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D E Schmidt

Publications and source records attributed to D E Schmidt.

At least 19 recordsLinked to original sources
PubMed1992

Visualization of extrastriatal dopamine D2 receptors in the human brain.

[123I]Epidepride, a potent and selective dopamine D2 radioligand, was administered to a 27 year old normal male volunteer. Single photon tomography revealed that peak striatal uptake occurred at 4 h after injection with a striatal:cerebellar ratio of 7.8 rising to over 100 at 18 h post injection. Uptake above the levels seen in cerebellum was also noted in the thalamus, pituitary, hypothalamus and temporal lobe, particularly medially. Single photon tomography with [123I]epidepride allows visualization of extrastriatal dopamine D2 receptors in man.

Adult↗
PubMed1991

High affinity dopamine D2 receptor radioligands. 2. [125I]epidepride, a potent and specific radioligand for the characterization of striatal and extrastriatal dopamine D2 receptors.

Epidepride, (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxybenzamide+ ++, the iodine analogue of isoremoxipride (FLB 457), was found to be a very potent dopamine D2 receptor antagonist. Optimal in vitro binding required incubation at 25 degrees C for 4 h at pH 7.4 in a buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2 and 1 mM MgCl2. Scatchard analysis of in vitro binding to striatal, medial frontal cortical, hippocampal and cerebellar membranes revealed a KD of 24 pM in all regions, with Bmax's of 36.7, 1.04, 0.85, and 0.37 pmol/g tissue, respectively. The Hill coefficients ranged from 0.91-1.00 in all four regions. The IC50's for inhibition of [125I]epidepride binding to striatal, medial frontal cortical, and hippocampal membranes for SCH 23390, SKF 83566, serotonin, ketanserin, mianserin, naloxone, QNB, prasozin, clonidine, alprenolol, and norepinephrine ranged from 1 microM to greater than 10 microM. Partial displacement of [125I]epidepride by nanomolar concentrations of clonidine was noted in the frontal cortex and hippocampus, but not in the striatum. Scatchard analysis of epidepride binding to alpha 2 noradrenergic receptors in the frontal cortex and hippocampus revealed an apparent KD of 9 nM. At an epidepride concentration equal to the KD for the D2 receptor, i.e. 25 pM, no striatal alpha 2 binding was seen and only 7% of the specific epidepride binding in the cortex or hippocampus was due to binding at the alpha 2 site. Correlation of inhibition of [3H]spiperone and [125I]epidepride binding to striatal membranes by a variety of D2 ligands revealed a correlation coefficient of 0.99, indicating that epidepride labels a D2 site. In vitro autoradiography revealed high densities of receptor binding in layers V and VI of prefrontal and cingulate cortices as well as in striatum. In vivo rat brain uptake revealed a hippocampal:cerebellar and frontal cortical:cerebellar ratio of 2.2:1 which fell to 1.1:1 following haloperidol pretreatment. These properties suggest that [125I]epidepride is a superior radioligand for the in vitro and in vivo study of striatal and extrastriatal dopamine D2 receptors.

Animals↗
PubMed1991

Strangers in a strange land: a psychobiological study of infant monkeys before and after separation from real or inanimate mothers.

Some rhesus monkey (Macaca mulatta) infants have a "despair" or depression-like response to mother-infant separation, while others do not. The presumed interrelation between early rearing conditions and the neurobiological status of the infant that might lead to increased risk for despair is not understood. In this study, the characteristics of the "mother" were controlled by rearing infant rhesus monkeys with their biological mothers, or with inanimate mothers. Behavioral data were collected before and after separation at 6-7 months of age. The neurobiological status of the infants was evaluated by measuring the concentration of norepinephrine, its major metabolite, and the metabolites of dopamine and serotonin in cerebrospinal fluid. The results suggest that despair is not simply a behavioral response to separation. Instead, despair may reflect the inability to cope with the separation environment. Coping with the separation environment appears to depend on neurobiological and behavioral characteristics of the infant that are related to, if not determined by, characteristics of the mother.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

High affinity dopamine D2 receptor radioligands. 1. Regional rat brain distribution of iodinated benzamides.

