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Biomedical subjects

R Hitzemann

Publications and source records attributed to R Hitzemann.

At least 55 records · Page 3Linked to original sources
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

The Dose Reduction in Schizophrenia (DORIS) Study: a final report.

Twenty-one medication-free chronic schizophrenics were randomly assigned to three treatment groups: 50% blockade of the bromocriptine growth hormone (GH) response, 100% blockade or 10 ng/ml haloperidol. Only seven of the 21 patients showed a significant improvement after 6 weeks in positive psychotic symptoms; six of the seven responders came from the 50 and 100% blockade groups, suggesting greater efficacy at lower doses. Fifty percent blockade was associated with an average daily haloperidol dose of 3.2 mg and plasma haloperidol levels below the limit of detection (< 1 ng/ml). 100% blockade was associated with a daily dose of 6.5 mg and a plasma haloperidol level of 1 ng/ml. Negative symptoms significantly improved in only four of the 21 patients, and three of these patients were from the 100% blockade group. Twenty-nine patients currently receiving 20 mg/day haloperidol were randomly assigned to three treatment groups: placebo, 100% blockade of the GH response and 10 ng/ml. Patients in the placebo group showed significant deterioration along both the positive and negative symptom dimensions. There were no significant symptom differences between the 100% blockade and the 10 ng/ml groups. The patients in the 100% blockade group had on average a daily dose reduction from 20 to 11 mg/day and a 65% reduction in the plasma haloperidol level. There was a 70% difference in the average daily dose for 100% blockade between the two study arms. The higher daily dose in the dose-reduction arm may reflect receptor up-regulation and/or other "tolerance'-like mechanisms associated with chronic neuroleptic administration.

Adult↗
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

Genetics, haloperidol-induced catalepsy and haloperidol-induced changes in acoustic startle and prepulse inhibition.

The acoustic startle response (ASR), prepulse inhibition (PPI) of the ASR and the effects of haloperidol on the ASR and PPI were examined in C57BL/6J (B6) and DBA/2 (D2) inbred mouse strains and their F1 and F2 progeny. The startle stimulus was a 60-ms, 110-dB, 10-kHz tone; the prepulse stimuli were 20-ms, white noise bursts at 56, 68 and 80 dB against a 50-dB background presented 100-ms before the startle pulse. The B6 strain showed modest PPI (25-40%); in contrast, the D2 strain showed on average no PPI and numerous individuals showed prepulse augmentation (PPA). The F2 progeny showed an intermediate PPI; however, the extreme values ranged from 200% PPA to essentially 100% PPI. Haloperidol in dose-dependent fashion, increased PPI in both the B6 and D2 strains; the threshold dose was in the range of 0.1-0.2 mg/kg. Raclopride (0.3 mg/kg), clozapine (2 mg/kg) and risperidone (0.4 mg/kg) also increased PPI in both strains. The effects of haloperidol (0.4 mg/kg) on PPI in 140 F2 progeny were examined. For all prepulse intensities, there were highly significant (r > 0.80) and negative correlations between baseline PPI and the haloperidol-induced change in PPI. Thus, those animals that showed the greatest PPA showed the greatest haloperidol-induced increase in PPI. There was, however, significant variance in the haloperidol response; plots of the regression residuals showed the most and least responsive animals differed by almost 100% in effect on PPI. The F2 progeny were subsequently phenotyped for haloperidol-induced catalepsy. There was no association between the variation in effects on catalepsy and PPI. However, it was observed that those individuals with the poorest baseline PPI were catalepsy non-responsive.

Acoustic Stimulation↗
PubMed1997

Gender differences in cerebellar metabolism: test-retest reproducibility.

OBJECTIVE: The purpose of this study was to evaluate gender differences in baseline measures of regional brain metabolism and to assess their reproducibility. METHOD: Fifteen male and 13 female healthy subjects, whose mean age was 44 years, were tested with positron emission tomography and [18F]fluorodeoxyglucose (FDG) under resting conditions; eight of the men and 11 of the women underwent a second FDG scan under the same conditions 4-6 weeks later to assess the reproducibility of the previous results. RESULTS: There were no differences in whole brain metabolism between the women and the men. In the first evaluation the female subjects showed significantly higher metabolism in the temporal poles and cerebellum than the male subjects. During the second evaluation the female subjects had significantly higher metabolism only in the cerebellum. CONCLUSIONS: This study documents significant and reproducible gender differences in cerebellar metabolism; their functional significance merits further evaluation.

