Disrupted pattern of D2 dopamine receptors in the temporal lobe in schizophrenia. A postmortem study.

BACKGROUND: Anatomical substrates for the clinical efficacy of D2 dopamine receptor antagonism in ameliorating positive symptoms, including auditory hallucinations, in schizophrenia are not fully known. We previously identified a modular organization of D2 receptors unique to the temporal lobe. The dense bands of D2 receptors showed highest frequency in auditory and speech association cortices (Brodmann areas 22, 39, and 42) and auditory-visual association areas (Brodmann areas 20 and 37) but were rarely found in somatosensory association regions (Brodmann area 21). Since the anatomical localization of these bands mirrors the presumed sites underlying hallucinations in schizophrenia, the modular and laminar distribution of D2 receptors was studied in the temporal cortex in the brains of schizophrenic and control subjects. METHODS: Tissue obtained post mortem from 12 elderly schizophrenic subjects and 13 controls matched for age and postmortem interval was examined by quantitative receptor autoradiography for D2 receptor binding with [125I]epidepride. All regions of the temporal lobe were sampled in all cases. RESULTS: Schizophrenia cases exhibited significantly disrupted patterns of D2 receptors in the perirhinal, superior, and inferior temporal cortices, including disrupted patterns in the modular D2 receptor bands. The schizophrenic cases had reduced concentrations of D2 receptors in the supragranular layers and elevated concentrations of D2 receptors in the granular layer in isocortical regions of the temporal lobe. This disruption does not appear to be due to long-term treatment of antipsychotic drugs and is regionally specific as there were no differences between groups for concentrations or patterns of expression in the hippocampal complex. CONCLUSIONS: Blockade of the disrupted distribution of D2 receptors in auditory and auditory-visual association cortices is a likely mechanism for the clinical efficacy of D2 antagonists in reducing hallucinations. The regionally specific, aberrant pattern of D2 receptors may be a symptom of anomalous cortical development in these regions.

Mesolimbic dopamine D3 receptors and use of antipsychotics in patients with schizophrenia. A postmortem study.

BACKGROUND: The pharmacological properties and distribution of a recently cloned member of the dopamine D2 receptor subfamily, the D3 receptor, has led directly to the hypothesis that it may be the target of antipsychotic action. METHODS: To quantify D3 receptors, we characterized the conditions for selective binding of the radioligand iodine 125-labeled (R)-trans-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)-amino] tetralin ([125I]trans-7-OH-PIPAT) to the human D3 receptor. We then measured by quantitative autoradiography in postmortem tissue the concentration of D3 receptors in the caudal and rostral basal ganglia regions in patients with schizophrenia and control subjects. RESULTS: We found about 2-fold elevations in the number of D3 receptors in the basal ganglia and ventral forebrain of long-term hospitalized patients with schizophrenia who received no antipsychotic drugs for at least a month before death (n = 7) compared with matched control subjects (n = 15). Patients with schizophrenia receiving antipsychotic drugs less than 72 hours before death (n = 8) had levels similar to those of control subjects. There were no differences in the binding characteristics or affinity of [125I]trans-7-OH-PIPAT binding to D3 receptors between control subjects and patients with schizophrenia. CONCLUSION: In contrast to the previously detected elevation of D2 and D4 receptor levels in schizophrenia, elevation of D3 receptor levels in limbic striatum and its efferents observed in patients with schizophrenia may be reduced by antipsychotic drugs.

White matter changes associated with deletions of the long arm of chromosome 18 (18q- syndrome): a dysmyelinating disorder?

PURPOSE: To evaluate the MR findings in the central nervous systems of patients with deletions of the long arm of chromosome 18 (18q- syndrome). METHODS: Sixteen patients with 18q- syndrome ranging in age from 3 to 46 years (mean, 17 years) were studied with high-field-strength MR imaging. Images were analyzed for abnormal T2 hyperintensity in the white matter, abnormal T2 hypointensity in the deep gray matter, and atrophy. RESULTS: Ten of 16 patients had abnormal white matter. Diffuse, bilaterally symmetric deep white matter T2 hyperintensity, most pronounced in the periventricular regions, was most common, noted in eight cases. Focal deep white matter lesions and/or abnormalities involving the subcortical white matter were also noted in four cases. The cerebellum, brain stem, and corpus callosum were spared. Ventriculomegally associated with volume loss, and abnormal T2 hypointensity in the basal ganglia and/or thalami were each present in 11 patients. CONCLUSIONS: The 18q- syndrome is associated with white matter disease and abnormal T2 hypointensity in the deep gray matter. The basis for the white matter abnormalities is unknown, but may be related to one of the two genes for myelin basic protein included in the deleted segment of chromosome 18.

