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R J Hitzemann

Publications and source records attributed to R J Hitzemann.

At least 19 recordsLinked to original sources
PubMed1995

Evaluation of age-related changes in serotonin 5-HT2 and dopamine D2 receptor availability in healthy human subjects.

We assessed the relation between serotonin 5-HT2 receptor availability and aging and compared it with that for dopamine D2 receptors on 19 healthy male volunteers (age range, 21-49 years) using positron emission tomography (PET) and F-18 N-methylspiperone (NMS). 5-HT2 Receptor availability was obtained using the ratio of the distribution volume in the region of interest to that in the cerebellum (Bmax'/Kd' + 1). 5-HT2 Receptor measures were obtained in frontal and occipital cortices. D2 receptor availability in striatum was measured using the "ratio index". 5-HT2 Receptor availability decreased significantly with age. This effect was significantly more accentuated for 5-HT2 receptor availability in the frontal (r = 0.92, p < or = 0.0001) than in the occipital (r = 0.67, p < or = 0.0016) cortex (df = 1, p < 0.025). Dopamine D2 receptors were also found to decrease significantly with age (r = 0.63, p < or = 0.007). In a given subject, striatal D2 receptor availability significantly correlated with 5-HT2 receptor availability in the frontal (r = 0.51, p < or = 0.035) but not in the occipital cortex. These results document a decline in 5-HT2 and D2 receptor availability with age and showed an association between frontal 5-HT2 and striatal D2 receptors.

Adult↗
PubMed1992

Quantitative autoradiography of cocaine binding sites in human brain postmortem.

Quantitative autoradiography was used to study cocaine binding sites in the human brain postmortem. Tritiated cocaine was applied to brain sections from three drug- and disease-free subjects at a low (10 nM) concentration and at a high (1 microM) concentration, the latter being in the range of brain concentrations of cocaine found in users of the drug. Nonspecific binding was assessed in the presence of 100 microM unlabeled cocaine. At low (10 nM) concentrations of labeled cocaine, the basal ganglia exhibit the highest density of binding sites, with considerably lower densities in thalamus, cortex, and hippocampus. Cocaine binding at high (1 microM) concentrations displayed a different distribution pattern, more homogeneous with some cortical regions exhibiting binding site densities close to those seen in the basal ganglia. Preliminary competition experiments with several drugs indicate that dopamine uptake inhibitors completely block cocaine binding to the basal ganglia, while serotonin uptake inhibitors were more effective in the hippocampus. These findings suggest that cocaine binds to dopamine uptake sites in the human basal ganglia postmortem but that it also interacts with other classes of binding sites, depending on the concentration and brain region examined.

Animals↗
PubMed1990

Further evidence against the coupling of dopamine receptors to phosphoinositide hydrolysis in rat striatum.

The effects of D1 and D2 dopamine receptor agonists on phosphoinositide hydrolysis were studied by measuring the accumulation of radioactive inositol phosphates in slices of rat corpus striatum prelabelled with [3H]inositol. All assays were performed in the presence of lithium. Neither the D1 receptor agonist SKF 38393 nor the D2 receptor agonist quinpirole, alone or in combination, had an effect on basal accumulation of inositol phosphates. The muscarinic receptor agonist carbachol produced a robust increase in the accumulation of inositol monophosphate and a smaller increase in the accumulation of inositol bisphosphate. These effects were not altered by the presence of quinpirole. Additionally, quinpirole also had no effect when assays were conducted in the presence of the muscarinic receptor antagonist scopolamine, the glutamic acid receptor antagonist kynurenic acid, and the antioxidant glutathione. These results are discussed in relation to recent contradictory reports and lend support to the position that D2 dopamine receptors are not coupled to phosphoinositide hydrolysis in rat striatum.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Prenatal phenytoin exposure decreases neuronal membrane order in rat offspring hippocampus.

