain loss-chasing behavior. The findings may have implications for the understanding of dopamine dysfunctions and impaired decision-making in pathological gambling and substance-related addictions.

Neuromodulation in a minipig MPTP model of Parkinson disease.

Large animal neuroscience enables the use of conventional clinical brain imagers and the direct use and testing of surgical procedures and equipment from the human clinic. The greater complexity of the large animal brain additionally enables a more direct translation to human brain function in health and disease. Economical, ethical, scientific and practical issues may on the other hand hamper large animal neuroscience. Large animal neuroscience should therefore either be performed in order to examine large animal species dependent problems or to complement promising small animal basic studies by constituting an intermediate research system, bridging small animal CNS research to the human CNS. We have, accordingly, during the last ten years used the Gottingen minipig to examine neuromodulatory treatment modalities such as stem cell transplantation and deep brain stimulation directed towards Parkinson disease. This has been accomplished by the development of a MPTP-based large animal model of Parkinson disease in the Gottingen minipig and the development of stereotaxic and surgical approaches needed to manipulate the Gottingen minipig CNS. The instituted changes in the CNS can be evaluated in the live animal by brain imaging (PET and MR), cystometry, gait analysis, neurological evaluation and by post mortem examination based on histology and stereological analysis.

A reversible tracer analysis approach to the study of effective dopamine turnover.

Changes in dopamine turnover resulting from disease states such as Parkinson's disease may be reflected in corresponding changes in the kinetics of the positron emission tomographic tracer [(18)F]fluorodopa. The authors had previously refined the conventional irreversible-tracer graphical approach to determine both the uptake rate constant K(i) and the rate constant kloss that describes the slow loss of the trapped kinetic component. Because these parameters change in the opposite sense with disease, their ratios may be more powerfully discriminating than either one alone. The ratio k(loss)/K(i) is indicative of effective dopamine turnover. Its inverse, K(i)/k(loss), can be interpreted as the effective distribution volume (EDV) of the specific uptake compartment referred to the fluorodopa concentration in plasma. Here the authors present a new approach to the estimation of EDV based on reversible-tracer graphical methods. When implemented with a plasma input function, the method evaluates EDV directly. When implemented with a tissue input function, the outcome is proportional to the ratio of the distribution volumes of the specific uptake and precursor compartments. Comparison of the new and previous approaches strongly validates this alternative approach to the study of effective dopamine turnover.

Distribution and kinetics of 3-O-methyl-6-[18F]fluoro-L-dopa in the rhesus monkey brain.

Most attempts to model accurately [18F]-DOPA imaging of the dopamine system are based on the assumptions that its main peripheral metabolite, 3-O-methyl-6-[18F]fluoro-L-DOPA ([18F]3-OM-DOPA), crosses the blood-brain barrier but is present as a homogenous distribution throughout the brain, in part because it is not converted into [18F]DOPA in significant quantities. These assumptions were based mainly on data in rodents. Little information is available in the primate. To verify the accuracy of the above assumptions, we administered 18F-labeled 3-OM-DOPA to normal rhesus monkeys and animals with lesions of the DA nigrostriatal system. No selective 18F regional accumulation in brain was apparent in normal or lesioned animals. The plasma metabolite analysis revealed that only the negatively charged metabolites (e.g., sulfated conjugates) that do not cross the blood-brain barrier were found in significant quantities in the plasma. A one-compartment, three-parameter model was adequate to describe the kinetics of [18F]3-OM-DOPA. In conclusion, assumptions concerning [18F]3-OM-DOPA's behavior in brain appear acceptable for [18F]DOPA modeling purposes.

Evaluation of dopaminergic presynaptic integrity: 6-[18F]fluoro-L-dopa versus 6-[18F]fluoro-L-m-tyrosine.

The effectiveness of 6-[18F]fluoro-L-m-tyrosine (6FMT) to evaluate dopamine presynaptic integrity was compared to that of 6-[18F]fluoro-L-dopa (6FDOPA) in vivo by positron emission tomography (PET). Six normal and six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys received 6FDOPA and 6FMT PET scans on separate occasions with identical scanning protocols. Four measures, the rate of uptake of tracer into striatum using either the arterial input function (Ki) or the activity in the occipital cortex as the input function (Kc), the rate of loss of striatal radioactivity (k(loss)), and an index of "effective turnover" of dopamine (k(loss)/Ki), were obtained for both tracers during extended PET studies. 6-[18F]Fluoro-L-m-tyrosine was as effective as 6FDOPA in separating normals from MPTP-lesioned subjects on the basis of the uptake rate constants Ki and Kc. However, in contrast to 6FDOPA, it was not possible to differentiate the normal from the lesioned animal using k(loss) or k(loss)/Ki for 6FMT. Thus, FMT appears to be a reasonable, highly specific tracer for studying the activity of aromatic dopa decarboxylase enzyme as an index of presynaptic integrity. However, if one is interested in investigating further the metabolic pathway and obtaining an in vivo estimate of the effective turnover of dopamine (after pharmacologic manipulation, for example), 6FDOPA remains the tracer of choice.

