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Biomedical subjects

R Hitzemann

Publications and source records attributed to R Hitzemann.

At least 73 records · Page 4Linked to original sources
PubMed1995

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.

Adult↗
PubMed1995

Depression of thalamic metabolism by lorazepam is associated with sleepiness.

Though it is well recognized that the pharmacological actions of benzodiazepines are mediated by facilitation of GABAergic neurotransmission, the consequences of these changes in regional brain function are not well understood. This study measured regional brain glucose metabolism using Positron Emission Tomography and 2-deoxy-2[18F]fluoro-D-glucose in normal controls (n = 21) investigated with and without lorazepam (30 micrograms/kg IV) and with flumazenil given after lorazepam (n = 9). Lorazepam markedly decreased metabolism in thalamus (23 +/- 8%) and occipital cortex (19 +/- 8%), and flumazenil partially reversed these changes. Changes in metabolic activity in thalamus were significantly correlated with lorazepam-induced sleepiness (r = .69, df 20, p < .0005) and there was a trend of an association between the reversal by flumazenil of lorazepam-induced change in thalamus and in sleepiness (r = .63, df 8, p = .07). Benzodiazepine-induced changes in thalamic activity may account for their sedative properties.

Adult↗
PubMed1995

Regional brain metabolic response to lorazepam in subjects at risk for alcoholism.

The mechanisms underlying the blunted response to alcohol administration observed in subjects at risk for alcoholism are poorly understood and may involve GABA-benzodiazepine receptors. The purpose of this study was to investigate if subjects at risk for alcoholism had abnormalities in brain GABA-benzodiazepine receptor function. This study measured the effects of 30 micrograms/kg (i.v.) of lorazepam, on regional brain glucose metabolism using positron emission tomography and 2-deoxy-2[18F]fluoro-D-glucose in subjects with a positive family history for alcoholism (FP) (n = 12) and compared their response with that of subjects with a negative family history for alcoholism (FN) (n = 21). At baseline, FP subjects showed lower cerebellar metabolism than FN. Lorazepam decreased whole-brain glucose metabolism, and FP subjects showed a similar response to FN in cortical and subcortical regions, but FP showed a blunted response in cerebellum. Lorazepam-induced changes in cerebellar metabolism correlated with its motor effects. The decreased cerebellar baseline metabolism in FP as well as the blunted cerebellar response to lorazepam challenge may reflect disrupted activity of benzodiazepine-GABA receptors in cerebellum. These changes could account for the decreased sensitivity to the motor effects of alcohol and benzodiazepines in FP subjects.

Adult↗
PubMed1994

Decreased dopamine transporters with age in health human subjects.

The effects of aging on brain dopamine transporters was evaluated in 26 healthy male volunteers (age range, 21-63 years) using positron emission tomography and [11C]cocaine. The ratio of the distribution volume for [11C]cocaine in basal ganglia to that in cerebellum was used as a model parameter for dopamine transporter availability and showed a significant negative correlation with age (r = 0.65, p < 0.0005). This results document an age-related decline in dopamine transporters in healthy individuals.

Adult↗
PubMed1994

Imaging endogenous dopamine competition with [11C]raclopride in the human brain.

This study images dopamine release in response to a neurochemically specific challenge with the psychostimulant drug methylphenidate. Changes in synaptic dopamine induced by methylphenidate were evaluated with positron emission tomography and [11C]raclopride, a D2 receptor radioligand that is sensitive to endogenous dopamine. Methylphenidate significantly decreased striatal [11C]raclopride binding. The decrease was variable and was negatively correlated with age. Mood and anxiety at baseline, were also correlated with methylphenidate-induced DA changes. This strategy provides a tool to investigate the responsiveness of the dopamine system in the normal and diseased human brain and to investigate the neurochemical correlates of behavior.

Adult↗
PubMed1994

Recovery of brain glucose metabolism in detoxified alcoholics.

