Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex.

OBJECTIVE: The role of dopamine in the addictive process (loss of control and compulsive drug intake) is poorly understood. A consistent finding in drug-addicted subjects is a lower level of dopamine D2 receptors. In cocaine abusers, low levels of D2 receptors are associated with a lower level of metabolism in the orbitofrontal cortex. Because the orbitofrontal cortex is associated with compulsive behaviors, its disruption may contribute to compulsive drug intake in addicted subjects. This study explored whether a similar association occurs in methamphetamine abusers. METHOD: Fifteen methamphetamine abusers and 20 non-drug-abusing comparison subjects were studied with positron emission tomography (PET) and [11C]raclopride to assess the availability of dopamine D2 receptors and with [18F]fluorodeoxyglucose to assess regional brain glucose metabolism, a marker of brain function. RESULTS: Methamphetamine abusers had a significantly lower level of D2 receptor availability than comparison subjects (a difference of 16% in the caudate and 10% in the putamen). D2 receptor availability was associated with metabolic rate in the orbitofrontal cortex in abusers and in comparison subjects. CONCLUSIONS: Lower levels of dopamine D2 receptor availability have been previously reported in cocaine abusers, alcoholics, and heroine abusers. This study extends this finding to methamphetamine abusers. The association between level of dopamine D2 receptors and metabolism in the orbitofrontal cortex in methamphetamine abusers, which replicates previous findings in cocaine abusers, suggests that D2 receptor-mediated dysregulation of the orbitofrontal cortex could underlie a common mechanism for loss of control and compulsive drug intake in drug-addicted subjects.

L-tryptophan attenuation of the dopaminergic and behavioral responses to cocaine.

This study assessed the effects of acute intravenous L-tryptophan (neutral amino acid precursor for serotonin) administration on cocaine-induced dopaminergic responses. Male Sprague-Dawley rats were surgically implanted with guide cannulas in the nucleus accumbens 5 days prior to the study and with vascular catheters (carotid artery and jugular vein) on the day prior to the study. Using microdialysis, extracellular nucleus accumbens dopamine levels were measured in freely moving rats. Following a 2 h equilibration period, animals were randomized (n=7-8 per group) to receive either a constant intravenous (IV) infusion of L-tryptophan (200 mg/kg/h) or an equal volume (2 ml/h) of saline. Ninety minutes into the infusion, cocaine (20 mg/kg) was injected intra-peritoneally. Cocaine increased nucleus accumbens microdialysate dopamine levels (500% at 30 min). This was associated with marked hyperactivity. Tryptophan infusion elevated plasma tryptophan (8-fold), and blunted the cocaine-induced increase in nucleus accumbens microdialysate dopamine levels by approximately 60%. Furthermore, tryptophan attenuated the cocaine-induced locomotor activity. These neurochemical and behavioral effects of tryptophan were associated with a marked increase in brain tissue serotonin content. The results of these studies demonstrate the feasibility of acute dietary manipulation of neurochemical and behavioral responses to cocaine. The duration, adaptation and tolerance to these effects remain to be elucidated.

Increased activity of the temporal insula in subjects with bradycardia.

Though it has been postulated that cortical brain regions participate in the regulation of heart rate, their involvement is poorly understood. Using PET and [18] FDG (to measure regional brain glucose metabolism, which serves as an index of brain function) we compared the regional brain metabolic activity between healthy subjects with bradycardia (<60 beats per minute) with those with normal heart rates in the 75-100 beats per minute range. Statistical Parametric Mapping (SPM) analyses revealed significant differences between the groups predominantly localized to the temporal insula. This finding was corroborated by a separate analysis that measured the metabolic activity for each subject in preselected regions located in the temporal insula. Subjects with bradycardia had significantly higher metabolic activity in the right (p < 0.0001) and in the left temporal insula (p < 0.015) than those with normal heart rates. Moreover, resting heart rates were negatively correlated with metabolism in the right (r = -0.77, p < 0.0001) and in the left temporal insula (r = -0.44, p < 0.05). These results corroborate the importance of the temporal insula in the regulation of resting heart rate in humans. The temporal insula is interconnected with limbic brain region and autonomic centers and suggests that this may be a mechanism by which emotional responses regulate heart rate.

Design and synthesis of the CB1 selective cannabinoid antagonist AM281: a potential human SPECT ligand.

In the search for a radioligand capable of imaging cannabinoid CB1 receptors in the living human brain by SPECT (single photon emission computed tomography),N-(morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM281) was synthesized. This compound is an analog of the potent, CB1 receptor selective antagonist SR141716A [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide]. AM281 bound to brain and spleen membrane preparations (CB1 and CB2 receptors, respectively) with K(i) values of 12 nM and 4200 nM, respectively. AM281 also inhibited the response of guinea-pig small intestine preparation to a cannabinoid receptor agonist. Thus, AM281 behaves as a CB1 receptor selective antagonist. Methods for the rapid, high-yield synthesis and purification of [123I]AM281 were developed, and transaxially reconstructed brain SPECT images obtained after continuous infusion of [123I]AM281 in baboons. Thus [123I]AM281 may be suitable for imaging CB1 receptors in humans.