Cerebral glucose metabolism, CSF 5-HIAA levels, and aggressive behavior in rhesus monkeys.

OBJECTIVE: Considerable evidence suggests that low concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in CSF are associated with a history of aggressive behavior in both human and nonhuman primates. The purpose of this investigation was to examine the relationships among CSF 5-HIAA concentration, history of aggressive behavior, and cerebral glucose metabolism in a group of nonhuman primates whose CSF 5-HIAA had been sampled several times over the preceding 2 years and whose social behavior had been observed since birth. METHOD: The subjects were nine adult male rhesus monkeys studied under isoflurane anesthesia. Cerebral glucose utilization was measured by [18F]fluorodeoxyglucose positron emission tomography. Aggressiveness ratings were made by a primatologist who had had frequent contact with the animals over several years. RESULTS: There was a significant negative correlation between ratings of aggressive behavior and CSF 5-HIAA concentrations. There was also a negative correlation between the dose of pentobarbital required to induce anesthesia and level of CSF 5-HIAA. Moreover, there were significant negative correlations between CSF 5-HIAA levels and both whole brain glucose utilization and regional glucose utilization in the orbital-frontal cortex. CONCLUSIONS: These results suggest that both increased aggressiveness and low concentrations of CSF 5-HIAA are associated with higher brain glucose metabolism in rhesus monkeys under standardized anesthesia. Aggressive nonhuman primates with low CSF 5-HIAA concentrations may have "innate" tolerance toward functional gamma-aminobutyric acid A receptor agonists such as pentobarbital, isoflurane, and possibly alcohol.

MRI and PET studies of manganese-intoxicated monkeys.

Using MRI and PET, we investigated the consequences of manganese intoxication in a primate model of parkinsonism and dystonia. Three rhesus monkeys were injected intravenously with doses of 10 to 14 mg/kg of MnCl2 on seven occasions, each a week apart. Two animals became hypoactive with abnormal extended posturing in the hind limbs. These motor disturbances did not improve with administration of levodopa. In all three monkeys, T1-weighted MRI demonstrated high signal intensities in the regions of the striatum, globus pallidus, and substantia nigra. No significant changes were found on [18F]6-fluoro-L-dopa, [11C]raclopride, or [18F]fluorodeoxyglucose PET. These results are consistent with the pathologic findings, which were primarily confined to the globus pallidus, and indicate that manganese intoxication is associated with preservation of the nigrostriatal dopaminergic pathway, despite clinical evidence of parkinsonian deficits. Chronic manganese intoxication may cause parkinsonism by damaging output pathways downstream to the nigrostriatal dopaminergic pathway. This is consistent with the demonstrated lack of therapeutic response to levodopa.

Effects of catechol-O-methyltransferase inhibition on the rates of uptake and reversibility of 6-fluoro-L-Dopa trapping in MPTP-induced parkinsonism in monkeys.

The uptake rate constant and the loss rate constant that expresses the reversibility of the uptake process of 6-[18F]fluoro-L-Dopa (FDOPA) were measured by positron emission tomography in the striatum of normal rhesus monkeys and in monkeys with unilateral lesions of the dopaminergic nigro-striatal pathway, induced by intracarotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Each animal was studied twice: with and without pretreatment of the catechol-O-methyltransferase (COMT) inhibitor Ro 40-7592, tolcapone. After pretreatment with tolcapone, there was a very significant increase in plasma FDOPA throughout the course of the study, accompanied by a significant decrease in its main metabolite, 3-O-methylfluorodopa. Tolcapone did not induce a significant change in the uptake rate constant in either the normal or the MPTP-treated striatum. However, after tolcapone pretreatment, there was a significant decrease in the loss rate constant in the MPTP-treated striatum (25%) and a smaller, non-significant decrease in the normal striatum (13%). It is concluded that the COMT inhibitor tolcapone exhibits clear peripheral and central activity. As compared to peripheral COMT inhibitors, this central effect may help preserve and stabilize the synaptic levels of DA and, thus, further improve the effects of L-DOPA therapy in parkinsonian patients.

