PubMed Health⌕ Search

Biomedical subjects

H Szechtman

Publications and source records attributed to H Szechtman.

At least 19 recordsLinked to original sources
PubMed2006

Obsessive-compulsive disorder as a disturbance of security motivation: constraints on comorbidity.

Patients with OCD often meet criteria for additional psychiatric disorders, with the incidence of comorbidity being as high as 75% in some studies. Here we examine the theoretical plausibility that in OCD much of the domain of co-morbid presentations encompasses related perturbations of the security motivation system. According to a recent proposal, the security motivation system represents a biologically primitive special motivation that is activated by potential (as opposed to imminent) danger to self or intimate others and engages a set of specialized species-typical behaviors (such as checking and washing) to handle potential danger. Because the task of security motivation is open ended, in the sense that no consummatory stimuli can exist in the real world to indicate the absence of potential danger, the shutdown of security motivation is produced by a self-generated feeling of knowing, a satiety signal termed yedasentience. In this schema, OCD results from a failure to generate or respond to the yedasentience signal: without this negative feedback the patient persists abnormally long in a strong motivational state having to do with primal, basic threats to existence, a condition that leads to prolonged engagement in security-related behaviors, such as the checking and washing, characteristic of OCD compulsions and obsessions. Considering the proposed neuronatomy of security motivation system and OCD, we discuss the likelihood that the phenomenon of "spread of allied reflexes" can produce other security-related psychiatric conditions, as well as the possibility that disturbances along different pathways of the security motivation system can lead to apparently different disorders.

Anxiety↗
PubMed2002

Preliminary evaluation of oral anticonvulsant treatment in the quinpirole model of bipolar disorder.

A potential model for bipolar disorder, quinpirole-induced biphasic locomotion, was used for a preliminary evaluation of behavioral effects of oral anticonvulsant treatment. Quinpirole, a D2/D3 agonist, induces a biphasic locomotor response starting with inhibition and followed by excitation, resembling the oscillating nature of bipolar disorder. The present study developed a paradigm for oral administration of anticonvulsants that resulted in therapeutic blood levels and tested the effects of treatment on the quinpirole-induced response. Eleven days treatment with valproate (12 g/liter water), phenytoin (6 g/kg food), and carbamazepine (8 g/kg food) resulted in therapeutic blood levels and in a borderline significant reduction in quinpirole-induced hyperactivity without effects on the hypoactive phase. Valproate effects became more significant at the height of the hyperactivity response. Eleven days treatment with topiramate (30 mg/kg) resulted in a significant attenuation of quinpirole-induced hyperactivity, qualitatively similar to the effects of the other anticonvulsants. The results suggest that mood-stabilizing anticonvulsant drugs including topiramate may attenuate quinpirole-induced hyperactivity.

Administration, Oral↗
PubMed2002

Monoamine oxidase inhibitor-induced blockade of locomotor sensitization to quinpirole: role of striatal dopamine uptake inhibition.

Previous studies have shown that the monoamine oxidase inhibitor (MAOI) clorgyline, blocks locomotor sensitization to the D(2)/D(3) dopamine agonist quinpirole and sensitizes self-directed mouthing behavior in rats by a mechanism independent of MAO inhibition. However, clorgyline is also an inhibitor of striatal dopamine uptake, and this mechanism could account for the effect of clorgyline on quinpirole sensitization. To investigate this possibility, the effects of clorgyline and pargyline were examined. Of these two MAOIs, only clorgyline inhibits dopamine uptake in the striatum. Rats received subcutaneous injections of clorgyline (1 mg/kg), pargyline (10 mg/kg) or vehicle 90 min prior to each injection of quinpirole (0.5 mg/kg, s.c., x8, twice weekly) or saline. Clorgyline and pargyline blocked the development of quinpirole-induced locomotor sensitization and sensitized self-directed mouthing behaviors in quinpirole rats. Thus, it is unlikely that clorgyline blocks locomotor sensitization to quinpirole via an inhibition of striatal dopamine uptake. Both MAOIs increased dopamine metabolism in the striatum, showed opposite effects in the prefrontal cortex, and eliminated the correlation between prefrontal dopamine and striatal DOPAC content found in quinpirole sensitized rats. We suggest that clorgyline and pargyline may affect the behavioral and neurochemical response to quinpirole via a previously reported MAOI-displaceable quinpirole binding site, a site which we hypothesize serves as a 'switch' to select what motor output becomes sensitized to repeated injections of quinpirole.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Neurotoxic properties of cerebrospinal fluid from behaviorally impaired autoimmune mice.