OBJECTIVE: To differentiate withdrawal-related abnormalities in brain glucose metabolism among alcoholics from abnormalities that may be irreversible or antedate alcohol use, the authors evaluated metabolic recovery during alcohol detoxification. METHOD: Regional brain glucose metabolism was measured with positron emission tomography and 2-deoxy-2-[18F]fluoro-D-glucose in 10 male alcoholics at 8-15 days, 16-30 days, and 31-60 days after last use of alcohol. The alcoholics' metabolic values were compared with those of 10 age-matched male healthy volunteers. RESULTS: Brain metabolism increased significantly during detoxification. There were significant differences in global and regional measures between the first and last time points but not between the second and third points, suggesting that recovery occurred predominantly within 16-30 days. Regional increases in metabolism were greater in the frontal regions. Whereas during the first evaluation the alcoholics showed significantly lower metabolism in various brain regions than the comparison group, at the end of detoxification the alcoholics showed significantly lower absolute and relative metabolic values in the basal ganglia and lower relative metabolic values in the parietal cortex. Among the alcoholics, but not the comparison group, metabolism in the frontal, parietal, and left temporal cortexes was negatively correlated with years of alcohol use and with age. CONCLUSIONS: This study shows significant increases in brain metabolism during alcohol withdrawal and documents persistent low metabolic levels in the basal ganglia of detoxified alcoholics.

Adult↗
PubMed1994

Further studies on the relationship between dopamine cell density and haloperidol-induced catalepsy.

Previous data have suggested that the genetic variability in the sensitivity to haloperidol-induced catalepsy is associated with the number of dopamine neurons in the substantia nigra zona compacta (SNZc). To further investigate this relationship, neuroleptic responsive (NR) and neuroleptic nonresponsive (NNR) lines were selected from the new heterogeneous stock/Northport (Np). At the fourth selected generation (S4), the NR/Np and NNR/Np lines differed more than 5-fold in their haloperidol ED50, but showed no difference in their ED50 to SCH 23390. Confirming the previous results, tyrosine hydroxylase (TH)-positive cell number in the SNZc was significantly higher in the NNR/Np as compared to the NR/Np line. The difference was most pronounced in the rostral SNZc, where TH cell number was increased 23%. Cell number also was increased significantly (38%) in the caudal ventral tegmental area (VTA). Fifty-two C57BL/6J:DBA/2J (B6D2)F2 hybrids were phenotyped for haloperidol response before determination of TH cell number. Paralleling the results in the selected lines, TH cell number in the SNZc was significantly (range, 10-28%) higher in the most nonresponsive F2 hybrids. TH cell number was determined in the SNZc and VTA of 10 standard inbred mouse strains for which the ED50 for haloperidol-induced catalepsy was known. TH cell number showed significant differences among inbred strains, with the largest difference (88%) noted between the 129/J and P/J strains in the rostral SNZc. In the VTA, differences as large as 95% were noted (AKR/crl vs. P/J). Among the inbred strains, there was no significant relationship between cell number and response except in the medial SNZc, where the most responsive strains had the highest cell number.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers.

Decreased dopaminergic function has been postulated to underlie cocaine addiction. To examine the possibility that dysfunction of brain regions subserved by the dopamine system could promote cocaine self-administration, positron emission tomography and a dual-tracer approach was used to examine dopamine D2 receptor availability and regional brain glucose metabolism in cocaine abusers. When compared to normal controls, cocaine abusers showed significant decreases in dopamine D2 receptor availability which persisted 3-4 months after detoxification. Decreases in dopamine D2 receptor availability were associated with decreased metabolism in several regions of the frontal lobes, most markedly orbito-frontal cortex and cingulate gyri. Dopamine dysregulation of these brain areas which are involved in the channeling of drive and affect could lead to loss of control resulting in compulsive drug-taking behavior.

Adult↗
PubMed1993

The 5-HT3 antagonist zacopride attenuates cocaine-induced increases in extracellular dopamine in rat nucleus accumbens.

