Biomedical subjects

H Szechtman

Publications and source records attributed to H Szechtman.

At least 37 records · Page 2Linked to original sources

PubMed1997

Monoamine oxidase inhibitor sensitive site implicated in sensitization to quinpirole.

Clorgyline (1.0 mg/kg/day) administered via osmotic minipumps blocked the development of locomotor sensitization to the dopamine receptor agonist quinpirole (0.5 mg/kg every 3 days for 8 injections). In male rats already well sensitized to quinpirole, the continuous infusion of clorgyline (1.0 mg/kg/day for 28 days) produced a progressive decline in locomotor activity, despite a continued regimen of quinpirole injections (0.5 mg/kg every 3 days). It is suggested that the development, as well as the maintenance, of locomotor sensitization to quinpirole is modulated by the activation of an monoamine oxidase inhibitor-sensitive site. This site may be a dopamine D2 receptor-linked monoamine oxidase inhibitor-displaceable quinpirole binding site, the enzyme monoamine oxidase-A, or other clorgyline binding sites.

Animals↗

PubMed1997

Animal models for nervous system disease in systemic lupus erythematosus.

Animal models have much to teach us about nervous system dysfunction in SLE. It should be stressed that the murine strains described in this review have variable expression in the onset and severity of clinical and serological features, perhaps making them more like a heterogeneous human population with SLE. With this in mind, studies involving animal models like those involving human subjects should use a sample size that ensures adequate power. It is not surprising that studies that use sample sizes as low as four to five animals per group would find discrepant results, especially in outcomes that are measured prior to the terminal phases of the disease. Similar to human SLE patients, murine models have systemic autoimmune as well as neurological manifestations. Studies with murine models must continue to consider some type of SLE disease activity measures in order to control for the effects of systemic disease on nervous system dysfunction. Because of the short time window between the earliest evidence of neurologic dysfunction and severe autoimmune disease manifestations, especially in MRL/lpr mice, the disease acceleration model may allow a more careful dissection of how immunological events are related to nervous system dysfunction. Alternatively, the study of MRL/lpr mice ultraearly (e.g., 3 weeks of age) could also provide invaluable information about the first events leading to nervous system dysfunction in SLE. Both approaches promise to identify predictors of specific nervous system manifestations that may suggest novel and more specific therapeutic interventions.

Animals↗

PubMed1997

Dopamine D2 receptors quantified in vivo in human narcolepsy.

Assays in brain tissues from humans suffering from narcolepsy, and from genetically narcoleptic dogs have suggested that dopamine function may be disturbed in this condition. We have used the specific D2 receptor ligand N-(3-[18F]fluoropropyl)-spiperone and positron tomography to study a group of 6 well-characterized medication-free, HLA-DR2 DRW15 DW6-positive narcoleptic patients and a group of age- and sex-matched control individuals during life. We found no difference in striatal D2 receptor binding between these two groups. These results suggest that narcolepsy is not associated with alterations in D2 receptor density and affinity.

Adolescent↗

PubMed1997

Locomotor sensitization to quinpirole: environment-modulated increase in efficacy and context-dependent increase in potency.

This study examines whether behavioural sensitization to the dopamine agonist, quinpirole, reflects an increase in the drug's potency and/or efficacy to induce locomotion, and how these parameters are influenced by environmental context. Three experiments were conducted in which animals received either chronic quinpirole (10 x 0.5 mg/kg, twice weekly) or saline injections in either the home cage environment, an alternate environment or the testing environment (activity monitors), followed by a dose-response test for the expression of sensitization in the activity monitors. Compared to the acute dose-response relationship, chronic quinpirole increased the maximum response. This increase in efficacy was significantly higher in animals treated with quinpirole in a non-home cage environment compared to those that received chronic treatment in the home cage. A leftward shift in the dose-effect function was observed only in animals with prior drug experience in the testing environment. Results indicate that locomotor sensitization to quinpirole reflects an environment-modulated increase in the drug's efficacy, and an environment-dependent increase in drug potency. Efficacy and potency may be subject to sensitization by non-associational and associational mechanisms, respectively.

Animals↗

PubMed1997

Neurobehavioral alterations in autoimmune mice.