Pregnant Sprague-Dawley CD rats were administered 0 or 200 mg/kg of phenytoin by gavage on days 7-18 of gestation, with controls pair-fed to the phenytoin exposed dams. At birth, litter sizes were standardized to 10, balancing for sex, and were reared by their biological dams until either day 3 or 28. At each of these ages half of the litters from each group were used to determine synaptic plasma membrane order in selected brain regions (cerebellum, cortex, hippocampus) by fluorescence polarization using the probe 1,6-diphenyl-1,3,5-hexatriene (DPH). No significant differences in membrane anisotropy were noted in 3-day-old phenytoin offspring, but a reduction in anisotropy in 28-day-old phenytoin offspring hippocampal regions was observed. The effect was specific in that no changes were found in the cerebellum or cortex at this age. The magnitude of the change corresponded to an approximately 3-5 degrees C increase in temperature and to changes produced by other known membrane disordering agents, such as ethanol. The data, together with previous findings of memory impairments in phenytoin offspring, support an association between the hippocampal membrane disordering effect and functional impairments produced by prenatal phenytoin exposure.

Aging↗
PubMed1990

The utility of 1-[18F]fluoro-3-iodopropane for the synthesis of certain dopamine D-1 and benzodiazepine receptor radioligands.

No-carrier-added (NCA) R(+)-7-chloro-8-hydroxy-3-(3'-[18F]fluoropropyl)-1-phenyl-2,3,4,5- tetrahydro-3-benzazepine (2b) (an analog of dopamine D-1 receptor ligand SCH 23390), ethyl 8-fluoro-5,6-dihydro-5-(3'-fluoropropyl)-6-oxo-4H- imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (4b) and 3'-[18F]fluoropropyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H- imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (6b) (analogs of the benzodiazepine RO 15-1788) were synthesized by alkylation of the corresponding nor-compound with NCA 1-[18F]fluoro-3-iodopropane in 10-15% yield (EOB) in approximately 110 min and with a mass of 2-3 nmol. Compound 2 is less potent (approximately 12-14 times) than SCH 23390 in binding to rat striatal membranes in vitro. Compounds 2b, 4b and 6b exhibit no specific anatomical distribution to mouse brain. These results suggest that the substituent at position 3 of SCH 23390, and position 5 and carboxylate group of RO 15-1788 are critical determinants both of affinity and selectivity for receptor binding, and underscores the evaluation necessary when even minor changes (C1 to C3) are made in bioactive compounds.

Animals↗
PubMed1989

Long-term treatment with antipsychotics does not alter the phosphoinositide response to muscarinic or D2 dopaminergic agonists in rat striatum.

The effects of the muscarinic agonist carbachol and the D2 dopaminergic agonist quinpirole on phosphoinositide hydrolysis were studied in the corpus striatum of rats which had been treated for one year with either haloperidol or clozapine. In the presence of LiCl, carbachol increased the accumulation of inositol monophosphate (greater than 100%) and bisphosphate (greater than 20%). Quinpirole had no effect on either basal or carbachol-stimulated accumulation of inositol phosphates. There was no difference in these responses between the drug-treated animals and age-matched controls.

Animals↗
PubMed1989

Effects of non-electrolyte molecules with anesthetic activity on the physical properties of DMPC multilamellar liposomes.

The effects of 13 non-electrolytes with moderate anesthetic potency on the order of DMPC liposomes were examined. Changes in order were monitored by steady-state fluorescence polarization techniques using 1,6-diphenyl-1,3,5-hexatriene (DPH) and 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPG). At 30 degrees C, all of the compounds tested decreased the DPH steady-state anisotropy (rs), with potencies highly correlated to their oil/water partition coefficients. However, only the most hydrophobic anesthetics decreased TMA-DPH RS. Some of the most hydrophilic compounds, including ethanol and urethane, actually increased TMA-DPH rs, suggestive of an increase in membrane order. The concept of selectivity was borrowed from partitioning theory and used to explain some effects on anesthetic potency of decreasing temperature to 18 degrees C. In the gel as opposed to the liquid crystalline phase, selectivity for decreasing membrane order (as monitored by DPH) markedly increased, suggesting that anesthetic partitioning and/or the site of anesthetic action was occurring in a more hydrophobic domain. The solute-independent difference (or capacity) between two membranes for perturbation was defined as membrane sensitivity. Sensitivity appeared to also decrease with decreasing temperature, despite the decrease in membrane partitioning. This effect is thought to result from the selective delivery of the anesthetic solute to the membrane interior and away from more hydrophilic domains where anesthetics may order membrane structure.

