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Biomedical subjects

R Hitzemann

Publications and source records attributed to R Hitzemann.

At least 91 records · Page 5Linked to original sources
PubMed1992

D1 and D2 dopamine receptor distribution in the neuroleptic nonresponsive and neuroleptic responsive lines of mice, a quantitative receptor autoradiographic study.

The present study uses quantitative receptor autoradiography to examine D1 and D2 receptor binding in the neuroleptic responsive and neuroleptic nonresponsive (NNR) lines of mice. The neuroleptic responsive and NNR mice have differed for at least eight generations by an order of magnitude in their sensitivity (ED50s) to catalepsy induced by neuroleptics with a high D2/D1 receptor activity profile. Across the entire rostral-caudal dimensions of the lateral caudate-putamen (CPu), of the dorsomedial CPu, the nucleus accumbens and substantia nigra zona reticulata, we found no difference in the density of [3H]SCH 23390 binding sites. [3H]Spiroperidol binding sites were not different in the dorsomedial CPu or nucleus accumbens but were significantly decreased (20-30%) in the NNR line in the caudal aspect of the lateral CPu. The NNR line also showed a significant elevation of D2 autoreceptors across all the midbrain dopamine cell groups (A8, A9 and A10); the increases ranged from 20 to 50%. Overall, the data show that selection of mice for response and nonresponse to neuroleptic-induced catalepsy is associated with significant changes in D2 but not D1 receptor density.

Animals↗
PubMed1992

Distribution and kinetics of carbon-11-cocaine in the human body measured with PET.

The extent to which the toxic properties of cocaine are related to its accumulation in various organs is not known. This study investigates cocaine uptake in the human body using 11C-cocaine and PET in 14 healthy males. The rate of uptake and clearance of 11C-cocaine varied among organs: peak uptake occurred in the lungs at 45 sec, in the heart and kidneys at 2-3 min, in the adrenals at 7-9 min, and in the liver at 10-15 min. Half-peak clearances were 90 sec in the lungs, 10 min in the heart and kidneys and 22 min in the adrenals. Liver radioactivity plateaued 10-15 min after injection and remained constant thereafter (40 min). Lung radioactivity paralleled that of plasma. The average uptake at peak was 0.007% (s.d., 0.001) dose/cc in the heart, 0.014% (s.d., 0.002) dose/cc in the kidney, 0.014% (s.d., 0.002) dose/cc in the liver and 0.034% (s.d., 0.001) dose/cc in the adrenals. The significant accumulation of cocaine in human heart, kidneys, adrenals and liver could contribute to its toxicity.

Adult↗
PubMed1991

On the selection of mice for haloperidol response and non-response.

Mice have been selected over eight generations for response and non-response to haloperidol-induced catalepsy. The selection has been asymmetric, with significantly faster divergence for the haloperidol non-responder (HNR) line as compared to the haloperidol responder (HR) line. After six generations of selection, the ED50 in the HNR line was 4.3 mg/kg and 0.4 mg/kg in the HR line. Spiroperidol, fluphenazine and trifluoperazine showed a 10-fold or greater discrimination between lines. Raclopride, a specific dopamine D2 antagonist, showed a 7-fold discrimination between lines. Chlorpromazine, thiothixene, (+) butaclamol and cis-flupenthixol showed a 3-4-fold discrimination between lines. The specific D1 antagonist, SCH 23390, was the most potent cataleptogenic agent tested (ED50 = 0.1 mg/kg) and did not discriminate between the lines. The HR and HNR lines did not differ in post-synaptic D2 receptor affinity or density as assessed by quantitative receptor autoradiography and membrane binding assays. However, A-9 somatodendritic receptor density was 80% higher in the HNR line as compared to the HR line.

Animals↗
PubMed1991

Membranes and the genetics of ethanol response.

A combination of fluorescence polarization (FPZ) and nuclear magnetic resonance (NMR) techniques have revealed that ethanol has diverse and domain dependent effects on membrane order. Under some conditions, in the more superficial membrane domains, ethanol actually orders rather disorders membrane structure. Using 1H-NMR we have examined in synaptic membranes from LS and SS mice the effects of ethanol-d6 on membrane order. The lines differ most significantly in terms of the ethanol effects on the choline methyl resonances. Ethanol was significantly more potent in increasing choline methyl resonance intensity in LS synaptic membranes than in SS synaptic membranes; these data are interpreted to show a significantly greater disordering of the superficial domains in the LS membranes. The maximum ethanol effect was observed between 0.3% and 0.5% for the concentration range studied (0.1 to 1.0%). The methylene resonance data in general paralleled the choline methyl resonance data but with a somewhat attenuated response. Ethanol had only small effects on the terminal methyl resonance in both lines. Overall, we conclude that the LS and SS mice differ in the ethanol-induced perturbation of membrane structure, primarily at more superficial membrane domains.

