Contributions of hippocampal cellular damage and NMDA receptor dysfunction to behavioral markers of schizophrenia.

Pathological changes in the hippocampal formation have been noted in schizophrenic patients and manipulation of neurochemical functions within the limbic system has been shown to yield behavioral changes consistent with schizophrenia. The present study evaluated the impact of kainic acid induced hippocampal cellular damage and manipulation of NMDA receptor function (agonism and antagonism) on common behavioral markers of schizophrenia (habituation and prepulse inhibition of the acoustic startle response in rats). Cellular damage significantly impaired habituation and NMDA antagonism disrupted prepulse inhibition. Damage induced impairment of habituation is consistent with effects on latent inhibition (which is also unaffected by NMDA antagonism) while the antagonist disruption of prepulse inhibition is consistent with effects on associative plasticity. The current findings provide further support for a diverse neurobiological substrate of schizophrenic symptoms suggesting that pharmacologic intervention may need to be multifaceted and could involve competing mechanisms. Cognitive impairments may reflect diminished NMDA receptor function whereas positive symptoms may reflect heightened engagement of anatomically disturbed cellular elements.

Unilateral hippocampal damage impairs spatial cognition in rats.

Unilateral temporal lobectomy to treat seizure disorders in humans often results in cognitive impairment after the surgery. To determine the potential utility of a rodent model of unilaterally induced cognitive deficits, the present experiment evaluated spatial cognition in adult rats after either left or right hemisphere lesioning of temporal neocortex and underlying hippocampal regions. Evaluation of performance in the eight arm radial maze revealed that both lesioned groups committed more reference memory errors than did nonoperated controls. Working memory errors did not differ statistically between groups. The production of a spatial learning deficit by unilateral damage suggests that this rodent model could serve to test potential improvements in interventional strategies aimed at attenuating cognitive effects of the surgical treatment.

Manipulation of NMDA-receptor activity alters extinction of an instrumental response in rats.

The effects of pharmacologically manipulating N-methyl-D-aspartate(NMDA)-receptor activity were examined during extinction of an appetitive instrumental response in rats. After reaching acquisition criterion, subjects were treated with the antagonist dizocilpine maleate (MK801; 0.1 mg/kg), the agonist D-cycloserine (3 mg/kg), or vehicle-alone (control) and tested during a non-reinforced (extinction) session. The antagonist decreased the average number of responses occurring during the test session whereas the agonist increased the average number in contrast to controls. The effect on retention performance may be mediated by differential influence on the N-methyl-D-aspartate-dependent synaptic plasticity that occurs during associative learning. In conjunction with other studies, these data suggest that N-methyl-D-aspartate agonism may be an effective intervention for memory dysfunction.

Prior instrumental conditioning improves spatial cognition and attenuates changes in hippocampal function in aged rats.

These experiments examined the effects of long-term instrumental training on subsequent radial arm maze performance and synaptic transmission within the hippocampal formation. In the first experiment, young (3 mo) and aged (18 mo) male rats underwent 12 weeks of appetitive instrumental conditioning; half were continually reinforced and the other half alternated between reinforcement and extinction. Afterward, spatial cognition was evaluated using an eight-arm radial maze. Subjects undergoing instrumental training performed at rates superior to untrained (control) animals regardless of age or training condition; age-related differences did not exist in the trained groups. In the second experiment, subjects underwent 12 weeks of instrumental training with continuous reinforcement, and excitability of the hippocampus was examined by paired-impulse stimulation of the perforant path. Training enhanced maximal facilitation of population spikes evoked in the granule cell layer of the dentate gyrus of aged subjects to the degree that no statistical difference existed between young and aged animals. Data from untrained control animals indicated a robust decline in paired-impulse excitability in aged subjects. These findings suggest that learning-induced plasticity may attenuate both behavioral and neurobiological changes observed in aged subjects. It is postulated that disuse may underlie some of the cognitive changes exhibited across the life span.

Experience with the iodine-123 and technetium-99m labelled anti-granulocyte antibody MAb47: a comparison of labelling methods.