The chronic, lupus-like autoimmune disease in MRL-lpr mice is associated with leucocyte infiltration into the choroid plexus, brain cell death, and deficits in motivated behavior. The presence of lymphoid cells in the ventricular lumen and the increased number of TUNEL-positive cells in periventricular areas led to the hypothesis that immune cells enter into the cerebrospinal fluid (CSF) and induce primary neuronal damage in regions bordering the cerebral ventricles. Using an in vitro approach, we presently examine the possibility that CSF from autoimmune mice is neurotoxic and/or gliotoxic. The CSF and serum from diseased MRL-lpr mice, less symptomatic MRL +/+ controls, and healthy Swiss/Webster mice (non-autoimmune controls) were frozen until their effects on the viability of pyramidal neurons and astrocytes were assessed in a two-color fluorescence assay. Significant reduction in neuronal viability (in some cases as low as 67%) was observed in the co-cultures of hippocampal neurons and astrocytes incubated for 24 h with CSF from autoimmune MRL-lpr mice. The viability of astrocytes did not differ among the groups, and the CSF from autoimmune mice appeared more toxic than the serum. The behavior of MRL-lpr mice differed significantly from the control groups, as indicated by impaired exploration, reduced intake of palatable food, and excessive immobility in the forced swim test. The present results suggest that CSF from the behaviorally impaired lupus-prone mice is neurotoxic and are consistent with the hypothesis that neuroactive metabolites are produced intrathecally in neuropsychiatric lupus erythematosus.

Animals↗
PubMed2001

Compulsive checking behavior of quinpirole-sensitized rats as an animal model of Obsessive-Compulsive Disorder(OCD): form and control.

BACKGROUND: A previous report showed that the open field behavior of rats sensitized to the dopamine agonist quinpirole satisfies 5 performance criteria for compulsive checking behavior. In an effort to extend the parallel between the drug-induced phenomenon and human obsessive-compulsive disorder (OCD), the present study investigated whether the checking behavior of quinpirole rats is subject to interruption, which is an attribute characteristic of OCD compulsions. For this purpose, the rat's home-cage was placed into the open field at the beginning or the middle of a 2-hr test. RESULTS: Introduction of the home-cage reduced checking behavior, as rats stayed inside the cage. After 40 min, checking resurfaced, as quinpirole rats exited the home-cage often. An unfamiliar cage had no such effects on quinpirole rats or saline controls. CONCLUSIONS: Checking behavior induced by quinpirole is not irrepressible but can be suspended. Results strengthen the quinpirole preparation as an animal model of OCD compulsive checking.

Animals↗
PubMed2001

Behavioral effects of infection with IL-6 adenovector.

The onset of autoimmunity in lupus-prone mice is accompanied by a constellation of behavioral deficits, termed Autoimmunity-Associated Behavioral Syndrome (AABS). In particular, a spontaneous increase in serum interleukin-6 (IL-6) levels in five-week old MRL-lpr mice coincides temporally with blunted responsiveness to sucrose and excessive immobility in the forced swim test. These relationships, along with evidence that sucrose intake drops after systemic IL-6 overexpression is induced in healthy mice, have led to the hypothesis that sustained elevation in serum IL-6 also induces other aspects of AABS. This hypothesis is tested by comparing the behavioral profiles of healthy mice infected with Ad5mIL6 adenovirus (2 x 10(8) pfu of virus/mouse i.p.) with those of animals infected with control Ad5 virus. This methodology was used to achieve high circulating levels of IL-6, to overcome the problem of its short half-life, and to avoid the stressful effects of repeated injections. The Ad5mIL6 infection (known to induce excessive IL-6 levels over five days) transiently reduced food, water, and sucrose intake, as well as rectal temperature in MRL +/+ and AKR/J mice. Although the level of locomotor activity did not decline, Ad5mIL6-infected AKR/J mice demonstrated less novel object exploration. Performance in the step-down, plus-maze, and spontaneous alternation tests were disturbed to various degrees in all infected animals. The present results suggest that prolonged exposure to circulating IL-6 primarily impairs ingestive behavior, likely reflecting enhanced catabolism. The inability of circulating IL-6 to alter other aspects of behavior supports the hypothesis that multiple immuno-neuroendocrine mechanisms contribute to the pathogenesis of AABS.