Pretreatment with the serotonin-3 (5-HT3) antagonist racemic (+/-)-Zacopride hydrochloride (ZAC, 0.1 mg/kg, IP) has been previously found to completely abolish the locomotor activity induced by cocaine (10 mg/kg, IP). To determine if this effect was mediated by fluctuations in the extracellular levels of forebrain dopamine (DA), we examined the ability of ZAC to attenuate cocaine-induced increases in extracellular DA levels. Microdialysis samples were collected from the nucleus accumbens region (NAS) of awake, male, Sprague-Dawley rats. ZAC treatment alone (0.1 mg/kg, IP) did not alter DA levels relative to baseline. However, this dose of ZAC given 1 h prior to cocaine challenge (10 mg/kg, IP) caused a 27% reduction in the peak level of extracellular DA produced by cocaine, relative to saline-pretreated control animals. These results suggest that the ability of ZAC to attenuate cocaine-induced increases in extracellular DA levels may contribute to ZAC's ability to suppress cocaine-induced locomotor activity in the rat. However, additional neurochemical mechanisms are likely to be important in mediating the robust behavioral effects previously reported.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Decreased cerebral response to inhibitory neurotransmission in alcoholics.

OBJECTIVE: Changes in gamma-aminobutyric acid (GABA)-benzodiazepine receptor function have been implicated in alcohol tolerance, withdrawal, and dependence. The purpose of this study was to investigate whether recently detoxified alcoholic subjects had abnormalities in brain GABA-benzodiazepine receptor function. METHOD: The effect of 30 micrograms/kg of lorazepam on regional brain glucose metabolism was studied in 12 normal subjects and 10 alcoholic subjects with the use of positron emission tomography and [18F]fluorodeoxyglucose. RESULTS: Lorazepam decreased whole brain glucose metabolism in both the normal subjects (13% change) and the alcoholic subjects (10% change), and the response was correlated with the concentration of lorazepam in plasma. Whereas the normal and alcoholic subjects showed similar responses to lorazepam in occipital and cerebellar metabolism, the alcoholic subjects showed significantly less of a response than the comparison subjects in the thalamus, basal ganglia, and orbitofrontal cortex. The rate of response in the orbitofrontal cortex was significantly correlated with cerebellar metabolism at baseline. CONCLUSIONS: The alcoholic subjects had a blunted response to lorazepam that was specific to certain brain regions. The association between cerebellar metabolism and response to lorazepam suggests that the cerebellum may contribute to the decreased sensitivity to lorazepam which was seen in the alcoholic subjects.

Adult↗
PubMed1993

D1 and D2 dopamine receptor turnover and D2 messenger RNA levels in the neuroleptic-responsive and the neuroleptic nonresponsive lines of mice.

The neuroleptic responsive (NR) and neuroleptic nonresponsive (NNR) selected lines of mice differ significantly in D2 receptor density. By comparison with the NR line, the NNR line has a lower receptor density in the caudal aspect of the lateral caudate-putamen (-30%) but a higher receptor density in both the substantia nigra ventral tegmental area (+40%). In the present study, the rates of D2 receptor synthesis and degradation were inferred from the repopulation kinetics after N-ethoxycarbonyl-2-ethoxy-1,2 dihydroquinoline administration. The higher D2 receptor density in the substantia nigra of the NNR line was associated with an increase in receptor synthesis, with no change in receptor degradation. As determined by nuclease protection assay, this increase in receptor synthesis was not associated with an increase in messenger RNA levels. D2 receptor turnover was decreased across the entire rostral-caudal axis in the lateral caudate-putamen; the decrease in the apparent rate of receptor synthesis was not associated with a change in messenger RNA levels. By contrast with the decrease in D2 receptor turnover, D1 receptor turnover in the NNR line was significantly increased. Overall, the data suggest that the changes in D2 receptor density correlated with the selection of the NR and NNR lines may involve translational or post-translational mechanisms.