Delayed L-phenylalanine infusion allows for simultaneous kinetic analysis and improved evaluation of specific-to-nonspecific fluorine-18-dopa uptake in brain.

The accumulation of 3-O-methyl-6-[18F]fluoro-L-DOPA (18F-30M-DOPA) in the brain from the circulation is responsible for most of the nonspecific background during 18F-DOPA positron emission tomography scanning. To increase the sensitivity of 18F-DOPA for imaging presynaptic dopamine systems, we took advantage of 18F-30M-DOPA's rapid clearance from the brain (T1/2 approximately 15-20 min). The infusion of the unlabeled amino acid L-phenylalanine, starting 75 min after 18F-DOPA administration, prevents 18F-30M-DOPA entrance into the brain through competition at the large amino acid transport system of the blood brain barrier. This method produces high specific-to-nonspecific contrast images of 18F accumulation beginning 15-30 min after onset of amino acid infusion and better sensitivity to small changes in 18F-DOPA uptake while still allowing for kinetic analysis of the data in the early time points. Kinetic and anatomical data were found to be strongly correlated.

Postinjection L-phenylalanine increases basal ganglia contrast in PET scans of 6-18F-DOPA.

The sensitivity of 18F-DOPA positron emission tomography for imaging presynaptic dopamine systems is limited by the amount of specific-to-nonspecific accumulation of radioactivity in brain. In rhesus monkeys, we have been able to increase this ratio by taking advantage of the lag time between 18F-DOPA injection and the formation of its main metabolite, the amino acid 18F-fluoromethoxydopa, the entrance of which into brain is responsible for most of the brain's nonspecific radioactivity. By infusing an unlabeled amino acid, L-phenylalanine, starting 15 min after 18F-DOPA administration, we preferentially blocked the accumulation of 18F-fluoromethoxydopa by preventing its entrance into brain through competition at the large neutral amino acid transport system of the blood-brain barrier. This method appears as reliable as the original and more sensitive, as demonstrated by the comparison of normal and MPTP-treated animals under both conditions.

Reproducibility studies with 11C-DTBZ, a monoamine vesicular transporter inhibitor in healthy human subjects.

UNLABELLED: The reproducibility of (+/-)-alpha-[11C] dihydrotetrabenazine (DTBZ) measures in PET was studied in 10 healthy human subjects, aged 22-76 y. METHODS: The scan-to-scan variation of several measures used in PET data analysis was determined, including the radioactivity ratio (target-to-reference), plasma-input Logan total distribution volume (DV), plasma-input Logan Bmax/Kd and tissue-input Logan Bmax/Kd values. RESULTS: The radioactivity ratios, plasma-input Bmax/Kd and tissue-input Bmax/Kd all have higher reliability than plasma-input total DV values. In addition, measures using the occipital cortex as the reference region have higher reliability than the same measures using the cerebellum as the reference region. CONCLUSION: Our results show that DTBZ is a reliable PET tracer that provides reproducible in vivo measurement of striatal vesicular monoamine transporter density. In the selection of reference regions for DTBZ PET data analysis, caution must be exercised in circumstances when DTBZ binding in the occipital cortex or the cerebellum may be altered.

Graphical analysis of 6-fluoro-L-dopa trapping: effect of inhibition of catechol-O-methyltransferase.

UNLABELLED: Graphical methods to analyze tracer time-course data allow reliable quantitation of the rate of incorporation of tracer from plasma into a "trapped" kinetic component, even when the details of the kinetic model are unknown. Applications of the method over long time periods often expose the slow reversibility of the trapping process. In the extended graphical method, both trapping rate and a presumed first-order loss rate constant are estimated simultaneously from the time-course data. METHODS: We applied the extended graphical method to 6-fluoro-L-dopa (6-FD), simultaneously estimating the rate of uptake (Ki) and the rate constant for loss from the trapped component (K(loss)) in a single fitting procedure. We applied this approach to study the effects of two catechol-O-methyl-transferase inhibitors on the kinetics of 6-FD in cynomolgus monkeys. RESULTS: Inhibition of peripheral O-methylation with either inhibitor, confirmed by high-performance liquid chromatography analysis of labeled compounds in arterial plasma, had no significant effect on Ki, in agreement with previously reported studies. In contrast, tolcapone, a catechol-O-methyl-transferase inhibitor, having central effects in addition to peripheral effects at the dosage used, decreased K(loss) by 40% from control values (p < 0.002), whereas nitecapone, which has no known central activity, had no significant effect. CONCLUSION: This method provides insight into the neurochemical basis for the kinetic behavior of 6-FD in both health and disease and may be used to define the action of centrally active drugs that influence the metabolism of dopamine.