Adenoviridae↗
PubMed2001

The morphogenesis of motor rituals in rats treated chronically with the dopamine agonist quinpirole.

Rats injected repeatedly with the dopamine agonist quinpirole develop motor rituals that evolve through a cascade of 4 behavioral processes. The 1st involves increased activity. The 2nd involves increased path stereotypy, reflected in traveling repeatedly along the same few paths. The 3rd is an increase in the frequency of stopping in a few places, along with a decrease in stopping in other places. The 4th is a decrease in the repetition of movements performed in the specific stopping places. Altogether, these processes culminate in stereotypy, a typical short set of movements composed of a single performance of each movement type. Thus, stereotypy arises from changes in the temporal and spatial organization, but not the content, of behavioral patterns. These results provide a model for the development of motor rituals and their linkage to normal behavior and to the physical properties of the environment.

Animals↗
PubMed2000

Immunosuppression prevents neuronal atrophy in lupus-prone mice: evidence for brain damage induced by autoimmune disease?

An early onset of systemic, lupus-like disease in MRL-lpr mice is accompanied by deterioration in their behavioral performance and atrophy of pyramidal neurons in the parietal cortex and the hippocampal CA1 area. Using the immunosuppressive drug cyclophosphamide (CY) to attenuate the disease, we have tested the hypothesis that the autoimmune/inflammatory process is responsible for changes in brain morphology. A modified Golgi impregnation method revealed that, in comparison to saline-treated controls, immunosuppressive treatment with CY (100 mg/kg/week i.p. over 8 weeks) increased dendritic branching and spine numerical density in the CA1 region of MRL-lpr mice and MRL +/+ mice, which develop less severe manifestations of the disease. More interestingly, CY selectively prevented the atrophy and aberrant morphology of pyramidal neurons in the parietal cortex of MRL-lpr mice. The neuropathological measures (in particular reduced dendritic spine density) significantly correlated with increased serum levels of antinuclear antibodies and splenomegaly. The present results support the hypothesis that chronic autoimmune disease induces functionally important changes in neuronal morphology, and provide an empirical basis for understanding the behavioral dysfunction in systemic lupus erythematosus and autoimmune phenomena reported in some forms of mental illness.

Animals↗
PubMed2000

Increased TUNEL staining in brains of autoimmune Fas-deficient mice.

Profound changes in brain morphology and behavior coincide with the spontaneous development of systemic autoimmune/inflammatory disease in Fas-deficient MRL-lpr mice. The dendrites atrophy, the density of hippocampal and cortical neurons decreases, and an anxious/depressive-like behavior emerges while lymphoid cells infiltrate into the choroid plexus of MRL-lpr mice. We hypothesized that the inherited lack of the Fas-dependent anti-inflammatory mechanism would lead to unsuppressed immune activity, characterized by reduced apoptosis in the MRL-lpr brain. Using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeled (TUNEL) method as an indicator of apoptosis, a surprisingly high incidence of TUNEL-positive cells was observed in the hippocampus, choroid plexus and periventricular regions of MRL-lpr mice, 5-10-fold higher than that found in the MRL +/+ control brain. Immunostaining with anti-CD3, CD4 and CD8 monoclonal antibodies showed limited overlap between CD-positive and TUNEL-positive cells, suggesting that the dying cells are for the most part (approximately 70%) not T-lymphocytes. Although further characterization of the phenotype of the dying cells and the mechanism of cell death are required, the present results suggest the involvement of a Fas-independent apoptotic process in neurodegeneration induced by systemic autoimmune disease.

Animals↗
PubMed2000

Locomotor sensitization to quinpirole in rats: effects of drug abstinence and sex.