Animals↗
PubMed1993

Dopamine and acetylcholine cell density in the neuroleptic responsive (NR) and neuroleptic nonresponsive (NNR) lines of mice.

The neuroleptic responsive (NR) and neuroleptic nonresponsive (NNR) selected lines of mice differ more than 10-fold in the ED50 for catalepsy induced by a wide variety of neuroleptics with a high dopamine D2/D1 receptor activity ratio, e.g., haloperidol. The NR and NNR lines also differ significantly in dopamine D2 somatodendritic receptor density; within the substantia nigra zona compacta and the ventral tegmental area, the increases in the NNR line are on average 33 and 48%, respectively. We now report that the NNR line has a higher number of dopamine neurons in the midrostral to the midcaudal aspect of the substantia nigra zona compacta. Within this region, the increase in dopamine cell number was on average 41%. In contrast to these data, there was no difference in cell number between lines in the ventral tegmental area. Thus, the increase of midbrain dopamine D2 receptor density in the NNR line can only be accounted for in part by an increase in the number of dopamine neurons. Although the number of dopamine neurons in the substantia nigra zona compacta was increased in the NNR line, the density of dopamine terminals in the caudate-putamen as estimated by the [3H] mazindol technique was modestly but significantly higher (8%) in the NR line. The selected lines also differed within the caudate-putamen in the number of cholinergic neurons. The NR line had a significantly higher number of cholinergic neurons in the rostral caudate-putamen. Overall, these data illustrate that selective breeding for neuroleptic response has yielded lines of mice with significant differences in both the cholinergic and dopaminergic systems of the basal ganglia.

Acetylcholine↗
PubMed1993

Reproducibility of repeated measures of carbon-11-raclopride binding in the human brain.

Carbon-11-raclopride has been successfully utilized with PET to assess changes in endogenous dopamine concentration after pharmacological intervention in the living baboon brain. For similar studies to be done in humans, measurements of 11C-raclopride with no intervention need to be reproducible. In order to test the reproducibility (test-retest) of 11C-raclopride binding in the human brain, we performed repeated studies on two different days. Studies were done in five normal controls with no pharmacological intervention. Time-activity (%dose/cc) curves for 11C-raclopride in the basal ganglia (BG) and cerebellum (CBL) were highly reproducible with an average difference in peak uptake for repeated studies in the same individual of 4%. The BG to CBL ratio for the average activity concentration between 30 and 60 min showed differences that ranged from -7% to 8% between the repeated studies. Graphical analysis to obtain the distribution volume revealed intrasubject values that ranged from -9% to 7% for the ratio of the distribution volume in BG to that in CBL. These studies demonstrate that in order to use 11C-raclopride to measure an individual's change in relative dopamine concentration secondary to pharmacological or behavioral intervention, a change in striatal 11C-raclopride binding in excess of 10% is required.

Adult↗
PubMed1992

Regional distribution and kinetics of haloperidol binding in human brain: a PET study with [18F]haloperidol.

The regional distribution and the kinetics of haloperidol uptake in human brain were examined using [18F]haloperidol and PET in 9 controls and 5 schizophrenics while on haloperidol medication and after haloperidol washout. The regional distribution of [18F]N-methylspiroperidol, a tracer for D2 receptors, was measured in 1 normal subject for comparison. The uptake of [18F]haloperidol in the whole brain in normals was high (6.6% of the injected dose at 2 hr), and regional distribution was much more extensive than could be accounted for by the distribution of dopamine D2 receptors. In normals, the cerebellum, basal ganglia, and thalamus showed a greater concentration than the cortex, and there was minimal clearance of 18F from the brain during the 10-hr period of the study. Medicated schizophrenics showed a total brain uptake of 4.0% and had a significant clearance of [18F]haloperidol from brain and a higher concentration of [18F]haloperidol in plasma. After withdrawal from medication, [18F]haloperidol clearance from brain became slower than while on medication. These results are discussed in terms of the pharmacokinetics of haloperidol in the human brain and its binding to dopamine D2 receptors and to sigma receptors.