Reproducibility of the distribution of carbon-11-SCH 23390, a dopamine D1 receptor tracer, in normal subjects.

UNLABELLED: The reproducibility of [11C]SCH 23390 in PET was studied in 10 normal human subjects. METHODS: The scan-to-scan variation of several measures used in PET data analysis, including the radioactivity ratio, plasma-input Logan total distribution volume (DV), plasma-input Logan DV ratio (DVR) and tissue-input Logan Bmax/Kd values, was determined. RESULTS: There were significant correlations among the radioactivity ratio, plasma-input DVR and tissue-input Bmax/Kd. With the cerebellum as the reference region, these three measures also had high reliability (86%-95%), high between-subject s.d. (7.7%-11.3%) and small within-subject s.d. (2.3%-3.6%), indicating that they are comparable and useful measures for the assessment of dopamine D1 receptor binding. CONCLUSION: The radioactivity ratio and the tissue-input Bmax/Kd may be preferred methods for the evaluation of dopamine D1 receptor binding because these two methods do not require arterial blood sampling and metabolite analysis. Our results show that cerebellum is a reliable reference region for SCH 23390. When the Logan plasma-input function method is used in data analysis for SCH 23390, DVRs rather than total DV values should be used because of the poor reliability of the DV values and their lack of correlation with other measures. Carbon-11-SCH 23390 is thus a reliable and reproducible ligand for the study of dopamine D1 receptor binding by PET.

Spatial memory improvement by levodopa in parkinsonian MPTP-treated monkeys.

RATIONALE: The ameliorative effects of levodopa (L-3,4-dihydroxy-phenylalanine) on the motor impairment in Parkinson's disease patients is well established, but characterization of its effects on the associated cognitive deficits is still incomplete. OBJECTIVE: The present study determined the effect of different doses of levodopa on performance on a test of working memory in MPTP-treated rhesus monkeys, an animal model of Parkinson's disease. METHODS: Four MPTP-treated monkeys and their age-matched controls with the same experimental history as the MPTP-treated monkeys were tested on a spatial delay response task. Each daily session consisted of five trials at each of seven randomly presented delays (0, 10, 20, 30, 40, 50 and 60 s). Training was continued for 5 days in each of five different conditions. In the first condition, control and MPTP-treated animals performed the task without levodopa. In the second condition, both groups were tested with a dose of 100 mg of levodopa. In the third and fourth conditions, in which the doses of levodopa were increased to 250 and 500 mg, respectively, only the MPTP-treated animals were tested. In the final condition, the MPTP-treated animals where retested without levodopa. RESULTS: Significant improvement was observed at all doses tested (range 100-500 mg). CONCLUSIONS: Levodopa can ameliorate memory impairments in this parkinsonian model.

Long-term cognitive impairment in MPTP-treated rhesus monkeys.

Following MPTP administration, monkeys manifest cognitive deficits on tasks known to assess the fronto-striatal system; there are, however, no data regarding long-term cognitive effects. In this study, we examined the cognitive abilities of monkeys 10 years after MPTP administration. MPTP-treated monkeys and age-matched controls performed a spatial delayed response task with fixed and random delays. The MPTP-treated monkeys were impaired in both versions of the task. Both groups performed at the same level at very short delays suggesting that the nature of the impairment is related to a spatial memory deficit that is still apparent 10 years after treatment. These results suggest that, like Parkinson's patients, the MPTP-treated primates display spatial deficits.

Activity of nigral dopaminergic neurons after lesion of the neostriatum in rats.

As shown by post-mortem analysis the major neuropathological trait of Huntington's chorea is a degeneration of the intrinsic neurons of the neostriatum (caudate nucleus and putamen). Such a situation can be reproduced by a destruction of the neostriatum by kainic acid. When injected into the caudate nucleus this excitatory amino acid destroys the intrinsic neurons of the neostriatum and spares fairly well the passing fibers. In the present work, we have chosen to examine the influence of neostriatal destruction on the activity of identified dopaminergic cells in the pars compacta of the substantia nigra. As a key element in the nigro-neostriato-nigral loop, this structure is a relevant site for observing the functional effects of neostriatal lesion. Our research hypothesis was based on the generally accepted view that the suppression of the important neostriato-nigral pathway and in particular the inhibitory GABAergic contingent, could generate a hyperactivity of nigral dopaminergic cells. One may therefore consider that the dopaminergic hyperactivity produces abnormal messages which can influence via several pathways the motoneurons, and which participates in the genesis of the hyperkinetic movements characteristic of chorea. After destruction of the neostriatum, we have shown that the pattern of discharge of most identified nigral dopaminergic neurons becomes greatly disorganized. This drastic change in the pattern of activity cannot be interpreted as the simple 'lift of a brake' on these cells by the suppression of the inhibitory GABAergic striato-nigral tract.