RATIONALE: Behavioral sensitization, induced by the chronic administration of psychomotor stimulants, serves as an experimental model for the development of behavioral pathology. Although many factors are known to influence the sensitization produced by indirect dopamine agonists, such as cocaine and the amphetamines, less is known about factors that influence the behavioral sensitization produced by direct dopamine receptor agonists. OBJECTIVE: As the extent to which behavioral sensitization is expressed following the repeated administration of indirect dopamine agonists can depend upon a period of drug abstinence, the present study determined the effects of drug abstinence on the expression of locomotor sensitization to the D2/D3 receptor agonist, quinpirole (QNP). METHODS: Male and female rats were administered ten, twice weekly, injections of 0.5 mg/kg QNP or saline (SAL), and then received one of five QNP doses (0-1.0 mg/kg; n=7-10/dose) in two dose-response tests for locomotor sensitization, conducted at 3 and 15 days following the cessation of chronic treatment. RESULTS: The sensitized locomotor response of QNP-treated animals was similar on the 2 test days in both male and female subjects. Compared to males, female rats displayed greater locomotor responding to QNP, both during chronic treatment and on the dose-response tests for sensitization. CONCLUSIONS: QNP locomotor sensitization is (a) not influenced by 2 weeks of QNP abstinence and (b) can be influenced by the sex of the animal. It is suggested that direct and indirect dopamine agonists produce locomotor sensitization via distinct mechanisms that differ in sensitivity to the passage of time but are both influenced by sex-specific variables.

Animals↗
PubMed2000

A switch mechanism between locomotion and mouthing implicated in sensitization to quinpirole in rats.

RATIONALE: Chronic treatment with the monoamine oxidase inhibitor (MAOI) clorgyline, blocks locomotor sensitization to the D2/D3 dopamine agonist quinpirole. It is unknown whether this blockade occurs via inhibition of the MAO enzyme or by another mechanism. OBJECTIVES: While clorgyline and moclobemide are equally effective MAOIs, only clorgyline has a high affinity for the MAOI-displaceable quinpirole binding site (MQB). This study compares the effects of both drugs on quinpirole sensitization. METHODS: To examine development of sensitization, rats received clorgyline (1 mg/kg/day), moclobemide (5 mg/kg/day), or vehicle via osmotic mini-pumps and were injected with quinpirole (0.5 mg/kg, s.c.) or saline every 3 days; locomotor and mouthing activity was recorded for each of the eight injections. A similar protocol was used to examine the expression of sensitization in rats previously sensitized to quinpirole. RESULTS: Clorgyline, but not moclobemide, blocked the development of locomotor sensitization to quinpirole. Clorgyline, but not moclobemide, blocked the sensitized locomotor response to quinpirole following the 25th day of treatment. Mouthing showed sensitization in quinpirole-treated rats co-treated with clorgy-line, but not moclobemide; this sensitized mouthing was predominantly directed towards self. Clorgyline and moclobemide equally inhibited MAO-A and had equal effects on tissue concentrations of dopamine, 3,4-dihydroxyphenylacetic acid, and serotonin in the striatum. CONCLUSIONS: Clorgyline (1) inhibits the development and the maintenance of locomotor sensitization to quinpirole by a mechanism that does not involve MAO and (2) changes the sensitized response to quinpirole from locomotion to mouthing. We suggest that clorgy-line affects the response to quinpirole via MQB and that this site acts as a switch that selects the motor pathway for sensitization to quinpirole.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Reduced corticotropin-releasing factor and enhanced vasopressin gene expression in brains of mice with autoimmunity-induced behavioral dysfunction.