Adult↗
PubMed1992

Long-term frontal brain metabolic changes in cocaine abusers.

Neurological complications from cocaine use are well recognized. We propose that chronic cocaine use can also cause clinically silent brain dysfunction. We investigated brain glucose metabolism with positron emission tomography (PET) and 2-deoxy-2[18F] fluoro-D-glucose (FDG) in 21 neurologically intact chronic cocaine abusers (C) and 18 normal controls (N). The cocaine abusers were tested 1-6 weeks after the last use of cocaine and seven were retested after a 3 month drug-free period. Global cerebral glucose metabolism was not significantly different between controls and cocaine abusers (N = 38.4 +/- 3, C = 36.5 +/- 5 mumol/100 g of tissue, min). However, cocaine abusers had significantly (P less than 0.05) lower metabolic activity in 16 of the 21 left frontal regions and 8 of the 21 right frontal regions. These decreases persisted after 3-4 months of detoxification and were correlated with the dose (P less than or equal to 0.01) and the years of cocaine use (P less than or equal to 0.05). This study shows reduced rates of frontal metabolism in neurologically intact cocaine abusers that persist even after 3-4 months of detoxification.

Adult↗
PubMed1992

5-HT3 receptor antagonists block cocaine-induced locomotion via a PCPA-sensitive mechanism.

We report results in rats pretreated with (+/-)-zacopride (0.03 mg/kg, IP), ICS 205-930 (0.1 mg/kg, IP), and MDL 72222 (1.0 mg/kg, IP) 15 min before challenge with (-)-cocaine (10.0 mg/kg, IP). At a dose of 10 micrograms/kg, zacopride significantly inhibited (approximately 50%) cocaine-induced locomotion. We also investigated whether or not 5-hydroxytryptamine3 (5-HT3) antagonists block the cocaine binding site on the dopamine transporter and/or affect the ability of dopamine to regulate this binding site. In well-washed striatal membranes, neither zacopride nor ICS 205-930 (10(-9)-10(-5) M) inhibited [3H]2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane ([3H]WIN 35,428) (0.3 nM) binding. Furthermore, neither of these compounds affected the ability of dopamine to block WIN 35,428 binding. To determine if 5-HT is required for the 5-HT3 antagonist effect, we examined the interaction between cocaine and zacopride in rats pretreated with p-chlorophenylalanine (PCPA) (3 days x 100 mg/kg/day). PCPA pretreatment shifted the cocaine dose-response curve to the right and blocked the ability of zacopride to reverse cocaine-induced activity.

Animals↗
PubMed1992

Decreased brain metabolism in neurologically intact healthy alcoholics.

OBJECTIVE: The extent to which cerebral dysfunction in alcoholics is related to the direct effects of alcohol in the brain rather than to indirect mechanisms and/or alcohol withdrawal remains unclear. The purpose of this study was to evaluate whether healthy alcoholics with no evidence of alcohol-associated complications showed changes in brain glucose metabolism. METHOD: Positron emission tomography and [18F]-fluorodeoxyglucose were used to measure regional brain metabolism. The study group consisted of 22 normal, healthy, right-handed volunteers and 22 neurologically intact, healthy, right-handed alcoholics tested 6 to 32 days after alcohol discontinuation. RESULTS: Alcoholics showed significantly lower whole brain metabolism than normal control subjects. Normalization of regional metabolic values to the whole brain metabolic rate revealed that the left parietal and right frontal cortices were the most affected regions. Although the whole brain metabolic rate was correlated with the amount of time since alcohol discontinuation, the "normalized" decreases in left parietal and right frontal glucose metabolism were not. CONCLUSIONS: These findings support the contribution of the direct effect of alcohol as well as alcohol withdrawal on the changes in regional brain metabolism seen in alcoholics. They also provide evidence of cerebral changes in neurologically intact healthy alcoholics.

Adult↗