Five 125I-labeled substituted benzamides, which are close structural analogues of (S)-sulpiride, eticlopride, and isoremoxipride, were evaluated for their selective in vivo uptake into dopamine D2 receptor rich tissue of the rat brain. "Iodopride" (KD 0.88 nM), an iodine substituted benzamide structurally related to sulpiride, displayed a maximal striatum: cerebellar uptake ratio of 7.6. Demonstration of saturation of the receptor with [125I]iodopride in striatum required uptake in frontal cortex to be used, rather than cerebellar uptake, to define nonspecific binding. Two other ligands structurally related to eticlopride, "iclopride" (KD 0.23 nM) and "itopride" (KD 0.16 nM), displayed maximal striatal: cerebellar uptake ratios of 9.8 and 3.3, respectively. The most potent ligands, "epidepride" (KD 0.057 nM) and "ioxipride" (KD 0.070 nM) showed striatal:cerebellar uptake ratios of 234 and 65, respectively. The observed uptake ratios correlated poorly with the affinity constants for the dopamine D2 receptor alone, but were highly correlated (r = 0.92) with the product of the receptor dissociation constant (KD) and the apparent lipophilicity (kw), as determined by reverse-phase HPLC at pH 7.5. Total striatal uptake also appeared dependent on lipophilicity, with maximal uptake occurring for ligands having log kw 2.4-2.8.

Animals↗
PubMed1990

Sodium-dependent isomerization of dopamine D-2 receptors characterized using [125I]epidepride, a high-affinity substituted benzamide ligand.

We have characterized the in vitro binding of a new ligand, [125I]epidepride, and used this substituted benzamide to assess the sensitivity of dopamine D-2 receptors to sodium. Both direct and indirect binding studies with [125I]epidepride and unlabeled epidepride, respectively, demonstrated that the affinity of D-2 receptors for the ligand was decreased from 20 to 30 pM in the presence of sodium to 350 to 500 pM in the absence of sodium. The density of binding sites for [125I]epidepride was identical in the presence and absence of NaCl. The time courses for association of [125I]epidepride to and dissociation from D-2 receptors in the presence of sodium were not consistent with simple bimolecular reactions, suggesting the possibility of a sodium-dependent ligand-induced receptor isomerization. Thus, dissociation of [125I]epidepride was biphasic in the presence of sodium, but monophasic in the absence of sodium. The rank order of potency for inhibition of [125I]epidepride binding by drugs was identical in rat striatum and cells expressing a D-2 receptor cDNA, and similar to the previously described pharmacological profile of D-2 receptors labeled by [3H]spiperone. [125I]Epidepride bound to two classes of binding sites in rat medial prefrontal cortex. One class, present at a density of 10 fmol/mg of protein and with a Kd value of approximately 40 pM, was pharmacologically indistinguishable from D-2 receptors in striatum and transfected cells. The pharmacological profile of the second class of sites was similar to that of alpha-2 adrenergic receptors. [125I]Epidepride had 50- to 100-fold lower affinity (approximately 2 nM) for alpha-2 receptors than for D-2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

A longitudinal study of the effect of different social rearing conditions on cerebrospinal fluid norepinephrine and biogenic amine metabolites in rhesus monkeys.

The purpose of this study was to determine whether disruption of early social attachment alters the activity of brain biogenic amine systems in rhesus monkeys (Macaca mulatta). Male rhesus monkey infants were deprived of maternal interaction, peer interaction, or both, during the first 22 months of life. Cerebrospinal fluid (CSF) was collected under rigorously controlled conditions approximately every month and assayed for levels of norepinephrine (NE), its major metabolite, and the metabolites of dopamine and serotonin. Mother-Deprived infants had lower levels of CSF NE than Mother-Reared infants. Mother-Deprived infants also failed to develop the same pattern of intercorrelations between compounds and month-to-month stability in levels of neurotransmitter and metabolites in CSF as the Mother-Reared infants. Finally, there were changes in CSF NE levels associated with social separation and social group formation. The brain NE system appears to be sensitive to changes in the social environment. Its level of activity, as reflected in levels of NE in CSF, appears to depend on both the prevailing social environment and the prior rearing environment.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Strain specific cholinergic changes in response to stress: analysis of a time-dependent avoidance variation.