Alcohols↗
PubMed1987

Repeated electroconvulsive shock: effect on sodium dependency and regional distribution of opioid-binding sites.

The effects of single and repeated electroconvulsive shock (ECS) on the binding of [3H]diprenorphine to rat brain membranes was studied. Repeated but not single ECS significantly increased the Bmax of [3H]diprenorphine binding when measured in the absence but not in the presence of NaCl. On a regional basis the effect of ECS was greatest in the olfactory bulb, nucleus accumbens, and striatum. More modest increases were found in the hippocampus, amygdala, septum, hypothalamus, and pyriform cortex. No significant effect was found in the brainstem and frontal cortex. Although the regional rank order of receptor increase does not match the receptor distribution of brain enkephalins, the receptor increase does parallel the regional increases in brain enkephalins following ECS.

Animals↗
PubMed1986

Ethanol-induced changes in neuronal membrane order. An NMR study.

The effects of ethanol-d6 on the lipid matrix of rat brain neuronal membranes were investigated by delayed Fourier transform 1H-NMR techniques. At 24 degrees C, neither 0.1 nor 0.2% (v/v) ethanol-d6 measurably affected the methylene resonance intensity. However, 0.4 and 1.0% ethanol-d6 increased resonance intensity, 35 and 51%, respectively. With increasing temperature, a decrease in resonance intensity for 0.1% ethanol-d6 was observed reaching a maximum of 20% at 42 degrees C. Furthermore, increasing temperature attenuated the increases in resonance intensity seen with 0.4 and 1.0% ethanol-d6. At 24 degrees C, no concentration of ethanol-d6 had a significant effect on the choline methyl resonance. However, with increasing temperature both 0.1 and 0.2% ethanol-d6 decreased this resonance's intensity. The intensity of the terminal methyl resonance was increased in a dose related fashion by ethanol-d6, reaching a maximum of +41% at 1.0% (24 degrees C). Increasing temperature attenuated this effect, but no concentration of ethanol-d6 significantly decreased resonance intensity. The increases and decreases in resonance intensity induced by ethanol-d6 are interpreted in terms of a decrease and an increase in membrane order, respectively. It is proposed that ethanol-d6 exerts two effects on neuronal membranes, an ordering effect on the membrane surface and a disordering effect in the membrane interior. A higher enthalpy of ethanol binding to the surface as compared to the interior of the membrane leads to an attenuation of the ethanol disordering effect with increasing temperature.

Animals↗
PubMed1986

Fluphenazine activity and antipsychotic response.

Plasma fluphenazine levels and plasma total neuroleptic activity (as quantitated by the neuroleptic receptor binding assay) were related to therapeutic response in 15 DSM-III schizophrenic patients who received a predetermined, fixed dose of fluphenazine for 14 days. Mean neuroleptic activity of the plasma was 84% greater than can be accounted for by the parent fluphenazine alone, and varied widely between patients. A sigmoidal relationship between total neuroleptic activity of plasma and response was found, with a continued plateau of response at higher total neuroleptic levels. Furthermore, the RBA data suggested (P less than 0.002) that two populations of drug-responsive schizophrenics exist which may be discriminated by the total D2 binding activity of plasma required for response.

Chromatography, Gas↗
PubMed1986

Growth hormone response to apomorphine and diagnosis: a comparison of three diagnostic systems.

Our study takes a further look at the apomorphine test in the psychoses and affective disorders, with special reference to the use of different diagnostic systems. Patients meeting Research Diagnostic Criteria (RDC) for schizophrenia, schizoaffective disorder, or manic disorder were included. In addition to the RDC, diagnosis was also made using the DSM-III and ICD-9. All patients underwent an evaluation of peak GH response to apomorphine administration. The results show that RDC and ICD-9 are similar, in that for both systems, a high GH response correlates with a schizoaffective disorder and distinguishes those patients significantly from manic patients. The DMS-III brings in some new dimensions, in that schizophreniform disorder (6-month cut-off) is distinguished from schizophrenia. In addition, patients with affective symptoms and mood-incongruent psychoses are more closely related to schizophreniform disorder than to classical manic disorder.