Animals↗
PubMed1991

Changes in brain glucose metabolism in cocaine dependence and withdrawal.

OBJECTIVE: The authors investigated changes in brain function associated with cocaine dependence and withdrawal to provide clues regarding the processes that lead to the uncontrollable self-administration of cocaine. METHOD: They measured regional brain metabolism with [18F]-fluorodeoxyglucose (FDG) and positron emission tomography in 15 outpatients with the diagnosis of cocaine abuse and 17 normal comparison subjects. Ten of the patients were studied less than 1 week after they had last had cocaine, and five were studied 2-4 weeks after withdrawal. RESULTS: Patients studied within 1 week of cocaine withdrawal but not those studied within 2-4 weeks of cocaine withdrawal had higher levels of global brain metabolism as well as higher levels of regional brain metabolism in the basal ganglia and orbitofrontal cortex than did normal subjects, probably as a consequence of less brain dopamine activity. There was also a significant relationship between the number of days since cocaine withdrawal and regional brain glucose metabolism in the orbitofrontal cortex and in the basal ganglia, and the correlations between cocaine craving and metabolic activity were significant in the prefrontal cortex and the orbitofrontal cortex. CONCLUSIONS: Although the time-dependent fall in metabolic activity suggests that the higher metabolic activity observed less than a week after cocaine withdrawal may represent a nonspecific expression of drug withdrawal, the selectivity of changes in glucose metabolism for the basal ganglia and for the orbitofrontal cortex suggests that the regional metabolic changes seen in cocaine abusers during detoxification are related to changes in brain dopamine activity.

Adolescent↗
PubMed1991

Increased lung permeability following long-term use of free-base cocaine (crack).

The clearance of inhaled 99mTc DTPA aerosol from the lungs is used as an index of lung epithelial permeability. Using the radioaerosol method, we investigated the effects of long-term "crack" (free-base cocaine) inhalation on lung permeability in 23 subjects. Eighteen control subjects (12 nonsmokers and 6 cigarette smokers) with no history of drug use were also studied. Subjects inhaled approximately 150 muCi (approximately 5.6 MBq) of 99mTc DTPA aerosol and quantitative gamma camera images of the lungs were acquired at 1-min increments for 25 minutes. Regions of interest (ROIs) were selected to include the following: (1) both lungs; (2) each individual lung; and (3) the upper, middle, and lower thirds of each lung. 99mTc DTPA lung clearance was determined from the slopes of the respective time-activity plots for the different RIOs. Radioaerosol clearance half-times (T1/2) for the seven nonsmoking crack users (61.5 +/- 18.3 minutes) were longer than for the seven cigarette-smoking crack users (27.9 +/- 16.9 minutes) and nine cigarette-smoking crack plus marijuana users (33.5 +/- 21.6 minutes). T1/2 for the nonsmoking crack users was significantly shorter (p less than 0.001) than for the nonsmoking control group (123.8 +/- 28.7 minutes). T1/2 for the cigarette-smoking drug users was similar to that of the cigarette-smoking control group (33.1 +/- 17.8 minutes), suggesting a similar mechanism of damage from the smoke of crack and tobacco. From these groups, one nonsmoker and 11 cigarette smokers displayed biexponential 99mTc DTPA clearances, indicative of greater lung injury than found in the usual cases of monoexponential clearance. The upper lungs of all crack users groups cleared faster than the lower lungs. The faster and biexponential clearance properties of inhaled 99mTc DTPA aerosol were the principal functional abnormalities found in all the drug users. In contrast, 19 of 23 crack users had normal spirometry and gas exchange. These results indicate that 99mTc DTPA may provide a sensitive and useful assay to evaluate the physiologic effects of cocaine inhalation in the lung.

Adult↗
PubMed1991

A new approach to dose reduction in chronic schizophrenia.

The bromocriptine growth hormone test (BGHT) was used to monitor D2 receptor activity in a group of 16 chronic schizophrenics who during the baseline phase were receiving greater than or equal to 20 mg/day haloperidol. In all subjects at baseline, the rise in plasma GH in response to the oral administration of bromocriptine (50 micrograms/kg) was blocked. The dose of haloperidol was then gradually reduced; the BGHT was repeated as each new dose was established. No escape from blockade of the GH response was observed until the dose of haloperidol was lowered to 10 mg/day (3 of 16 subjects escaped from blockade). At this dose the average plasma haloperidol level was 4 ng/ml. Two additional subjects escaped as the dose was reduced to 5 mg/day and six more escaped as the dose was reduced to 2.5 mg/day. The average haloperidol plasma level at 5 and 2.5 mg/day was 1.6 and 1.2 ng/ml respectively. The remaining five subjects escaped from blockade as the dose was reduced to 0 mg/day. In five subjects, escape from blockade was associated with a significant decrease in positive psychotic symptoms; in these subjects reestablishing the "just" blockade dose of haloperidol did not increase psychotic symptoms. In nine subjects escape from blockade was associated with an increase of positive psychotic symptoms; in six of these patients, reestablishing the "just" blockade dose of haloperidol attenuated psychotic symptoms to near baseline levels. We conclude that the GH challenge test is a useful adjunct to dose-reduction in the chronic patient. Furthermore, for some patients the "just" blockade dose appears to be near the minimum dose with the maximum therapeutic effect.