Four different methods of radiolabelling the anti-granulocyte monoclonal antibody MAb47 were compared and their influence on diagnostic value studied. The best clinical images were obtained following labelling with iodine-123 by the Iodogen method and direct labelling with technetium-99m after tris-(carboxyethyl)-phosphine treatment of MAb47 to achieve disulphide bridge reduction. 99mTc labelling using a specific ligand (MAb47-mtp), or a second method involving direct reduction with mercaptoethanol, led to an increased background activity in clinical studies, thus impeding the diagnosis of chronic disease. Fresh infections were clearly localized by all four preparations. The elimination of the activity from the blood was slower in the case of the iodinated MAb47, while the collected urine samples showed an excretion of about 10% of the injected activity per day independent of the labelling method. The results in terms of sensitivity and specificity were rather similar for all labelling methods and ranged from 90% to 99%.

Myocardial 18F-FDG-PET. Experiences with the euglycemic hyperinsulinemic clamp technique.

Myocardial positron emission tomography (PET) with 18F-Fluordeoxyglucose (FDG) is increasingly used for the detection of viable tissue in the infarcted myocardium. Previous studies show that the variable metabolic conditions determine the regional distribution of this tracer and that the inhomogeneities of uptake often observed even in the normal myocardium may relate to substrate availability. The authors tried to stimulate the myocardial FDG uptake by either the technically easier method of glucose loading or by the euglycemic hyperinsulinemic clamp (EHC) technique. In their hands both methods could be considered as equally practicable but differing in some important details in regard to both the study protocol (tracer dose, optimal scanning time) and the reproducibility of results. The EHC allows a quick stabilization of the metabolic environment and resulted in an earlier and markedly increased FDG uptake. However, the important standardization of the method was performed by a computer-controlled system only for the glucose and insulin infusions. Their experiences show that the EHC provides a useful framework for assessing altered cardiac metabolism and possibly describes changes after therapeutic interventions more precisely than the commonly used glucose-loading technique.

Hippocampal synaptic plasticity as a biological substrate underlying episodic psychosis.

Structural change in the hippocampal formation has become popular as a proposed neurobiological substrate for schizophrenic disorders. It is postulated that behavioral plasticity in the form of long-term potentiation of hippocampal synaptic transmission is an attractive putative mechanism for the mediation of transient psychosis. Moreover, the disturbed hippocampal neuroarchitecture found in schizophrenic brain may be susceptible to potentiation and dysfunctional to the degree that delusions and hallucinations develop. Partial and selective blockade of the receptors mediating potentiation may prove to be an efficient means of preventing psychotic episodes and avoiding further damage to the involved network. Basic research, utilizing experimental models such as intraventricular kainic acid injection, may help to clarify the anatomical and physiological substrate of psychosis.

Hippocampal damage does not impair instrumental appetitive conditioning with delayed reinforcement.

The present study evaluated the effects of bilateral hippocampal lesions on appetitive instrumental conditioning with delayed (5-s interval) reinforcement in rats. Acquisition of a bar press response was considerably slower than rates observed with immediate reinforcement; however, no significant differences between hippocampally lesioned and control groups were noted regarding training to criteria or ratio of responses to reinforcements. These results suggest that the hippocampus is not essential for the association of temporally discontinuous stimuli, and that deficits in other forms of associative learning, such as spatial cognition, must be mediated by the loss of other functions. Putative functions and underlying substrates are discussed for response modulation and sensory (cue relations) associations.

Immunoscintigraphy of infections using 123I and 99mTc-labeled monoclonal antibodies. Advanced experiences in 230 patients.

