Biomedical subjects

J E Kleinman

Publications and source records attributed to J E Kleinman.

At least 73 records · Page 4Linked to original sources

PubMed1994

The subnuclear distribution of 5-HT3 receptors in the human nucleus of the solitary tract and other structures of the caudal medulla.

The distribution of 5-HT3 receptors was examined in the human medulla using [3H]LY278584, a highly selective 5-HT3 receptor antagonist. The highest density of 5-HT3 receptors was found in the substantia gelatinosus subnucleus of nucleus of the solitary tract (NTS) throughout its rostrocaudal extent, followed by the dorsal subnucleus, the area postrema (AP), the commissural subnucleus, the medial subnucleus, and in an arc corresponding to the pars gelatinosus of the spinal trigeminal nucleus (nSp5). The distribution of 5-HT3 receptors in the brain may help explain some of the reported CNS activities of 5-HT3-selective drugs. The anti-emetic and antinociceptive activities of 5-HT3 antagonists may be mediated by receptors in sensory areas of the brainstem.

Adolescent↗

PubMed1994

Alterations in mRNA levels of D2 receptors and neuropeptides in striatonigral and striatopallidal neurons of rats with neuroleptic-induced dyskinesias.

Chronic neuroleptic treatment in rat produces vacuous chewing movements (VCMs), analogous to TD in humans. We hypothesized that these hyperkinetic movements were due to alterations in striatonigral and striatopallidal GABAergic spiny II neurons. Rats were treated for 36 weeks with haloperidol decanoate and withdrawn for 28 weeks. Striatonigral and striatopallidal neurons were assessed using in situ hybridization histochemistry for mRNA levels of D1 and D2 dopamine receptors, preproenkephalin (ENK), prodynorphin (DYN), protachykinin (substance P), and glutamate decarboxylase (GAD67) in the dorsolateral and ventromedial striatum as well as the nucleus accumbens. Rats that did not develop VCMs (-VCM) had increased D2 receptor and DYN mRNA, and reduced substance P mRNA in the dorsolateral striatum. Rats with persistent VCMs (+VCM) had increased D2 receptor, ENK, and DYN mRNA in both striatal regions, and increased ENK and DYN mRNA in the nucleus accumbens, compared with controls. Relative to -VCM rats, however, +VCM rats only had increased ENK mRNA in the nucleus accumbens. Considering the overall pattern of mRNA changes, the data suggest that alterations in both the D1-mediated striatonigral and the D2-mediated striatopallidal pathways play a role in the expression of the VCM syndrome. To the extent that gene expression parallels changes in neuronal activity, this implies that the VCM syndrome is associated with increased activity in both pathways.

Animals↗

PubMed1994

Alterations in TRH receptors in temporal lobe of schizophrenics: a quantitative autoradiographic study.

We utilized quantitative autoradiography to determine the distribution of receptors for thyrotropin-releasing hormone (TRH) throughout the human temporal lobe and to examine the distribution of these receptors in discrete subregions of the temporal lobe from patients diagnosed premortem with schizophrenia. When compared to non-neurologic controls, schizophrenic patients demonstrated an increase of 51% in the concentration of TRH receptors in the molecular layer of the dentate gyrus. Within nuclei of the schizophrenic amygdala, marked decreases were found in the central (44%), medial (38%), cortical (36%), accessory cortical (52%), lateral (54%), and medial basal (22%) nuclei. We also examined postmortem brain samples from patients with Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease for alterations in the distribution of TRH receptors. No significant differences from non-neuropsychiatric controls were noted within the hippocampus in any of these disease states; however, slight alterations were noted in the central and medial basal amygdala in Huntington's disease and in the cortical amygdala in Alzheimer's disease. These disease-specific findings suggest that TRH may play a role in the neurochemical dysfunction of schizophrenia.

Adult↗

PubMed1994

The dopamine transporter and dopamine D2 receptor messenger RNAs are differentially expressed in limbic- and motor-related subpopulations of human mesencephalic neurons.