Inbred MRL, NZB and BXSB strains of mice spontaneously develop a systemic, lupus-like autoimmune disease. The progress of autoimmunity is accompanied with a cascade of behavioral changes, most consistently observed in tasks reflective of emotional reactivity and the two-way avoidance learning task. Given the possibility that behavioral alterations may reflect a detrimental consequence of autoimmune-inflammatory processes and/or an adaptive response to chronic malaise, they are tentatively labeled as autoimmunity-associated behavioral syndrome (AABS). It is hypothesized that neuroactive immune factors (pro-inflammatory cytokines, brain-reactive antibodies) together with endocrine mediators (corticotropin-releasing factor, glucocorticoids) participate in the etiology of AABS. Since AABS develops natively, and has a considerable face and predictive validity, and since the principal pathway to autoimmunity is known, AABS may be a useful model for the study of CNS involvement in human autoimmune diseases and by extension, for testing autoimmune hypotheses of several mental disorders (major depression, schizophrenia, Alzheimer's disease, autism and AIDS-related dementia).

Animals↗

PubMed1997

Reduced preference for sucrose in autoimmune mice: a possible role of interleukin-6.

In a continuous one-bottle sucrose intake test, 4-month-old autoimmune MRL-Ipr mice show a shift to the right along the X-axis of the concentration-intake function, compared to congenic MRL +/+ controls. Using a brief (60-min) and a continuous (48-h) two-bottle test, the present report examines potential factors that could account for the reduced responsiveness to a palatable stimulus. Study 1 examines whether preference for sucrose is associated with age, changes in food/water intake, or impaired renal function. Reduced preference for sucrose was observed in 5-6-week-old MRL-Ipr males, although food/water intake or blood creatinine levels did not differ from control values. Immunosuppressive treatment abolished this deficit, suggesting a role of immune factor(s). Study 2 tests the hypothesis that chronic upregulation of the neuroactive cytokine interleukin-6 (IL-6), reported to occur from 3 weeks of age in young MRL-Ipr mice, reduces preference for sucrose. Sustained administration of IL-6 was produced by infecting healthy MRL +/+, C3H.SW and Balb/C mice with adenovirus vector carrying cDNA for murine IL-6. This resulted in high serum IL-6 levels over 5 days, a rapid decline in preference for sucrose and low blood glucose levels. The results from Study 1 indicate that impaired sensitivity to sucrose in MRL-Ipr mice can be detected before autoimmune disease is florid in MRL-Ipr mice. The results from Study 2 are consistent with altered motivation/emotional states after infection, and point to sustained IL-6 production as an early mechanism in behavioral alterations during chronic autoimmune/inflammatory conditions.

Aging↗

PubMed1997

Behaviour of MRL mice: an animal model of disturbed behaviour in systemic autoimmune disease.

Evidence is reviewed indicating that development of lupus-like disease in the MRL-lpr substrain of mice coincides with a change in behaviour, suggestive of altered emotional reactivity and cognitive performance. The altered behaviour, termed 'autoimmunity-associated behavioural syndrome', is related to abnormal autoantibody and cytokine production. Moreover, immunosuppressive treatment with cyclophosphamide prevents the appearance of some behavioural deficits. It is argued that the MRL strain of mice constitute an animal model of behavioural dysfunction in autoimmune disease, and can be used to investigate the mechanisms by which an insidious autoimmune/inflammatory process alters mood and behaviour and may result in some forms of mental disorders.

Animals↗

PubMed1997

Effect of cyclophosphamide on leukocytic infiltration in the brain of MRL/lpr mice.

Neuropsychiatric manifestations are a poorly understood and potentially life-threatening complication of systemic lupus erythematosus (SLE). MRL/lpr mice spontaneously develop a lupus-like syndrome which is similar to the human disease in many respects, including behavioural abnormalities. Our previous findings indicated that the age at which infiltration of immune cells into the choroid plexus is first observed coincides with the appearance of behavioural dysfunction in MRL/lpr mice. This present study quantified leukocyte infiltration in relation to prolonged administration of cyclophosphamide (CY), a treatment effective in preventing some behavioural deficits. Compared to MRL +/+ controls, saline-treated MRL/lpr mice had significantly more CD45-positive cells (leukocytes) and CD45R-positive (B) cells in the choroid plexus and in the brain parenchyma. A six week course of CY (100 mg/kg i.p.) significantly reduced the infiltration of CD45, but not of CD45R-positive cells into the choroid plexus of the MRL/lpr substrain. In addition, the presence of leukocytes correlated positively with measures on one behavioural test (floating in the forced swim test) but not on another test (novel object test). These findings suggest that CY treatment has a differential effect on the infiltration of leukocyte subtypes and strengthen the hypothesis that some abnormal behaviour in MRL/lpr mice may be related to the presence of immunocompetent cells in the brain.