Adult↗
PubMed1997

Effects of methylphenidate on regional brain glucose metabolism in humans: relationship to dopamine D2 receptors.

OBJECTIVE: The authors' goals were to determine whether baseline dopamine activity contributes to response to methylphenidate and to assess the pattern of metabolic responses associated with enhanced dopamine activity. METHOD: They used positron emission tomography with 2-deoxy-2[18F]fluoro-D-glucose to evaluate the effects of two sequential doses of methylphenidate on brain metabolism in 15 healthy subjects. Dopamine D2 receptor availability was measured with [11C]raclopride to evaluate its relation to methylphenidate-induced metabolic changes. RESULTS: Methylphenidate increased brain metabolism in six subjects, decreased it in two, and did not change it in seven; however, it consistently increased cerebellar metabolism. Methylphenidate significantly increased "relative" (region relative to the whole brain) metabolism in the cerebellum and decreased it in the basal ganglia. Regional metabolic changes in the cerebellum and the frontal and temporal cortices were significantly correlated with D2 availability. Frontal and temporal metabolism were increased in subjects with high D2 receptors and decreased in subjects with low D2 receptors. CONCLUSIONS: Methylphenidate induced variable changes in brain metabolism, but it consistently increased cerebellar metabolism. It also induced a significant reduction in relative metabolism in the basal ganglia. The significant association between metabolic changes in the frontal and temporal cortices and in the cerebellum and D2 receptors suggests that methylphenidate's metabolic effects in these brain regions are due in part to dopamine changes and that differences in D2 receptors may be one of the mechanisms accounting for the variability in response to methylphenidate.

Adult↗
PubMed1997

Regional brain metabolic response to lorazepam in alcoholics during early and late alcohol detoxification.

Changes in GABA function have been postulated to be involved in alcohol tolerance, withdrawal and addiction. In this study we measured regional brain metabolic responses to lorazepam, to indirectly assess GABA function (benzodiazepines facilitate GABAergic neurotransmission), in alcoholics during early and late withdrawal. Brain metabolism was measured using PET and 2-deoxy-2[18F]fluoro-D-glucose after placebo (baseline) and after lorazepam (30 micrograms/kg intravenously) in 10 alcoholics and 16 controls. In the alcoholics evaluations were performed 2 to 3 weeks after detoxification and were repeated 6 to 8 weeks later. Controls were also evaluated twice at a 6 to 8 weeks interval. While during the initial evaluation metabolism was significantly lower for most brain regions in the alcoholics than in controls in the repeated evaluation the only significant differences were in cingulate and orbitofrontal cortex. Lorazepam-induced decrements in metabolism did not change with protracted alcohol withdrawal and the magnitude of these changes were similar in controls and alcoholics except for a trend towards a blunted response to lorazepam in orbitofrontal cortex in alcoholics during the second evaluation. Abnormalities in orbitofrontal cortex and cingulate gyrus in alcoholics are unlikely to be due to withdrawal since they persist 8 to 11 weeks after detoxification. The fact that there was only a trend of significance for an abnormal response to lorazepam in orbitofrontal cortex indicates that mechanisms other than GABA are involved in the brain metabolic abnormalities observed in alcoholic subjects.

Adult↗
PubMed1997

Genetics ethanol and the Fos response: a comparison of the C57BL/6J and DBA/2J inbred mouse strains.