Investigators have established that the performance of an incompletely learned avoidance task is a U shaped function of the time since the original partial acquisition. Thus rats perform more poorly when retested at intermediate time intervals (1-8 hr) after training than they do when tested at longer post-acquisition intervals (24-48 hr). Studies have suggested that such time-dependent deficits are not related to changes in learning ability, but rather result from shock-induced motor suppression which interferes with active avoidance responding. Pharmacological studies utilizing drugs which effect cholinergic function have indicated that an inhibitory cholinergic system may be involved in mediating post-shock motor suppression. To obtain direct biochemical evidence for possible cholinergic mediation of post-shock motor suppression, measurements of high affinity choline uptake and acetylcholine turnover were made at varying time intervals following partial active avoidance training in F-344 rats. An increase in cholinergic function was found in the dorsal, but not the ventral hippocampus 30 min, 1 hr and 4 hr following acquisition training. These biochemical alterations were temporally correlated with deficits in active avoidance responding. We have reported that the immediate behavioral suppression observed in another rat strain (Sprague-Dawley, Zivic Miller Laboratories), which exhibits inferior active avoidance performance, is similarly correlated with cholinergic activation in the dorsal hippocampus [17]. These data support the hypothesis that the dorsal-hippocampal cholinergic system is involved in the mediation of stress-induced behavioral suppression.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1983

Effects of dietary lecithin on hormonal and neurobehavioral profiles in normal subjects.

Four normal subjects received lecithin supplements sufficient to elevate serum choline levels 3-fold. Despite persistent hypercholinemia over 48 hours of close observation, no increase was observed in serum ACTH, cortisol, and insulin concentrations, or in free urinary catecholamine excretion. Screening of a large group of other pituitary and gonadal hormones also failed to reveal any influence of lecithin supplements. EEG patterns and results of psychometric tests were also unaltered.

Acetylcholine↗
PubMed1981

Failure of muscarinic blockade to antagonize analepsis induced by thyrotropin-releasing hormone and MK-771 in the rat.

In the rat, the antimuscarinics atropine and scopolamine failed to block the reduction in pentobarbital-induced sleep time produced by either thyrotropin-releasing hormone (TRH) or MK-771 (a TRH analog). Previous reports have indicated that the marked analeptic effect produced by TRH is antagonized by such agents. It is not clear at this time whether the difference between our findings and these previous studies indicates a reduced sensitivity of cholinergic receptors in the rat to muscarinic blockade, a different neurochemical mechanism of action of TRH in the rat, or other unknown factors.

Animals↗
PubMed1979

Scaling current and energy with body weight: requirements for the transthoracic ventricular defibrillation of calves as they grow from 50 to 150 kg.

To test the hypothesis that the effectiveness of a shock in achieving ventricular defibrillation is relatively independent of body weight if electrode diameter is proportional to the one-third power and current is proportional to the two-thirds power of weight, we studied defibrillation rates in 10 calves as they increased weight. At 50 kg, each calf was subjected to 20 fibrillation-defibrillation episodes using 10.3-cm diameter electrodes and 32-amp, 4-msec rectangular pulses for defibrillation. Two days after the original study, each calf underwent 20 additional episodes involving 44-amp pulses. With the specified scaling of electrode diameter and pulse amplitude, the two studies were repeated at weight intervals of 25 kg as the animals grew. Six calves survived. In the study that started with 32-amp pulses, first-shock success values of 28%, 49%, 66%, 51% and 23% were found in the six surviving calves at 50, 75, 100, 125 and 150 kg, respectively. The corresponding values were 93%, 96%, 93%, 94% and 91% in the study that started with 44-amp pulses. While the results of the 32-amp study fail to support our initial hypothesis, those obtained in the 44-amp current study appear compatible with the hypothesis.

Animals↗
PubMed1978

Localization of fumarylacetoacetate fumarylhydrolase in rat liver.

The intracellular location of fumarylacetoacetate fumarylhydrolase (EC 3.7.1.2) has been demonstrated in rat liver tissue. Two fractionation procedures involving homogenization and differential centrifugation were adopted. The first fractionation procedure isolated the nuclear fraction while the second gave the mitochondrial, microsomal, and soluble phase fractions. The hydrolase is localized in the soluble phase of the rat liver tissue. The enzyme also showed a high relative specific activity in the soluble phase fraction. Fractionation efficiency was checked by microscopic studies and by determining the distribution of a number of marker enzymes.

Acetoacetates↗