Dysfunction of dopamine neural systems is hypothesized to underlie neuropsychiatric disorders and psychostimulant drug abuse. At least three dopamine systems have been characterized in the brain-nigrostriatal, mesolimbic, and mesocortical. Abnormalities of nigrostriatal dopamine neurons cause motor impairment leading to Parkinson's disease, whereas dysfunction of mesolimbic and mesocortical dopamine neurons are most implicated in psychotic disorders such as schizophrenia and in drug addition. One of the primary neural sites of action of potent antipsychotic agents and psychostimulant drugs of abuse are dopamine receptors and dopamine transporters which, respectively, mediate the induction and termination of dopamine's actions. Very limited information is, however, available about which particular set of dopaminergic cells in the human brain actually express the genes for these dopamine-specific proteins. In this study, we observed that the dopamine transporter and D2 receptor messenger RNAs are differentially expressed within the human mesencephalon: highest expression in ventral subpopulations of the substantia nigra pars compacta neurons with lowest expression in the mesolimbic/mesocortical ventral tegmental area and retrorubral cell groups. These findings suggest that motor- and limbic-related mesencephalic neurons in the human brain differ in the degree of dopamine transporter and D2 receptor gene expression.

Animals↗

PubMed1994

Autoradiographic characterization of 125I-neurotensin binding sites in human entorhinal cortex.

The laminar and rostro-caudal distribution of 125I-neurotensin binding sites is described in human entorhinal cortex using quantitative autoradiography. Specific binding was most prominent over the cell clusters of layer II of the entorhinal cortex throughout its rostro-caudal extent. Dense binding was also observed in the adjacent presubiculum and cortical amygdaloid transition area, whereas minimal binding was detected in the hippocampus and dentate gyrus. 125I-Neurotensin may serve as a selective probe for neurotensin receptor alterations and layer II-specific cytoarchitectural disturbances in the entorhinal cortex in neuropsychiatric diseases associated with abnormalities of the mesial temporal lobe.

Adult↗

PubMed1994

Fewer dopamine transporter receptors in the prefrontal cortex of cocaine users.

The authors investigated dopamine transporter receptor binding in the post-mortem prefrontal cortex of 13 subjects with histories of cocaine use who had positive blood screens for cocaine at autopsy and 13 comparison subjects with no history of cocaine use and negative blood screens for cocaine at autopsy. Synaptosomes from pulverized prefrontal cortex were assayed with [3H]GBR 12935 for dopamine transporter receptor. There was a 38% decrease in number of binding sites but no change in affinity constants in the cocaine users.

Adult↗

PubMed1994

Is there cognitive decline in schizophrenia? A cross-sectional study.

The issue of progressive cognitive decline in patients with schizophrenia has been debated. We performed a cross-sectional study of patients with chronic schizophrenia, aged from 18 to 69 years, in order to address this issue. The patients included in this study passed a rigorous screen for any comorbid condition with an adverse impact on central nervous system function. We assessed intellectual deterioration with a battery of neuropsychological tests known to be sensitive to cognitive impairment in progressive dementia. No evidence of accelerated intellectual decline was found. No significant differences were found between the five age-derived cohorts (18-29, 30-39, 40-49, 50-59, and 60-69 years of age) on the Mini-Mental State Examination, Dementia Rating Scale, or other tests sensitive to dementia. While performance on the Boston Naming Test significantly declined with age, this was mainly due to age rather than duration of illness. However, it is important to note that mean performances on the majority of the tests were abnormal across all cohorts studied. These results suggest that intellectual function does not markedly decline during the adulthood of patients with schizophrenia. The course of schizophrenia is more consistent with a static encephalopathy than a dementing disorder.

Adolescent↗

PubMed1993

Serotonin 5-HT3 receptors in schizophrenia: a postmortem study of the amygdala.

Alterations in density of some serotonin receptor sites (5-HT1A receptors, 5-HT2 receptors and 5-HT uptake sites) have been reported in postmortem studies of brain obtained from subjects with schizophrenia, suggesting a disturbance in serotonergic transmission in schizophrenia. The purpose of the present study is to investigate [3H]-LY278584 binding to serotonin 5-HT3 receptors in postmortem samples of amygdala from schizophrenic and matched control subjects. As all of the schizophrenic patients but none of the controls had been treated with neuroleptics, we first investigated in rodents the effects of short-term and long-term haloperidol administration on limbic 5-HT3 receptors, and we found no effects. No differences in the maximum number of 5-HT3 binding sites (Bmax) or equilibrium dissociation constant (Kd) between schizophrenics and controls were found in amygdala. This study does not support the presence of an alteration of 5-HT3 receptors in amygdala in schizophrenic patients.