The effect of ethanol (0.25 to 4 g/kg) on the number of Fos-like immunoreactive (Fos-li) neurons was studied in the C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains. The brain regions emphasized in the analysis were from the basal ganglia and some associated limbic nuclei. The question addressed was whether or not the D2 and B6 strains differed in these regions in a way that could explain the marked psychomotor stimulation of the D2, but not the B6, strain over the dose range of 1 to 2 g/kg of ethanol. Over the dose range of 0.25 to 2 g/kg, ethanol caused a modest increase in the number of Fos-li neurons within the caudate putamen (dorsolateral and dorsomedial) and the nucleus accumbens (core and shell), but there were no marked strain effects. There was no significant effect in either strain of ethanol treatment (0.25 to 2 g/kg) in the globus pallidus, ventral pallidum, and subthalamic nucleus. However, at 4 g/kg, there was a dramatic (> 100%) increase of Fos-li neurons in the D2 but not B6 strain. A similar effect was noted in the entopeduncular nucleus, the substantia nigra zona reticulata (and compacta), but not the ventral tegmental area. A marked and substantial (> 200%) Fos response was seen in the central amygdaloid nucleus (CeA) of the D2 strain over the entire dose range; in contrast, a substantial Fos response in the B6 strain was seen only at the 4 g/kg dose. The paraventricular thalamic nucleus, in general, paralleled data in the CeA; but, the Fos response was more modest, and the results for the D2 strain were significant only at the 2 g/kg dose. Overall, data suggest that ethanol at low to moderate doses induces significant, strain-dependent Fos responses in some limbic structures, but not in the basal ganglia. The possibility is considered that activation of some neurons in the CeA are permissive for expression of the ethanol-induced increase in motor activity.

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↗
PubMed1996

Measuring age-related changes in dopamine D2 receptors with 11C-raclopride and 18F-N-methylspiroperidol.

This study investigates the rate of age-related dopamine D2 receptor loss as determined by positron emission tomography (PET) and 11C-raclopride and compares it with D2 loss previously estimated with 18F-N-methylspiroperidol (NMS). Dopamine D2 receptors were measured with 11C-raclopride in 24 healthy volunteers (24-73 years of age) using the ratio of the distribution volume in striatum to that in cerebellum (Bmax/Kd + 1). The results were compared with those obtained in 20 healthy male volunteers (20-49 years of age) in whom D2 receptors were measured with NMS using the ratio index (slope of the striatum-to-cerebellum ratio as a function of time). Findings of correlational analysis between age and dopamine D2 receptor availability were significant for both ligands. Estimates of dopamine D2 receptor loss per decade corresponded to 7.9% for the 11C-raclopride study and 7.8% for the NMS study. Both ligands documented significant age-related decreases in dopamine D2 receptors that occurred relatively early in life (40 years of age).

Adult↗
PubMed1996

Temporal relationships between the pharmacokinetics of methylphenidate in the human brain and its behavioral and cardiovascular effects.

Positron emission tomography was used to compare the pharmacokinetics of [11C]methylphenidate in the human brain with the temporal course of the subjective and cardiovascular effects observed after intravenous methylphenidate (0.5 mg/kg). Four subjects were tested twice with [11C]methylphenidate, at baseline and after methylphenidate. All subjects showed almost identical uptake of 11C labeled drug in brain, as well as a very similar decrease in binding of [11C]methylphenidate in basal ganglia, after pretreatment with methylphenidate. In contrast, the magnitude of the behavioral and cardiovascular changes induced by methylphenidate varied among the subjects. The temporal course for methylphenidate effects paralleled closely the pharmacokinetics of [11C]methylphenidate in brain for the perception of "restlessness" and for changes in systolic blood pressure and heart rate. In contrast, methylphenidate induced "high", "anxiety" and changes in diastolic blood pressure decreased rapidly despite long lasting binding of the drug in brain. These results indicate that binding of methylphenidate in brain does not appear to predict individual responses to the drug and that more than one neurotransmitter and/or adaptation process are likely to be involved in the behavioral and cardiovascular effects of methylphenidate.

Adult↗
PubMed1996

Decreases in dopamine receptors but not in dopamine transporters in alcoholics.