Animals↗

PubMed1996

Associational and nonassociational mechanisms in locomotor sensitization to the dopamine agonist quinpirole.

A pairing paradigm was employed to explore the contribution of associational mechanisms to the expression of sensitization to the dopamine agonist quinpirole. Rats received ten quinpirole injections in the test environment (Group Paired) or in the home cage (Group Unpaired), and saline in the alternate environment. A third group received saline injections in both environments (Group Acute). Subjects received quinpirole on the 11th injection as a test for locomotor sensitization, and saline on the next injection as a test for conditioned activity. The range of discriminative stimuli predicting a drug versus a non-drug injection was increased across three independent experiments in an effort to detect a possible associational effect. Regardless of the strength of discriminative stimuli, both Paired and Unpaired groups showed locomotor sensitization to 0.5 mg/kg quinpirole compared with the Acute group. However, the Paired group showed more locomotion than the Unpaired group in the last minutes of the sensitization test. With a lower sensitizing dose of quinpirole (0.1 mg/kg) used in one experiment, only the Paired group showed locomotor sensitization. For both doses, the Paired, but not the Unpaired groups showed conditioned locomotion. It is suggested that with moderate doses of quinpirole, expression of locomotor sensitization does not require drug-signalling cues though such signals may have a modulatory influence. With lower quinpirole doses, however, quinpirole sensitization is context-dependent.

Animals↗

PubMed1996

Joint pathology and behavioral performance in autoimmune MRL-lpr Mice.

Young autoimmune MRL-lpr mice perform more poorly than age-matched controls in tests of exploration, spatial learning, and emotional reactivity. Impaired behavioral performance coincides temporally with hyperproduction of autoantibodies, infiltration of lymphoid cells into the brain, and mild arthritic-like changes in hind paws. Although CNS mechanisms have been suggested to mediate behavioral deficits, it was not clear whether mild joint pathology significantly affected behavioral performance. Previously we observed that 11-week-old MRL-lpr mice showed a trend for disturbed performance when crossing a narrow beam. The first aim of the present study was to test the significance of this trend by increasing the sample size and, second, to examine the possibility that arthritis-like changes interfere with performance in brief locomotor tasks. For the purpose of the second goal, 18-week-old mice that differ widely in severity of joint disease were selectively taken from the population and tested in beam walking and swimming tasks. It was expected that the severity of joint inflammation would be positively correlated with the degree of locomotor impairment. The larger sample size revealed that young MRL-lpr mice perform significantly more poorly than controls on the beam-walking test, as evidenced by more foot slips and longer traversing time. However, significant correlation between joint pathology scores and measures of locomotion could not be detected. The lack of such relationship suggests that mild joint pathology does not significantly contribute to impaired performance in young, autoimmune MRL-lpr mice tested in short behavioral tasks.

Animals↗

PubMed1996

Blunted sensitivity to sucrose in autoimmune MRL-lpr mice: a curve-shift study.

Lupus-prone MRL-lpr mice show an autoimmunity-associated behavioral syndrome that has many features similar to the effects of chronic stress. The present study evaluated whether autoimmune MRL-lpr mice show reduced responsiveness to sucrose, as observed in normal animals exposed to chronic mild stress. Sixteen-week old MRL-lpr mice and their age-matched congenic MRL +/+ controls were given 0%, 0.5%, 1%, 2%, 4%, 8%, or 16% sucrose solution to drink every 48 h in a one-bottle test. The MRL-lpr mice drank less than controls at all concentrations, except at 16%. The amount of sucrose consumed vs. solution concentration followed a saturation curve. Estimates were obtained for the concentration yielding the half-maximum response (X50) and the response at saturating concentration of sucrose (Rmax). The X50 was significantly higher in MRL-lpr than in MRL +/+ mice, indicating a shift to the right of the concentration-intake curve. The Rmax did not differ significantly between substrains, suggesting that the autoimmune process did not affect performance capacity. Pretreatment with the immunosuppressant cyclophosphamide diminished the substrain difference in X50, suggesting that reduced sensitivity to sucrose is related to autoimmune/inflammatory factors. These results support the similarity between autoimmunity-associated behavioral syndrome and behavioral changes produced by chronic stress, and suggest common neuroendocrine mechanisms. Because reduced sensitivity to palatable stimulus may reflect blunted hedonic responsiveness ("anhedonia"), it is hypothesized that an autoimmune/inflammatory factor(s) produces the depression found in human lupus, and some cases of affective disorder.

Animals↗

PubMed1995

Perseveration without hyperlocomotion in a spontaneous alternation task in rats sensitized to the dopamine agonist quinpirole.