Adult↗

PubMed1993

Selective abnormalities of prefrontal serotonergic receptors in schizophrenia. A postmortem study.

BACKGROUND: This study investigates serotonergic receptors in prefrontal cortex of patients with schizophrenia. METHODS: We measured serotonin 2 receptors and serotonin uptake sites in prefrontal and occipital cortex of schizophrenics, patients with chronic schizoaffective disorders, nonpsychotic suicides, and controls. Diagnoses were established according to DSM-III-R criteria from medical chart reviews. RESULTS: In prefrontal cortex, serotonin 2 density was decreased in chronic psychotics dying of natural causes, as opposed to psychotics dying of suicide, controls, and nonpsychotic suicide victims. Serotonin uptake sites were decreased in prefrontal cortex of schizophrenics and nonpsychotic suicides, but not in patients with schizoaffective disorder. None of the observed differences were clearly related to antemortem pharmacological treatments. In the occipital pole, no differences were found among the groups. CONCLUSIONS: Selective prefrontal alterations of both presynaptic and postsynaptic serotonin receptor densities are present in at least some schizophrenic patients.

Adult↗

PubMed1993

Properties of [3H]AMPA binding in postmortem human brain from psychotic subjects and controls: increases in caudate nucleus associated with suicide.

[3H]AMPA binding, a measure of the non-NMDA excitatory amino acid receptors, was measured in the frontal cortex, caudate nucleus, and nucleus accumbens of postmortem human brain tissue samples. In normal human frontal cortex, the binding data were best fit by a two-site model, with Kd values of 137 nM and 11.3 microM, and Bmax values of 2780 fmol/mg protein and 67.6 pmol/mg protein, respectively. Binding was linearly related to protein concentration and was strongly inhibited by glutamic acid and quisqualic acid. Binding was partially inhibited by kainic acid and glutamic acid diethyl ester and only slightly inhibited by N-methyl-D-aspartic acid. AMPA binding was not inhibited by neuroleptic drugs, in vitro. Freezing and storage did not result in a loss of AMPA binding, and there tended to be an increase in AMPA binding with extended freezer storage. When tissue frozen intact was compared to tissue frozen as a homogenate, the high-affinity binding parameters were unchanged, but there was an increase in the affinity and Bmax of the low-affinity site for the tissue frozen intact. Thus it appears that only the high-affinity site can be measured accurately in tissue frozen intact. AMPA binding was not significantly altered by premortem neuroleptic administration, age, postmortem delay, or by moderate durations of freezer storage. No differences in AMPA binding were found in psychotic subjects compared to normal controls. There was, however, a pronounced increase in total AMPA binding in the caudate nucleus in subjects that had committed suicide.

Brain↗

PubMed1993

The role of serotonin in schizophrenia: an overview of the nomenclature, distribution and alterations of serotonin receptors in the central nervous system.

Serotonin is a neurotransmitter that is widely distributed throughout the central nervous system. The role of serotonin in schizophrenia is still unclear. Postmortem studies of serotonin receptor subtypes in schizophrenia have been inconclusive for the most part. The most promising findings involve a reduction in 5-HT2 receptors and 5-HT reuptake sites in the prefrontal cortex of schizophrenic patients. In this paper we review the function, distribution and pharmacological characteristics of serotonin receptors. Postmortem studies are also reviewed, focusing upon the role of these receptors in schizophrenia.

Central Nervous System↗

PubMed1993

A topographical study of senile plaques and neurofibrillary tangles in the hippocampi of patients with Alzheimer's disease and cognitively impaired patients with schizophrenia.