It has been hypothesized that ethanol's actions on the dopamine (DA) system may participate in addiction. The purpose of this study was to evaluate the DA system in the brain of alcoholics. We evaluated 10 alcoholics and 17 nonalcoholics using positron emission tomography and [11C]raclopride to measure DA D2 receptors. In addition, in 5 of the alcoholics and 16 of the nonalcoholics, we also measured DA transporters with [11C]d-threo methylphenidate. The ratio of the distribution volumes in striatum to that in cerebellum, which corresponds to Bmax/Kd + 1, was used as model parameter of DA D2 receptor and transporter availability. Dopamine D2 receptor availability (Bmax/Kd) was significantly lower in alcoholics (2.1 +/- 0.5) than in nonalcoholics (2.7 +/- 0.6) (p < 0.05) and was not correlated with days since last alcohol use. Alcoholics showed DA transporter values similar to those in nonalcoholics. The ratio of DA D2 receptor to transporter availability was significantly higher in nonalcoholics (1.4 +/- 0.1) than in alcoholics (1.1 +/- 0.1) (p < 0.005). Alcoholics showed significant reductions in D2 receptors (postsynaptic marker) but not in DA transporter availability (presynaptic marker) when compared with nonalcoholics. Because D2 receptors in striatum are mainly localized in gamma-aminobutyric acid (GABA) cells these results provide evidence of GABAergic involvement in the dopaminergic abnormalities seen in alcoholics.

Adult↗
PubMed1996

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.

Animals↗
PubMed1996

Dopamine transporters decrease with age.

UNLABELLED: Postmortem studies have documented degeneration of dopamine cells with age, but the changes that occur in healthy aging individuals is less clear. The purpose of this study was to evaluate the extent to which age-induced changes in dopamine transporters occur in subjects with no evidence of motor impairment. METHODS: We evaluated 23 right-handed healthy volunteers (age range 20-74 yr) using PET and [11C]d-threo-methylphenidate. The ratio of the distribution volume for [11C]d-threo-methylphenidate in striatum to that in cerebellum was used as model parameter for dopamine transporter availability (Bmax/Kd + 1). RESULTS: Dopamine transporter availability was significantly lower in subjects > 40 yr of age than in those < 40 yr. Estimates of dopamine transporter availability showed a significant negative correlation with age both for the putamen (r = -0.72, p < 0.0001) and the caudate (r = -0.74, p < 0.0001). Dopamine transporter availability was higher in the left than in the right putamen but did not differ between the left and right caudate. CONCLUSION: This study documents a 6.6% decrease per decade of life in striatal dopamine transporters of healthy volunteers.

Adult↗
PubMed1996

Genetics, neuroleptic response and the organization of cholinergic neurons in the mouse striatum.

Compared with the neuroleptic nonresponsive (NNR) mouse line, the neuroleptic responsive (NR) line has a significantly higher number of striatal cholinergic neurons (Hitzemann et al., 1993). We now report additional information on this genetic association. At the fifth selected generation, a new selection of the NR and NNR lines differed 5-fold in their ED50 values (1 vs. 5 mg/kg) for haloperidol-induced catalepsy and 20% in the number of striatal cholinergic neurons (higher in the NR line). This association was further examined in 10 standard inbred mouse strains; eight of the strains had been crossed to form the heterogeneous stock from which the new NR and NNR lines were selected. In this panel, we detected no significant association between number of cholinergic neurons and haloperidol response. To examine the similarities and differences in the modes of inheritance for the two phenotypes, we formed a full Mendelian cross from the C57BL/6 (B6) and DBA/2 (D2) mouse strains. The B6 and D2 strains differ 9-fold in their haloperidol ED50 values (3.9 vs. 0.4 mg/kg) and more than 30% in the number of cholinergic neurons (higher in the D2 strain). Haloperidol-induced catalepsy was described by a simple additive genetic model; the narrow sense heritability was 0.60. In contrast, for the number of cholinergic neurons, the B6 genotype was dominant and heterosis was detected in the F1 cross. Despite the differences in heritability, among B6D2 F2 individuals, increasing haloperidol sensitivity was associated with increasing numbers of striatal cholinergic neurons. The BXD recombinant inbred series (25 strains) showed a 16-fold range of variation in the haloperidol ED50 and a greater than 50% variation in the number of striatal cholinergic neurons. However, we detected no significant association between haloperidol response and number of cholinergic neurons. Overall, the data suggest that the genetic association between the phenotypes is modest, complex and detectable only with some genetic strategies.

Animals↗