Adult↗
PubMed1990

Acute effects of ethanol on regional brain glucose metabolism and transport.

To evaluate the effects of ethanol in the human brain, we tested six normal subjects and six alcoholics using positron emission tomography and 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) under baseline conditions and 24 hours later after ethanol administration (1 g/kg). Ethanol inhibited cortical and cerebellar glucose metabolism with relative sparing of the basal ganglia and corpus callosum. This inhibition was more pronounced in the alcoholics than in the controls. Measurement of the constants for glucose transport and utilization showed that decreased glucose metabolism was due to a reduction in glucose phosphorylation and not to a change of glucose transport into the tissue. The pattern of regional metabolic inhibition by alcohol paralleled the distribution of benzodiazepine receptors in the human brain.

Adult↗
PubMed1990

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.

Brain↗
PubMed1989

One year treatment with haloperidol or clozapine fails to alter neostriatal D1- and D2-dopamine receptor sensitivity in the rat.

Rats were treated continuously with either haloperidol (HAL), clozapine (CLOZ) or tap water for one year. There were no differences between age-matched control and antipsychotic drug (APD) treated groups regarding the effects of the D1-agonist (+)-SKF 38393 or the D2-agonist quinpirole on striatal cAMP content. However, the combination of SKF (10 microM) and quinpirole (1 microM) produced a marked synergistic response in HAL-treated animals as compared to controls. Our data fail to support the hypothesis that APD produce their neurological side effects by inducing D2-receptor hypersensitivity in the basal ganglia. However, the results do suggest that chronic APD treatment alters the interaction between D1- and D2-neostriatal receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

RBC lithium transport in the psychoses.

In vitro and in vivo red blood cell (RBC) lithium (Li+) intracellular/extracellular ratios were determined in 93 DSM-III schizophrenics (SCZ) in 47 DSM-III schizophreniform disorder patients (SF), in 22 DSM-III bipolar manics (M), in 15 affective disorders patients with mood-incongruent psychotic features (AD-MIP), and in 40 normal controls. There were no significant differences among groups in the in vitro Li+ ratio. Similarly, there was no significant difference among patient groups in the in vivo Li+ ratio. Furthermore, there was no significant difference in the mean Li+ ratios between the Li+-responsive and nonresponsive schizophrenic-like subjects. However, the distribution of Li+ ratios (both in vitro and in vivo) in the Li+-responsive group was significantly abnormal, showing more ratios in the extremes of the distribution (a platykurtic distribution).

Bipolar Disorder↗
PubMed1989

Mapping cocaine binding sites in human and baboon brain in vivo.

The first direct measurements of cocaine binding in the brain of normal human volunteers and baboons have been made by using positron emission tomography (PET) and tracer doses of [N-11C-methyl]-(-)-cocaine ([11C]cocaine). Cocaine's binding and release from brain are rapid with the highest regional uptake of carbon-11 occurring in the corpus striatum at 4-10 minutes after intravenous injection of labeled cocaine. This was followed by a clearance to half the peak value at about 25 minutes with the overall time course paralleling the previously documented time course of the euphoria experienced after intravenous cocaine administration. Blockade of the dopamine reuptake sites with nomifensine reduced the striatal but not the cerebellar uptake of [11C]cocaine in baboons indicating that cocaine binding is associated with the dopamine reuptake site in the corpus striatum. A comparison of labeled metabolites of cocaine in human and baboon plasma showed that while cocaine is rapidly metabolized in both species, the profile of labeled metabolites is different, with baboon plasma containing significant amounts of labeled carbon dioxide, and human plasma containing no significant labeled carbon dioxide. These studies demonstrate the feasibility of using [11C]cocaine and PET to map binding sites for cocaine in human brain, to monitor its kinetics, and to characterize its binding mechanism by using appropriate pharmacological challenges.

Adult↗
PubMed1989

On the sensitivity of intact cells to perturbation by ethanol.