Behavioral sensitization induced by intermittent injections of the dopamine agonist quinpirole is characterized by hyperlocomotion and perseveration. This study tested whether in sensitized rats, the expression of perserverative behavior can be independent of hyperlocomotion. Rats received 10 injections of either quinpirole (0.5 mg/kg) or saline in a T-maze apparatus, a procedure that induced locomotor sensitization in the drugged animals. When tested later (under quinpirole) for spontaneous alternation in the same T-maze, in a discrete trial procedure, sensitized rats showed decreased spontaneous alternation, compared either to saline controls or acute quinpirole. The decrease in spontaneous alternation showed a tendency to be lower than chance level of alternation, suggesting perseveration. The possibility is discussed that the sensitization-reduced spontaneous alternation may relate to a diminution in the sense of task completion, and the increased perseveration may model a form of compulsive "checking" shown in obsessive-compulsive disorder.

Animals↗

PubMed1995

Immunosuppressive treatment prevents behavioral deficit in autoimmune MRL-lpr mice.

MRL-lpr mice, which develop severe autoimmune disease, explore novel objects less well than do their congenic MRL(-)+/+ controls, in which symptoms of the disease are relatively mild. Moreover, diminished exploration in MRL-lpr mice correlates with the elevated titers of antinuclear antibodies (ANA) in their sera, suggesting that this behavioral deficit is caused by the autoimmune process. To test the hypothesis that autoimmunity affects behavior, in this study we examine whether treatment of the autoimmune process will reduce the difference in performance between the two MRL substrains in the novel-object test. Forty mice in each substrain were treated from 4 to 10 wk of age with the immunosuppressive drug, cyclophosphamide (100 mg/kg/wk, IP) or a saline vehicle. The immunosuppressive treatment reduced ANA titers to low levels and eliminated ANA production completely in 55% of MRL-lpr mice, suggesting an attenuation of the autoimmune process. In addition, treatment with cyclophosphamide, but not saline, abolished significant differences in exploration between the MRL-lpr and MRL +/+ groups, as measured by the latency to touch a novel object and the time spent exploring it. Thus, the present results suggest that a treatment which ameliorates autoimmune symptoms can concurrently remove the substrain difference in behavior. The effect of cyclophosphamide in the MRL-lpr group is believed to reflect the suppression of pathogenic immune factor(s) that alter behavior during the onset of autoimmune disease.

Animals↗

PubMed1995

Asymmetrical influence of mesocortical dopamine depletion on stress ulcer development and subcortical dopamine systems in rats: implications for psychopathology.

The effects of left, right or bilateral depletion of the mesocortical dopamine innervation (medial prefrontal and anterior cingulate) with 6-hydroxydopamine were examined in male Sprague-Dawley rats tested for susceptibility to cold restraint-induced gastric stress pathology. All three types of lesions tended to potentiate the development of stress pathology (i.e. ulceration) in comparison to restrained shams, but only right cortical dopamine depletion produced a highly significant increase. The results support a protective role for mesocortical dopamine in helping the organism cope with stressful situations, and extend previous findings suggesting that dopamine activation in the right cortex is preferentially associated with uncontrollable stress. The right cortex is hypothesized to be at the top of a hierarchy in the processing of such stressful inputs, and endogenous dopaminergic modulation facilitates adaptive responses. Subcortical dopamine terminal regions were also examined for dopamine content and turnover. In addition to depleting cortical dopamine, the three lesion groups showed highly specific alterations in the status of subcortical dopamine systems, compared to either restrained or non-restrained shams. Left brain lesions resulted in significant bilateral increases in amygdala dopamine turnover. Right cortical lesions induced significant bilateral reductions of striatal dopamine content. Bilateral lesions increased dopamine content in the left amygdala and decreased dopamine in the right nucleus accumbens. Also in this group, dopamine turnover was increased in the right nucleus accumbens and decreased in the right amygdala. The data suggest that increases in stress vulnerability induced by cortical lesions may be related, in part, to neurochemical alterations in subcortical structures previously shown to modulate gastric stress pathology. The results also indicate that brain organization is inherently asymmetrical with respect to the regulation of responses to stress, which may be of significance for human psychopathology and its exacerbation by stress.

Amygdala↗

PubMed1995

Nervous system lupus: pathogenesis and rationale for therapy.