Neuropsychiatry of 18q- syndrome.

Our understanding of neuropsychiatric abnormalities in patients with deletions of the long arm of chromosome 18 (18q- syndrome) is based mainly on sporadic case reports. We characterized the neuropsychiatric phenotype in 27 patients across a wide age range (2-47 years) with breakpoints ranging from 18q22.3-18q21.2. Adaptive behavior scores (Vineland Composite) were significantly higher in females than in males (62 +/- 5 vs. 43 +/- 3). Intelligence ranged from borderline to severely deficient (IQ, 73- < 40), with academic achievement similarly impaired. Performance in specific neuropsychological functions, including attention, novel problem solving, memory, language, visuomotor integration, and fine motor dexterity, was consistently in the moderately-to-severely impaired range. Behavioral problems were common in both sexes, including aggressivity, hyperactivity, and temper tantrums. Contrary to the few previous reports, we found no evidence of psychosis in any patients. In a subset of patients selected on the basis of no prior knowledge of behavioral problems, 1 of 16 patients (6%) had autism, as defined by the Autistic Diagnostic Interview--Revised (ADI-R) [Lord et al., 1994: J Autism Dev Disord 24:659-685]. Thus, the prevalence of autism in 18q- syndrome is probably no greater than that in other developmental disabilities with a similar level of cognitive impairment. In contrast to what has been believed since 18q- was first described 30 years ago, we found no relationship between chromosome deletion size and any measure of cognition or behavior; nor were there any correlations between any of these measures with the presence or absence of abnormalities on MRI or somatosensory-evoked potentials.

Prospective clinicopathologic studies of schizophrenia: accrual and assessment of patients.

OBJECTIVE: The purpose of this study was to characterize the neuropsychiatric profile of elderly patients with schizophrenia and establish a patient registry for prospective ante-mortem and post-mortem studies. METHOD: Medical records of all chronically institutionalized patients in eight state hospitals who were over the age of 65 and had a chart diagnosis of schizophrenia (N = 528) were reviewed. Of the potential subjects, 192 were excluded because of clinical histories inconsistent with a diagnosis of schizophrenia, 56 because of insufficient information to establish a psychiatric diagnosis, and 122 because of family members' refusal to give consent for autopsy in the event of death. To date, 81 of the remaining 158 patients have undergone neuropsychiatric evaluation with standard assessment instruments. RESULTS: Mini-Mental State scores of the 81 patients indicated severe dementia, and Functional Assessment Scale scores showed that patients required assistance with activities of daily living. All patients were rated as severely ill on the Brief Psychiatric Rating Scale. Ratings on the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms indicated a predominance of negative symptoms over positive. Of 30 patients who have died to date, research autopsies have been conducted on 26. CONCLUSIONS: Establishing a well characterized, prospective patient registry for clinicopathologic studies of schizophrenia is feasible but labor intensive. Diagnosis of schizophrenia with a high degree of confidence can be achieved by means of detailed chart review and assessment of current neuropsychiatric functioning with standard rating instruments. These data provide a basis for correlations of clinicopathologic factors.

Smaller neuron size in schizophrenia in hippocampal subfields that mediate cortical-hippocampal interactions.