A comparison was made of ethanol's effects on the order of plasma membranes in intact cells and some isolated membrane preparations. Order was assessed by steady-state fluorescence polarization techniques using the non-permeant probe, TMA-DPH. The data show that two cultured cells, rat neonatal astroglial and N2A neuroblastoma, were sensitive to significant ethanol-induced disordering within the anesthetically relevant range (100 - 200 mM). Human erythrocytes, cultured fibroblasts and homogenized astroglial cells required higher ethanol concentrations (greater than 250 mM) to produce a similar effect. Intact erythrocytes were approximately twice as sensitive as erythrocyte ghost membranes to ethanol-induced perturbation. The neonatal glial and N2A cells were approximately five times more sensitive than synaptic membranes to ethanol effects. DMPC and DMPC + cholesterol liposomes and myelin membranes were insensitive to ethanol's effects. The incorporation of 10 mole % ganglioside GM1 sensitized the liposomes to ethanol-induced perturbation.

Cell Membrane↗
PubMed1989

Lithium antagonism of ethanol-induced intoxication: relationship to intracellular lithium levels.

Seventeen detoxified chronic alcoholics participated in a double-blind trial comparing placebo and lithium (Li+) effects on acute ethanol (1 g/kg) intoxication. In a repeated measures, split-half crossover design, subjects were maintained for 7 days on Li+ or placebo before the ethanol challenge. Plasma Li+ levels on day 7 averaged 1.3 +/- 0.3 mM. Li+ was not more effective than placebo in attenuating ethanol effects across the subjective dimensions of intoxication, desire to drink, and control of drinking and across the cognitive dimensions measured by Trail Making A, Speed of Closure, and the Minnesota Clerical Test. Li+ was not significantly more effective than placebo in preventing the ethanol-induced rise in plasma prolactin. Subjects were divided according to high and low red blood cell (RBC) Li+ intracellular/extracellular Li+ ratios. In a comparison of the Li+ to placebo arms of the trial, the high ratio subjects (n = 9) showed a significant 44% decrease in ethanol-induced intoxication, while the low ratio subjects (n = 8) showed a 15% increase. Furthermore, the high ratio subjects performed better than the low ratio subjects, independent of the ethanol effect, on all tests of cognitive performance. These preliminary data suggest that the Li+ ratio may be a useful tool in defining unique subgroups of alcoholic patients.

Adult↗
PubMed1988

Effects of short-term prenatal alcohol exposure on neuronal membrane order in rats.

Long-Evans rat dams were treated with ethanol (4 g/kg, twice daily) by gavage on gestational days 10-14. This dosage schedule has been shown to produce significant behavioral and ponderal teratogenicity. Pair-fed dams were gavaged with isocaloric amounts of sucrose. All offspring were reared by untreated, surrogate dams. Pups were sacrificed on days 3 and 28, and whole brain neuronal plasma membranes were prepared for analysis by a fluorescence polarization technique using 1,6-diphenyl-1,3,5-hexatriene as the membrane probe. On day 3, steady-state anisotropy was significantly decreased in the ethanol-treated pups. Arrhenius plots revealed that this difference was associated with a change on both membrane entropy and enthalpy. By day 28, the differences between groups disappeared. These data would be consistent with the view that the brief gestational ethanol exposure delays neuronal maturation.

Animals↗
PubMed1988

Lithium transport in human fibroblasts: relationship to RBC lithium transport and psychiatric diagnoses.

Cultured fibroblasts were prepared from six normal controls, five DSM-III manic patients, and six DSM-III schizophrenic patients. Lithium (Li+) uptake, 24-hour Li+ ratios, and steady-state membrane potential were measured in these cell lines. The uptake of 10 mM Li+ reached maximum at 2 hours, with an intracellular concentration of approximately 15 mM. No significant difference in uptake was found among subject groups. Twenty-four hour Li+ (ratio of intracellular/extracellular Li+) ratios were determined by incubating the cell lines for 24 hours in the presence of 2 mM Li+. No significant difference was observed among groups; nor was there any significant correlation between the fibroblast 24-hour ratios and 24-hour in vitro ratios determined in donor red cells. The relationship between membrane potential and the 24 hour Li+ ratio in fibroblasts was determined. The average potential in these cell lines was -56 mV and was not affected by Li+ treatment. No correlation between the Li+ ratio and membrane potential was found.

Adult↗
PubMed1986

Beneficial effects of polyunsaturated fatty acids in partially nephrectomized rats.

Evening primrose oil, safflower oil, and salmon oil, all with high polyunsaturated fatty acid content, were fed to partially nephrectomized rats; the effects were compared to those of feeding beef tallow. All three oils had favorable effects on progression of renal failure, salmon oil on kidney histology as well. The changes induced in platelet production of thromboxane A2, and in the renal production of various eicosanoids may explain the protective role of these oils.

Animals↗