Advanced experiences show an extremely high diagnostic potential in immunoscintigraphy of infections using monoclonal antigranulocytes antibodies (Mab). There was no hampering of the biological properties of the granulocytes after in vivo labeling with 123I or 99mTc-tagged Mabs. There were mostly identical findings and an equal functional behavior of the granulocytes observed with the use of different agents. Diagnosis of infections was made mostly within four to six hours p.i. 99mTc labeling is more advantageous than 123I because of better image quality, constant availability, and lower costs. 123I Mab 47 seems to be recommended in some cases of chronic osteomyelitis and spondylitis. No relevant antigenicity was observed in follow-up studies of testing HAMA serum levels. Only a few short-time reactions were seen after repeated administration of 99mTc Mab. There were no side effects and no allergic or adverse reactions. Despite these methodical advantages of the immunoscintigraphic detection of infectious and inflammatory lesions, this method should be further restricted to severe cases or patients in whom other methods would not be practicable or have failed. HAMA controls are continued in all our patients undergoing immunoscintigraphy.

Partial hippocampal pyramidal cell loss alters behavior in rats: implications for an animal model of schizophrenia.

A putative biological substrate of schizophrenia involves cellular pathology within the hippocampus. While hippocampal dysfunction is associated with impaired learning and memory, schizophrenics have been observed to acquire simple conditioned reflexes at rates superior to controls. The present study evaluates the acquisition of shuttlebox avoidance responses in animals with partial damage to hippocampus. Intraventricular microinjections of kainic acid (0.5 or 1.5 nM) were utilized to partially destroy the pyramidal cell population. Animals in the high dosage group acquired the response at rates superior to controls; the low dosage group performed at an intermediate level. Consequently, partial loss of pyramidal neurons may be sufficient to significantly alter simple acquisition. Results are discussed in reference to the "embryological hypothesis" of schizophrenia and mechanisms for induction of schizophrenic behavior in intractable seizure disorders are considered.

Non-homogeneous intrahepatic drug distribution in intraportal infusional chemotherapy demonstrated by Tc-99m-MAA perfusion SPECT.

Perioperative adjuvant cytotoxic chemotherapy given through a portal vein catheter may reduce the incidence of metachronous liver metastases following curative resection of colorectal carcinoma. It has generally been assumed that positioning the tip of the catheter in the stem of the portal vein will ensure homogeneous drug distribution to the whole liver. This hypothesis has been put to the test in 10 patients receiving intraportal chemotherapy according to protocol 40/81 of the Swiss Group of Clinical Cancer Research. Catheter position in the stem of the portal vein was checked angiographically the first and last day of a 7-day chemotherapy course. Perfusion scans using 99m-Tc-MAA made during therapy were compared to static liver scans obtained with 99m-Tc sulfur colloid one day after conclusion of chemotherapy. The results were evaluated on planar scans and by SPECT. Slow infusion of the tracer substance under conditions duplicating those of cytotoxic drug infusion used in the protocol resulted in decreased or missing perfusion of the left liver lobe and gross non-homogeneous perfusion in nearly all of the patients.

In vivo labelling of granulocytes using 123I-tagged anti-granulocyte antibodies.

On the basis of previous work with various monoclonal antibodies (Mab) raised against carcino-embryonic antigen (CEA), the anti-CEA Mab 47 was identified which selectively reacted with a surface glycoprotein (95 kDa; NCA 95) of normal human granulocytes. This new tracer was quality tested and radioiodinated with 123I (123I Mab 47) for clinical use according to established procedures. Extended in vitro studies revealed a high selectivity for granulocytes without inhibiting their vital functions. In vivo cell binding to the granulocyte pool was completed very rapidly and remained unchanged over 24 h. For clinical use one dose consisting of 120 mcg of Mab was labelled with 4-5 mCi of 123I. Clinical interest was mainly concentrated on cases of osteomyelitis, infected allografts and abdominal and brain abscesses. After injection of 123I Mab 47, infectious lesions were usually seen after 3-5 h or could be excluded after 24 h. Because of high counting rates the image quality was excellent and single photon emission computerized tomography (SPECT) could be performed for an exact topographical localization of the lesions. No adverse reactions have been seen. It is concluded that there are distinct advantages of the new method compared with scanning of 111In-labelled leucocytes. However, despite this and the low dose of antibodies administered, we recommend restriction of immunoscintigraphy of infectious lesions before a clinically relevant immunization can be excluded.