Neuropsychological testing of elderly schizophrenic patients reveals that a significant portion of this population exhibit varying degrees of cognitive impairment. Since Alzheimer's disease is the most common cause of dementia in geriatric patients, we investigated whether the cognitive decline observed in schizophrenia is the result of degenerative changes analogous to those characteristic of Alzheimer's disease. For this purpose, the number and distribution of senile plaques and neurofibrillary tangles were mapped in the hippocampi of 10 cognitively impaired schizophrenic patients, 10 patients with Alzheimer's disease, and 10 patients with dementia not attributed to either schizophrenia or Alzheimer's disease. In Alzheimer's disease, degenerative changes invariably predominated in the CA1 subfield, subiculum, and proisocortex. By contrast, findings characteristic of Alzheimer's disease were virtually never observed in the hippocampi of schizophrenic and other cognitively impaired patients. In some patients with Alzheimer's disease, the presence of senile plaques in the molecular layer of the dentate gyrus suggested the existence of an underlying entorhinal cortex lesion. Similar dentate gyrus pathology was never found in any of the other patients. The authors conclude that cognitive impairment in schizophrenia is not the result of degenerative changes analogous to those found in Alzheimer's disease.

Aged↗

PubMed1993

Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenics.

Serotonin (5-HT) uptake sites were mapped by autoradiographic means with [3H]cyano-imipramine ([3H]CN-IMI), the 5-HT1A receptor with [3H]8-hydroxy-2-[di-n-propyl-amino]tetralin ([3H]8-OH-DPAT), and the 5-HT2 receptor with both [3H]ketanserin and [125I]lysergic acid diethylamide ([125I]LSD) in eight nonneurologic controls and 10 cases with a diagnosis of schizophrenia. In the striatum, there was a marked heterogeneous patterning of 5-HT uptake sites that corresponded to the striosomal/matrix compartmentalization of the striatum. This organization was not matched with an equally heterogeneous pattern of either 5-HT2 or 5-HT1A receptors. For the isocortex, a general organizational scheme was observed with the 5-HT1A receptor expression high in the external laminae and deep laminae, but 5-HT2 receptor expression was higher in the internal laminae. There was a laminar distribution of 5-HT uptake sites that approximated the combined distributions of the 5-HT1A receptor and the 5-HT2 receptor. In the parahippocampal gyrus and hippocampus, the distribution of 5-HT uptake sites was complementary to the distribution of 5-HT1A and 5-HT2 receptors. In schizophrenic cases, there was a large increase in the number and altered striosomal/matrix organization of 5-HT uptake sites in the striatum. There was also an increase in the numbers of 5-HT2 receptors in the nucleus accumbens and ventral putamen of the schizophrenics. The number of 5-HT1A receptors was not modified. There was a marked reduction in 5-HT uptake sites in the external and middle laminae of the anterior cingulate, frontal cortex, and posterior cingulate, and no changes were observed in the motor cortex, temporal cortex, or hippocampus. Increased numbers of 5-HT1A receptors were found in the posterior cingulate, motor cortex, and hippocampus. Serotonin2 receptors were substantially elevated in the posterior cingulate, temporal cortex, and hippocampus, but not in the frontal, anterior cingulate, or motor cortices. Examination of the temporal lobe and hippocampus of a group of nonschizophrenic suicides (n = 8) indicated the alterations in 5-HT system in the limbic regions of the striatum, the limbic cortex, and hippocampus of the schizophrenic cases may be disease specific.

Adolescent↗

PubMed1993

Course of schizophrenia: neuropsychological evidence for a static encephalopathy.

The course of cognitive function in schizophrenia has often been debated. In one view, it is thought to be akin to that of a progressive dementia with relentless cognitive decline. In another view, the deficits are thought to remain relatively stable, analogous to those of a static encephalopathy. Review of longitudinal and cross-sectional studies strongly supports the latter interpretation. In particular, we present data from a recent cross-sectional study in which cohorts of patients in their third, fourth, fifth, sixth, and seventh decades of life were administered a battery of tests known to be sensitive to progressive dementing diseases. All patients were carefully screened to exclude those with neurologic, systemic, or psychiatric comorbid conditions, and cohorts were matched on estimated premorbid intellectual capacity. Although scores on most tests were impaired, no evidence of decline across groups was observed. These results are also consistent with neuroimaging and neuropathological studies in that no evidence for an active degenerative process has been discovered.

Aged↗

PubMed1993

Pharmacological and regional characterization of [3H]LY278584 binding sites in human brain.