OBJECTIVE: The goal of this study was to characterize the hippocampal formation in patients with schizophrenia by measuring neuron density, neuron size, and variability of neuronal axis orientation. METHOD: Brain tissue was obtained at autopsy from 14 prospectively accrued elderly patients with chronic schizophrenia and 10 age-compatible individuals without psychiatric disorder. Eight hippocampal regions of interest and two internal control regions (primary motor and visual cortices) were identified on Nissl-stained sections. Morphometric measurements were made without knowledge of diagnosis by means of a computer-based image analysis system. RESULTS: The patients exhibited smaller neuron size in the hippocampal regions relative to the control regions, which was significant only for the subiculum, CA1, and layer II of the entorhinal cortex. Neuron size in the control regions was nearly identical in the two groups. No significant differences in neuron density or in variability of neuronal axis orientation were identified for any region. There was no correlation between neuron size in any area and several potentially confounding variables (age, post-mortem interval, neuroleptic exposure, sex, brain hemisphere studied, duration of illness), with the exception of a negative correlation with age in layer II of the entorhinal cortex. Regression analyses indicated that the findings could not be attributed to these age effects. CONCLUSIONS: The subiculum, entorhinal cortex, and CA1 are the major subfields of the hippocampal region that maintain the afferent and efferent connections of the hippocampus with widespread cortical and subcortical targets. The smaller size of neurons in these subfields may reflect the presence of structural or functional impairments that disrupt these connections, which in turn could have important behavioral sequelae.

Molecular mapping of the Edwards syndrome phenotype to two noncontiguous regions on chromosome 18.

In an effort to identify regions on chromosome 18 that may be critical in the appearance of the Edwards syndrome phenotype, we have analyzed six patients with partial duplication of chromosome 18. Four of the patients have duplications involving the distal half of 18q (18q21.1-qter) and are very mildly affected. The remaining two patients have most of 18q (18q12.1-qter) duplicated, are severely affected, and have been diagnosed with Edwards syndrome. We have employed FISH, using DNA probes from a chromosome 18-specific library, for the precise determination of the duplicated material in each of these patients. The clinical features and the extent of the chromosomal duplication in these patients were compared with four previously reported partial trisomy 18 patients, to identify regions of chromosome 18 that may be responsible for certain clinical features of trisomy 18. The comparative analysis confirmed that there is no single region on 18q that is sufficient to produce the trisomy 18 phenotype and identified two regions on 18q that may work in conjunction to produce the Edwards syndrome phenotype. In addition, correlative analysis indicates that duplication of 18q12.3-q22.1 may be associated with more severe mental retardation in trisomy 18 individuals.

Regional neuropathology in schizophrenia: where are we? Where are we going?

This paper presents a neurologic formulation for the clinical features of the schizophrenic syndrome, and tests it against a systematic, region by region review of available postmortem neuroanatomical and neuropharmacological data. Based on this review a model is proposed that postulates a developmental lesion affecting the midline neurotransmitter-specific ascending projection systems. Due to the facilitatory role these systems play in the development of the brain regions to which they project, such a lesion is one parsimonious, and testable, explanation for virtually all the clinical, laboratory, and pathological findings reported to date in schizophrenia research. A case is made for establishing a global antemortem-postmortem collaboration using a Latin square design; the alternative may be that, as has happened in the past, the best efforts of dilligent researchers around the world may lead to little improvement in our understanding of schizophrenia.

Negative chronotropic factor in patients with fungemia.

OBJECTIVE: To study the effect of serum from patients with fungemia and control patients on sinoatrial node function. DESIGN: Prospective, observational study. SETTING: Surgical ICU in a university hospital. PATIENTS: Fourteen patients with fungemia and 14 control patients. MEASUREMENTS AND MAIN RESULTS: Serum samples from all patients were assayed in an in vitro sinus node preparation. Serum samples from 11 (78%) of the 14 fungemic patients caused a decrease in sinus node activity, while serum samples from only one (7%) of 14 control patients caused slowing of the sinus node. CONCLUSIONS: Serum from many patients with fungemia causes slowing of an in vitro sinus node preparation. This in vitro finding may explain bradyarrhythmias seen clinically in the setting of fungemia.

Chronic treatment with clozapine or haloperidol differentially regulates dopamine and serotonin receptors in rat brain.