Immunoscintigraphic localization of inflammatory lesions: pharmacokinetics and estimated absorbed radiation dose in man.

Five patients with inflammatory lesions received anti-granulocytes murine monoclonal antibody (Mabgc) infused over 5 to 15 min at doses between 3.4 and 5.4 mCi 123I (120 micrograms antibody). Clearance of 123I from blood pool closely fits a biexponential mathematical model with the two effective half-lives 0.73 h and 9.3 h. The spontaneous release of 123I was found to be relatively low in the blood pool. The cumulative urinary excretion of the 123I label over 120 h was in the range of 63% of the totally administered dose and is assumed to represent only a low molecular compound or 123I alone as iodide. Analysis of the label in spleen, liver and red marrow showed that the concentration of label in these tissues remains more or less constant over a period of 20 h after infusion. With data of liver, spleen, red marrow and whole body activity over a period of 24 h, an estimated radiation dose was calculated. Compared with 111In labelled leucocytes, especially in spleen, the absorbed dose is lower by a factor of ten per examination.

Immunoscintigraphic localization of inflammatory lesions: clinical experience.

This clinical study was based on the experimental results reported in the two preceding papers, showing that the highly selective affinity of the 123I-anti-CEA monoclonal antibody 47 (123I-Mabgc) for human granulocytes makes this compound suitable for the immunoscintigraphic detection of inflammatory lesions. Forty five patients with suspected infections have been studied after infusion of 4 mCi (148 MBq) 123I-Mabgc corresponding to 120 micrograms labeled protein. No adverse reactions have been seen. Because of the high number of labeled cells, the quality of the images was excellent. SPECT was performed in 15 cases in order to define the extent of the lesion. Infectious foci were usually seen 3-5 h postinjection, but the unimpaired function of the granulocytes guarantees diagnostically relevant examinations over a much longer period of time. Scans were read as being negative if no pathological accumulation of activity was detected after 24 h. The new scanning method is technically easy to perform and provides distinct advantages over other techniques necessitating in vitro labeling of the white blood cells. Therefore, recommended indications are acute infections of unknown origin or extent, especially recurrent episodes of osteomyelitis and infections of joint prostheses.

Immunoscintigraphic localization of inflammatory lesions: concept, radiolabelling and in vitro testing of a granulocyte specific antibody.

Current nuclear medicine techniques for the localization of inflammatory processes are based on injection of 111In labelled autologous granulocytes which need to be isolated and radiolabelled in vitro before reinjection. A new technique is presented here that obviates the need for cell isolation by the direct intravenous injection of a granulocyte specific 123I labelled monoclonal antibody. In this publication the basic parameters of the antibody granulocyte interaction are described. Antibody binding does not inhibit vital functions of the granulocytes, such as chemotaxis and superoxide generation. Scatchard analysis of binding data reveals an apparent affinity of the antibody for granulocytes of 6.8 X 10(9) l/mol and approximately 7.1 X 10(4) binding sites per cell. Due to the high specificity of the antibody, the only expected interference is from CEA producing tumors.

Imaging of inflammatory and infectious lesions after injection of radioiodinated monoclonal anti-granulocytes antibodies.

Successful detection of inflammatory lesions by planar scintigraphy and SPECT after injection of iodine-123 labelled monoclonal antibodies directed against human granulocytes (123I-Mabgc) is demonstrated. This new tracer has been compared with indium-111 labelled white blood cells (111In-WBC) in selected patients with proven infectious lesions. Scans were equally positive in all cases, but the methodical advantages of the new marker were obvious, namely, there is no need for cell separation and the images of inflammatory lesions were better defined. In addition, SPECT could be performed with 123I-Mabgc and allowed a better anatomic localization and a three-dimensional description of the lesions. No adverse reactions have been seen. It is concluded, therefore, that 123I-Mabgc is a promising agent for the detection of acute focal inflammatory lesions which may, with advantages, replace 111In-WBC.