Binding of [3H]LY278584, which has been previously shown to label 5-hydroxytryptamine3 (5-HT3) receptors in rat cortex, was studied in human brain. Saturation experiments revealed a homogeneous population of saturable binding sites in amygdala (KD = 3.08 +/- 0.67 nM, Bmax = 11.86 +/- 1.87 fmol/mg of protein) as well as in hippocampus, caudate, and putamen. Specific binding was also high in nucleus accumbens and entorhinal cortex. Specific binding was negligible in neocortical areas. Kinetic studies conducted in human hippocampus revealed a Kon of 0.025 +/- 0.009 nM-1 min-1 and a Koff of 0.010 +/- 0.002 min-1. The kinetics of [3H]LY278584 binding were similar in the caudate. Pharmacological characterization of [3H]-LY278584 specific binding in caudate and amygdala indicated the compound was binding to 5-HT3 receptors. We conclude that 5-HT3 receptors labeled by [3H]LY278584 are present in both limbic and striatal areas in human brain, suggesting that 5-HT3 receptor antagonists may be able to influence the dopamine system in humans, similarly to their effects in rodent studies.

Adult↗

PubMed1993

Choline acetyltransferase in schizophrenia.

OBJECTIVE: To test the hypothesis that schizophrenia involves altered cholinergic tone in the pons, the authors studied post-mortem brain tissue from subjects with schizophrenia. METHOD: The authors used Western immunoblot to measure the concentration of choline acetyltransferase, an acetylcholine synthesizing enzyme, in the post-mortem brain tissue of 25 schizophrenic subjects and 28 nonschizophrenic comparison subjects. They also measured the concentration of glial fibrillary acidic protein, a protein from astrocytes, to examine the question of neurodegeneration. RESULTS: The pontine choline acetyltransferase concentrations of the schizophrenic subjects were 46% lower than those of comparison subjects, a significant difference. Glial fibrillary acidic protein concentrations did not differ between the two groups. CONCLUSIONS: The lower concentration of choline acetyltransferase in the pontine tegmentum of schizophrenic subjects compared with comparison subjects suggests involvement of pontine cholinergic neurons in schizophrenia.

Acetylcholine↗

PubMed1993

Contrasts between patients with affective disorders and patients with schizophrenia on a neuropsychological test battery.

OBJECTIVE: This study was designed to ascertain the degree and specificity of cognitive impairments in patients with schizophrenia and patients with affective disorders. METHOD: Cognitive function was assessed with a neuropsychological test battery in consecutively admitted patients with schizophrenia (N = 57), unipolar depression (N = 29), and bipolar disorder (N = 16). RESULTS: The performance of the schizophrenic group was significantly below that of the groups with affective disorders on measures of attention and psychomotor speed, verbal and visual memory, and problem solving and abstraction. IQ was lower in the schizophrenic group and appeared to have deteriorated from a normal premorbid level that was not different from that of the affective disorder groups, as determined by the Wide Range Achievement Test--Revised reading test, a putative measure of premorbid intelligence. When IQ was controlled, differences between the groups in problem solving and visual memory remained. Psychiatric symptoms had a larger impact on test performance in the affective disorder groups than in the schizophrenic group. CONCLUSIONS: These results suggest that patients with schizophrenia perform systematically worse on cognitive measures than patients with affective disorders, which is consistent with their generally poorer outcome. The results also indicate that schizophrenia and affective disorders are qualitatively distinguishable in neuropsychological terms, given differences in apparent intellectual deterioration, profiles of cognitive impairment, and associations between cognitive performance and psychopathology.

Adult↗

PubMed1993

The effect of clozapine on cognition and psychiatric symptoms in patients with schizophrenia.

Psychiatric symptoms and cognition were assessed in 13 patients with schizophrenia, one patient with schizoaffective disorder, and one patient with psychosis not otherwise specified while they received a conventional neuroleptic and again after an average of 15 months on clozapine. Despite improvements in psychiatric symptoms, attention, memory, and higher-level problem-solving were essentially unchanged. This suggests that certain cognitive deficits are relatively independent of psychotic symptoms in schizophrenia, and are probably central and enduring features of the disorder. Cognitive disability appeared to have been rate-limiting in the sample's rehabilitation, as patients' social and vocational adjustment remained marginal during the study. We also observed that treatment with clozapine was associated with a decline in some memory functions; the potent anticholinergic properties of the drug may have been responsible for this.

Clozapine↗