Several different pathogenic mechanisms appear to be involved in CNS lupus. These include: B-cell/autoantibody-mediated nervous system compromise; immune complex deposition and vasculitis; microthrombosis and vasculopathy; aberrant MHC Class II antigen expression with T-cell mediated disease (multiple-sclerosis model); and, cytokine-induced brain inflammation. These processes are not mutually exclusive: there exist in vitro and in vivo models for each of these. A number of autoantibodies, especially those with specificities for shared neuronal/lymphocyte antigens, are associated with certain forms of cognitive dysfunction or overt nervous system manifestations. In MRL/lpr mice, lymphoid infiltrates in the brain parenchyma are related to a neurobehavioural dysfunction which develops very early in the course of autoimmune disease. Recent results, both in animal models and in human studies on the therapeutic effects of corticosteroids, immunosuppressive drugs or anticoagulants on clinical and subclinical manifestations of CNS lupus are highlighted in an attempt to develop a rationale for intervention based upon presumed pathogenesis.

Animals↗

PubMed1994

Left/right nigrostriatal asymmetry in susceptibility to neurotoxic dopamine depletion with 6-hydroxydopamine in rats.

Male Sprague-Dawley rats were investigated for the existence of a left/right hemispheric population asymmetry in the extent of striatal dopamine depletion following unilateral lesions with 6-hydroxydopamine (6-OHDA) in the left or right substantial nigra. Four doses of 6-OHDA were employed (with left and right lesion groups at each dose). Analysis of striatal dopamine depletion revealed significant main effects not only for dose of 6-OHDA, but also for side of lesion, with right-lesioned rats having greater dopamine depletion across doses. In a group of non-lesioned rats, randomly selected from this population, striatal dopamine turnover showed a significant right-sided bias. It is suggested that the latter functional asymmetry may have been responsible for the neurotoxic depletion asymmetry seen in lesioned animals, and that side of lesion should be considered when attempting to produce consistent and maximal dopamine depletion in large scale studies with the unilateral 6-OHDA lesion paradigm.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Asymmetrical orientation to edges of an openfield: modulation by striatal dopamine and relationship to motor asymmetries in the rat.

Rats with unilateral 6-hydroxydopamine (6-OHDA, 4 or 8 micrograms) or sham lesions of the substantia nigra were examined (undrugged) for asymmetrical orientation to edges of a large openfield. Lesioned rats preferentially aligned with the edge such that the intact striatum was contralateral to the edge. The magnitude of this asymmetry was greatest in rats lesioned with the highest dose of 6-OHDA. There was no population left/right hemispheric asymmetry in the extent to which unilateral striatal dopamine (DA) depletion produces this behavioral bias. In sham-lesioned rats, endogenous imbalances in striatal DA activity (DOPAC/DA) were related to the direction of edge orientation, such that the more active striatum tended to be contralateral to the edge. Also in shams, the direction of this orientational asymmetry was not significantly related to the direction of motor bias measured as amphetamine- and apomorphine-induced turning behavior in rotometers (having no edges). However, the magnitudes of sensorimotor (edge behavior) and motor (turning) asymmetries were negatively correlated. The results extend previous findings that asymmetrical edge behavior is a sensitive index of imbalances in striatal DA activity, not only in DA-depleted rats, but in intact rats as well. Furthermore, sensorimotor and motor asymmetries, while both under DAergic influence, are largely independent processes.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Behavior and immune status of MRL mice in the postweaning period.

The notion that the MRL-lpr substrain is a useful model of behavioral and cognitive deficits found in systemic autoimmune diseases is supported by the recent findings of behavioral dysfunction in autoimmune MRL-lpr mice compared to their congenic control MRL +/+ mice. However, it has not been established whether the altered behavioral profile in MRL-lpr mice is the result of the autoimmune process itself or reflects a subtle difference in genetic background or both. To address the question whether MRL-lpr mice are born with behavioral dysfunction the present study compares the behavior of the two MRL substrains in the early postweaning period, when their immune status does not show detectable difference. Results show that the prediseased (4- to 6-week-old) MRL-lpr mice are not distinguishable from the congenic MRL +/+ controls on most behavioral measures except for speed of locomotion and novelty-induced hyperactivity in activity monitors. The immune status of the two substrains is also similar except for a lower hematocrit in the MRL-lpr group. Surprisingly, low amounts of antinuclear and brain-reactive antibodies (possibly transferred from diseased mothers) were detected in the serum of about 50% of the mice in both groups. The lack of major differences in behavior in the premorbid period suggests that appearance of previously reported behavioral dysfunction in the disease state reflects the presence of autoimmunity, time-determined genetic activation, or both.

Age Factors↗