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.

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.

Mapping the genes for haloperidol-induced catalepsy.

The strain means for haloperidol-induced catalepsy were determined in the 26 strain BXD recombinant inbred series. The ED50 values ranged from 0.55 mg/kg (strain 30) to 7.9 mg/kg (strain 2). Heritability for the catalepsy response was 0.78 and the number of effective loci was estimated to be four. The strain means were correlated with the strain distribution patterns for 1300 marker loci of known chromosomal location and polymorphic between the C57Bl/6J and DBA/2J strains. Six quantitative trait loci (QTLs) were identified at P < .01. Two of the six QTLs were confirmed in a sample of B6XD2 F2 animals (n = 144), phenotyped for haloperidol response and genotyped for microsatellites closely linked to the QTLs. The confirmed QTL on chromosome 4 is near the b locus. The confirmed QTL on chromosome 9 is closely linked to Drd2, the D2 dopamine receptor gene. One hundred of the F2 individuals were phenotyped for D2 dopamine receptor binding using the ligand [125I] epidepride as the ligand. Consistent with previous results, the nonresponsive F2 individuals showed modestly higher receptor binding in all brain regions examined: the nucleus accumbens core, the nucleus accumbens shell, the lateral caudate putamen, the dorsomedial caudate putamen, the substantia nigra zona compacta and the ventral tegmental area. The DBA/2J allele of the chromosome 9 QTL was associated with higher receptor binding in all brain areas except the ventral tegmental area. Overall, the data illustrate that either near or part of Drd2 is a QTL which has significant effects on both haloperidol response and D2 dopamine receptor binding. However, the data also illustrate that most of the genetic variance in either haloperidol response or D2 dopamine receptor binding is not associated with Drd2.

Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain.

BACKGROUND: The purposes of this study were to investigate the pharmacokinetics of methylphenidate hydrochloride (Ritalin) in the human brain, to compare them with those of cocaine, and to evaluate whether cocaine and methylphenidate compete for the same binding sites. METHODS: We used positron emission tomography to measure the temporal and spatial distribution of carbon 11 (11C)-labeled methylphenidate. These results were compared with those obtained previously for [11C]cocaine. Eight healthy male subjects, 20 to 51 years of age, were scanned with [11C]methylphenidate. Three were tested twice to assess test-retest variability, four were tested at baseline and after administration of methylphenidate, and one was tested with [11C]methylphenidate and [11C]cocaine. Two baboons were scanned to evaluate whether there was competition between cocaine and methylphenidate for the same binding sites in the brain. RESULTS: The uptake of [11C]methylphenidate in the brain was high (mean +/- SD, 7.5% +/- 1.5%), and the maximal concentration occurred in striatum. Pretreatment with methylphenidate decreased binding only in striatum (40%). Although the regional distribution of [11C]methylphenidate, was identical to that of [11C]cocaine and they competed with each other for the same binding sites, these two drugs differed markedly in their pharmacokinetics. Clearance of [11C]methylphenidate from striatum (90 minutes) was significantly slower than that of [11C]cocaine (20 minutes). For both drugs, their fast uptake in striatum paralleled the experience of the "high." For methylphenidate, the high decreased very rapidly despite significant binding of the drug in the brain. In contrast, for cocaine, the decline in the high paralleled its fast rate of clearance from the brain. CONCLUSION: We speculate that because the experience of the high is associated with the fast uptake of cocaine and methylphenidate in the brain, the slow clearance of methylphenidate from the brain may serve as a limiting factor in promoting its frequent self-administration.

Visual evoked potentials and positron emission tomographic mapping of regional cerebral blood flow and cerebral metabolism: can the neuronal potential generators be visualized?

Visual evoked potentials (VEPs) and visual evoked spectrum array (VESA) to flashes and pattern-reversal were correlated with regional cerebral blood flow (rCBF) or local cerebral glucose metabolism in 4 hemianopsic patients and one subject with cortical blindness. Normal VEPs, topographical distribution and occipital rCBF were noted in hemianopsic patients with macular sparing. A dissociation of topographical distribution of VEPs to flashes and pattern-reversal was demonstrated in one patient with hemianopsia and macular splitting. In this case, rCBF showed unilateral activation of visual areas 17, 18 and 19 of the cortex. The distribution of surface-recorded potentials reflected the complex interaction of electrical field potentials within at least 3 cortical areas rather than volume transmission of striate dipoles alone. VEPs were preserved in a cortically blind patient. rCBF and local cerebral glucose metabolism revealed a functioning island of occipital cortex that most likely represented the generator of the VEP. The combination of VEP and PET permits the correlation of electrophysiological events with the visualization of cortical areas presumably activated by the same visual stimulus.