Long-term administration of the atypical neuroleptic clozapine (CLZ) poses a much lower risk of extrapyramidal side effects (EPS) than does the use of typical neuroleptics such as haloperidol (HAL). To investigate the neural mechanisms of the differing CNS activities of these two drugs, we used quantitative autoradiography to measure changes in dopamine and serotonin receptors in rats after injection with CLZ or HAL for 21 days at clinically relevant dose ratios. Levels of D1, D2, and 5-HT2 receptors were determined in frontal cortex, caudate-putamen, and nucleus accumbens. Rats that received CLZ chronically showed CNS receptor changes markedly different from those in chronic HAL-treated animals. Whereas rats treated chronically with HAL showed enhanced striatal D2 binding (average increase of 42%), those treated with CLZ did not. In contrast, chronic CLZ, but not chronic HAL, induced enhanced striatal D1 binding (average increase of 43%). Finally, CLZ treatment decreased 5-HT2 receptor binding by an average of 37%, while HAL had no significant effect. The effects of chronic HAL or CLZ treatment on receptors were similar in all forebrain areas examined. However, since D1 and 5-HT2 receptors are more abundant than D2 sites in limbic and neocortical areas, the preferential modulation of D1 and 5-HT2 receptors by CLZ suggests a greater impact of this atypical neuroleptic on activity of the limbic system than that achieved by the typical neuroleptic, HAL. These findings suggest that the clinical profile of atypical neuroleptics such as CLZ may be attributed to their effects on a receptor profile differing in pharmacological characteristics and anatomical distribution from that affected by typical neuroleptics.

A two-population model of rat rotational behavior: effects of unilateral nigrostriatal 6-hydroxydopamine on striatal neurochemistry and amphetamine-induced rotation.

Rats received intrastriatal or intranigral injections of 6-hydroxydopamine (6-OHDA) on the same side towards which they made most of their turns during a previous test of amphetamine-induced rotational behavior. One week later they were retested for amphetamine-induced rotational behavior and it was found that only approximately half of them increased their rotational behavior towards the lesioned side more than non-lesioned controls. In fact, compared to their pre-operative behavior numerous rats decreased or actually reversed their net turning towards the lesioned side. While the post-lesion rotational behavior of the two groups of rats was clearly different, pre-operative turning was not. Furthermore, the neurochemical effects of the intracerebral 6-OHDA injections were not different in the two groups of rats, either with respect to the magnitude of the resulting dopamine (DA) depletion, or with respect to the compensatory increase in the turnover of DA by surviving DA neurons on the lesioned side. The data are discussed in terms of their lack of support for current notions about the role of nigrostriatal DA in turning, and in terms of their support for a two-population model we have previously proposed. An additional, unrelated, finding from the present work was that bilateral striatal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels decreased bilaterally one week following unilateral intrastriatal administration of 6-OHDA.

Role of hypotension in decreasing cerebral blood flow in porcine endotoxemia.

The role of reduced arterial blood pressure (MAP) in decreasing cerebral blood flow (CBF) during endotoxemia was studied in pentobarbital-anesthetized pigs. Microspheres (15 microns diam) were used to measure regional CBF changes during MAP manipulations in animals with and without endotoxin. Endotoxin (0.2 mg/kg iv) decreased MAP to 50 mmHg and decreased blood flow to the cortex and cerebellum without affecting cerebral cortical oxygen consumption (CMRO2). Elevating MAP from 50 to 70 mmHg during endotoxemia with norepinephrine (1.82 +/- 0.58 micrograms . kg-1 . min-1, iv) did not change cortical blood flow or CMRO2 but increased cerebellar blood flow. Brain stem blood flow was not affected by endotoxin or norepinephrine. When MAP was decreased to 50 mmHg by hemorrhage without endotoxin, no change in blood flow to cortex, cerebellum, or brain stem was observed from base-line levels. These results suggest that decreased MAP below a lower limit for cerebral autoregulation does not account for the decreased CBF observed after endotoxin.

Nocturnal rotational behavior in rats: further neurochemical support for a two-population model.