MPTP primate model of Parkinson's disease: a mechanographic and electromyographic study.

Movement parameters and electromyographic (EMG) studies were carried out in two macaque monkeys performing a rapid arm movement before and after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Hypokinesia and rigidity were seen after repeated doses. Disturbances in both movements and EMG activity were similar to those reported in Parkinsonian patients.

Opiate receptor avidity is increased in rhesus monkeys following unilateral optic tract lesion combined with transections of corpus callosum and hippocampal and anterior commissures.

Opiate receptor avidity (B(max)'/K(D)) was measured in four rhesus monkeys following unilateral lesioning of the optic tract combined with transection of the corpus callosum and the hippocampal and anterior commissures depriving one hemisphere of visual input (Tract and Split), two animals with transection of commissures only (Split), and nine healthy monkeys with positron emission tomography (PET) and 6-deoxy-6-beta-[(18)F]fluoronaltrexone (cyclofoxy, CF), a mu- and kappa-opiate receptor antagonist. Opiate receptor avidity was found to be significantly higher in the Tract and Split animals, only, bilaterally, throughout the lateral cortex and in the cingulate and posterior putamen (41-117%). Ipsilateral changes were consistently greater than those contralateral, but this asymmetry was of statistical significance only in the parietal and occipital cortices. Cyclofoxy avidity was decreased in the medial cortex of both the Tract and Split and Split animals ( approximately 25%). The results suggest that opiate pathways undergo extensive alteration in response to changes in brain functional activities brought about through hemispheric visual deprivation.

Opiate receptor avidity is reduced in non-motor impaired MPTP-lesioned rhesus monkeys.

Opiate receptor avidity, roughly equivalent to the ratio of unoccupied receptor density to the receptor dissociation constant (B'max/KD), was measured in four MPTP (1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine)-lesioned rhesus monkeys and nine normal controls with positron emission tomography (PET) and 6-deoxy-6-beta-[18F]fluoronaltrexone (cyclofoxy, CF), a mu- and kappa-opiate receptor antagonist. Although the MPTP-lesioned monkeys were dopamine deficient as measured with [18F]-L-fluorodopa ([18F]-DOPA) and PET [Doudet et al., 6-[18F]-L-DOPA imaging of the dopamine neostriatal system in normal and clinically normal-MPTP-treated rhesus monkeys, Exp. Brain Res. 78 (1989) 69-80], they had clinically recovered from the acute motor effects of MPTP exposure. Opiate receptor avidity was found to be reduced by 30-35% in the opiate-receptor rich areas of caudate, anterior putamen, thalamus, and amygdala of the MPTP-lesioned animals. The results suggest that opiate pathways make a significant contribution to the adjustment of cortico-striatal-thalamic pathway activity and thereby to behavior in rhesus monkeys following dopamine loss.

Effects of monoamine oxidase and catechol-O-methyltransferase inhibition on dopamine turnover: a PET study with 6-[18F]L-DOPA.

The consequences of monoamine oxidase and catechol-O-methyltransferase inhibition on the effective turnover of dopamine were investigated using 6-[18F]L-3-4-dihydroxyphenylalanine (6-[18F]L-DOPA) and positron emission tomography. The effective dopamine turnover was expressed as the ratio between the rate of reversibility of 6-[18F]L-DOPA trapping (k[loss]) and the rate of uptake of 6-[81F]L-DOPA (Ki) in the striatum of normal cynomolgus monkeys. The monkeys received 6-[18F]L-DOPA scans, untreated or after pretreatment with either the peripheral catechol-O-methyltransferase inhibitor nitecapone; the peripheral and central catechol-O-methyltransferase inhibitor tolcapone; the monoamine oxidase inhibitors deprenyl or pargyline; a combination of tolcapone and the monoamine oxidase inhibitors. Tolcapone alone or combined with the monoamine oxidase inhibitors produced a significant decrease in the dopamine turnover (55 to 65%). Neither nitecapone nor monoamine oxidase inhibition alone produced significant changes. These results may have implications for the use of central catechol-O-methyltransferase inhibitors added to routine levodopa therapy in parkinsonian patients.