Adult↗
PubMed1986

Developmental changes in synaptic membrane order: a comparison of regions in the rat brain.

Developmental changes in synaptic membrane order were followed in 5 regions of the rat brain, the cortex (Cx), cerebellum (Cb), brainstem (BS), lateral subcortex (LSCx) and midline subcortex (MSCx). Membrane order was assessed by the fluorescence polarization technique, using 1,6-diphenyl-1,3,5-hexatriene (DPH) as the probe. The results illustrate that the developmental increase in membrane order proceeds from caudal to rostral brain regions. Thus, at the earliest time point examined (day 3) steady-state anisotropy (rs) in the BS was significantly higher than in the Cx and reached adult values by day 14 while the Cx values were still significantly less than the adult value even at day 30. The thermotropic behavior of the membranes was investigated over the range of 20-37 degrees C. The Arrhenius slopes among the Cx, BS, LSCx and MSCx were similar across all ages studied, suggesting that the developmental increase in order primarily results from a change in entropy. In contrast, the Arrhenius slopes for the Cb increase greater than 100% during development, suggesting that a change in enthalpy is important for the increase in membrane order. Multilamellar liposomes prepared from membrane lipid extracts generally showed the same developmental changes in order as the intact membranes. These data indicate that the increase in membrane order results from a marked change in bulk lipid composition rather than a secondary lipid matrix change (e.g. in membrane asymmetry) and/or from the developmental increase in the protein/lipid ratio.

Animals↗
PubMed1986

Electroconvulsive shock activates endogenous opioid systems: behavioral and biochemical correlates.

From the evidence reviewed above, there is little doubt that ECS activates endogenous opioids and modifies their receptors. Thus, this form of SIA is accompanied by many other corollaries of opioid-like actions, including catalepsy, similar EEG patterns, common autonomic effects, and increases in opioid receptor binding sites. Investigations have further indicated that the amnestic effects of ECS can also be attenuated by naloxone, and that pituitary-derived opioids may play an important role as a predominant source of opioids that contribute to these opioid-like effects following ECS. It is hoped that these many attempts to correlate SIA with other behavioral and physiological endpoints following ECS will provide a more global perspective on the role of endogenous opioid systems in ECS. From these results, it is suggested that other forms of SIA may also share many of these properties in common with ECS-induced SIA. Nonetheless, ECS and other forms of SIA, such as cold water exposure and restraint, share with ECS a common history of clinical use in the treatment of human depression. It is possible that the common thread linking these experimental observations to endogenous opioid systems may provide new insights into the cause and treatment of mental disorders as well as the perception of pain.

Analgesia↗
PubMed1985

1H-NMR spectra of rat synaptic plasma membranes: effect of temperature and comparison with fluorescence polarization.

1H-NMR spectra of rat synaptic plasma membranes obtained over the temperature range of 24-46 degrees C are presented. The data illustrate that a transition occurs from a more ordered to less ordered state at approximately 37 degrees C. This phenomenon was not related to using D2O as the solvent and was replicated, although with less sensitivity, using fluorescence polarization methodology.

Animals↗
PubMed1985

Determination of ethanol partition coefficients to the interior and the surface of dipalmityl-phosphatidylcholine liposomes using deuterium nuclear magnetic resonance spectroscopy.

The binding of ethanol-d6 to dipalmityl-phosphatidylcholine liposomes (DPPC) can be separated into two processes, namely, ethanol in the bilayer and on the surface of the bilayer. For the deuterons of the methylene group, the T2 of both bound states is shorter than the respective preexchange lifetime (tau beta) and therefore the amount of ethanol bound to both sites can be determined from the decrease in the methylene intensity resonance in the presence of DPPC. For the methyl resonance, however, only the T2 of deuterons on ethanol bound to the surface is less than its tau beta and the amount of surface bound ethanol-d6 can be determined. Subtraction yields the amount of ethanol bound within the bilayer. The partition coefficient for internally bound ethanol remains constant from 0 to 3.5 m ethanol. Surface binding is, however, highly cooperative.

Ethanol↗