The relationship between circling behavior and the concentrations of dopamine (DA), serotonin, and their metabolites in corpus striatum was investigated in rats. We have previously reported evidence indicating that in both sexes there are two kinds, or populations, of rats: those with their turning biases directed away from (Contra greater than Ipsi rats), and those with their turning biases directed towards (Ipsi greater than Contra rats), the side containing the striatum with the greater dopaminergic innervation. In the present experiment rats were classified according to whether the contralateral or ipsilateral striatum contained the greater dopamine concentration. Whereas the ipsilateral striata were found to contain the same concentrations of dopamine, the contralateral sides were found to differ significantly; and the difference between the contralateral and ipsilateral dopamine concentrations was significantly correlated with the contralateral, but not the ipsilateral, dopamine concentration. These results are identical to those we previously reported using the Vmax for dopamine uptake in vitro as the measure for striatal dopaminergic innervation. As an initial attempt to determine what neurochemical mechanisms might underlie the differences between the "Contra greater than Ipsi" and "Ipsi greater than Contra" rats, it was found that dopamine turnover, as measured by the ratios of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid to DA, was higher in the striata of the latter group than in the former group. The present results are discussed in terms of their support for the two-population model, and in relation to previous work on behavioral and neurochemical asymmetry in rats.

Differences in spontaneous and amphetamine-induced rotational behavior, and in sensitization to amphetamine, among Sprague-Dawley derived rats from different sources.

Nocturnal rotational behavior was found to vary severalfold among Sprague-Dawley derived rats obtained from seven different breeders; net rotations per night (18 hours) varied from 5.0 to 31.0 in males and from 6.2 to 42.4 in females. Rats from three sources were tested twice (a week between tests) for rotation induced by d-amphetamine. Rats from two sources showed evidence of sensitization to d-amphetamine, there being significantly greater rotation in response to the second dose than in response to the first dose; the d-amphetamine-induced rotational behavior of rats from the third source did not significantly change from one week to the next. However, the latter rats had a greater initial response to the first dose of d-amphetamine than did rats from the other two breeders. Further analysis revealed that, among rats from all three breeders, rats rotating weakly in response to d-amphetamine on the first test tended to rotate more on the second test whereas rats rotating strongly in response to d-amphetamine on the first test tended to rotate less on the second test. This relationship was found to apply to previously collected data as well and was discussed with reference to a proposed mechanism involving asymmetry in sensitization to d-amphetamine-induced release of striatal dopamine. Interindividual differences among seemingly similar experimental subjects appear to contribute importantly to reported differences in results among laboratories.

Striatal dopamine uptake asymmetries and rotational behavior in unlesioned rats: revising the model?

The relationship between circling behavior and the dopaminergic (DA) innervation of the striatum was investigated in rats. Vmax for DA uptake in crude mitochondrial (P2) fractions was used as a measure of the density of striatal DA terminals. Females, as a group, rotated away from (i.e., contralateral to) the side containing the higher Vmax for DA uptake, while there was a nonsignificant trend in the opposite direction for the males. Further analysis suggested that in both sexes there are two kinds, or populations, of rats: those with their turning biases directed away from (Contra greater than Ipsi rats), and those with their turning biases directed towards (Ipsi greater than Contra rats) the side containing the striatum with the higher Vmax for DA uptake. Evidence supporting this two-population hypothesis includes: (a) For both groups of rats the slope of the best fit linear relationship between the contralateral/ipsilateral Vmax asymmetry and rotational behavior is equal in magnitude, though opposite in sign; (b) Mean contralateral Vmax is greater for the Contra greater than Ipsi rats than for the Ipsi greater than Contra rats, while the mean ipsilateral Vmax is virtually identical for the two groups; (c) The two groups of rats can be differentiated behaviorally on the basis of a measure of total lateralized activity, % turning. In addition, the Km for DA uptake for the females (1.81 +/- 0.07 X 10(-7) M) was found to be significantly greater than for the males (1.51 +/- 0.04 X 10(-7) M; P less than 0.005).

Perceived helpfulness of messages on a community-based telephone support service for ex-smokers.

Callers to a community-based telephone support service for ex-smokers evaluated the perceived helpfulness of six categories of taped messages. These categories were: behavioral coping, cognitive coping, negative health, positive health, informational, and supportive. Supportive messages were rated as significantly more helpful than negative health, informational, and behavioral coping. The implications of these findings are discussed.

A simple and rapid technique for preparing histological sections of brain.

A rapid technique for preparing histological sections of rodent brain is described. Sectioning and staining may be completed within two hours of sacrifice.