The spontaneous development of autoimmune disease in MRL-lpr mice induces behavioral and endocrine changes that resemble effects of chronic stressors. To further examine the correspondence between autoimmune disease and chronic stress, we asked whether the brains of autoimmune mice show a shift in the corticotropin-releasing factor (CRF) to vasopressin (AVP) ratio. Using in situ hybridization histochemistry with 35S-labelled mouse riboprobes, the levels of mRNA transcripts encoding CRF and AVP were compared between autoimmune MRL-lpr and control MRL +/+ brains. CRF transcript levels were lower in the hypothalamic paraventricular nucleus and in the central nucleus of the amygdala in MRL-lpr mice. AVP transcript levels were higher in the paraventricular and the supraoptic nuclei in MRL-lpr mice compared to controls. CRF mRNA levels were inversely related to performance in stress-sensitive tasks and to measures of autoimmunity. As found previously for behavioral performance, immunosuppressive treatment with cyclophosphamide abolished the group difference in neuropeptide gene expression. These results indicate that an autoimmune disease process is necessary for the shift in the brain CRF:AVP ratio. Furthermore, they support the parallel between chronic stress and chronic autoimmunity/inflammation, and suggest common central mechanisms relevant to endocrine function and behavior.

Animals↗
PubMed1998

Progressive atrophy of pyramidal neuron dendrites in autoimmune MRL-lpr mice.

The autoimmune-prone MRL-lpr substrain of mice develop an autoimmunity-associated behavioral syndrome (AABS) which resembles in many respects the behavior of animals exposed to chronic stress. The present study examined whether these mice show changes in the morphology of neuronal dendrites, as found in animals exposed to chronic stress. A modified Golgi-Cox procedure was used to visualize the dendrites of pyramidal neurons in the parietal cortex and in the CA1 hippocampal field of 5-week and 14-week old MRL-lpr mice and MRL + / + controls. Reduced dendritic branching and length, and an up to 20% loss of dendritic spines were observed in parietal and hippocampal pyramidal neurons of MRL-lpr mice at both ages. In the parietal cortex, there was an age-dependent potentiation in the reduction of basilar, but not apical, dendrite branching and length, as well as in the loss of spines on basilar segments. Loss of spines in the hippocampus followed an age-related course for apical but not basilar dendrites. Moreover, compared to age-matched controls, brain weight was smaller in MRL-lpr mice at 14 but not 5 weeks of age. Considering that dendritic atrophy becomes more extensive when autoimmune disease is florid in MRL-lpr mice, it is proposed that immune/inflammatory factor(s) produce dendritic loss. Reduced dendritic complexity may represent, at least in part, a structural basis for the altered behavioral profile of MRL-lpr mice.

Animals↗
PubMed1998

Where the imaginal appears real: a positron emission tomography study of auditory hallucinations.

An auditory hallucination shares with imaginal hearing the property of being self-generated and with real hearing the experience of the stimulus being an external one. To investigate where in the brain an auditory event is "tagged" as originating from the external world, we used positron emission tomography to identify neural sites activated by both real hearing and hallucinations but not by imaginal hearing. Regional cerebral blood flow was measured during hearing, imagining, and hallucinating in eight healthy, highly hypnotizable male subjects prescreened for their ability to hallucinate under hypnosis (hallucinators). Control subjects were six highly hypnotizable male volunteers who lacked the ability to hallucinate under hypnosis (nonhallucinators). A region in the right anterior cingulate (Brodmann area 32) was activated in the group of hallucinators when they heard an auditory stimulus and when they hallucinated hearing it but not when they merely imagined hearing it. The same experimental conditions did not yield this activation in the group of nonhallucinators. Inappropriate activation of the right anterior cingulate may lead self-generated thoughts to be experienced as external, producing spontaneous auditory hallucinations.

Adult↗
PubMed1998

Association of altered whole-body metabolism with locomotor sensitization induced by quinpirole.

Repeated exposure to drugs classed as psychostimulants can produce behavioral sensitization, defined as augmented motor responses to fixed doses of such compounds. For example, chronic treatment of rats with the dopamine D2/D3 agonist quinpirole increases the locomotor response to this drug to levels that are several times higher than after acute treatment. To determine if such enhanced activity is associated with changes in energy metabolism, one group of rats (n = 16) received 11 injections of quinpirole (0.5 mg/kg every second day) while a second received equal numbers of saline injections. Immediately after each injection, rats were placed in individual metabolic chambers where oxygen (O2) consumption, carbon dioxide (CO2) output, and motor activity were measured every 5 min for the next 2 h. Locomotor responses to quinpirole doubled during the course of treatment, thereby confirming the establishment of behavioral sensitization. The magnitude of energy metabolism and motor activity were positively correlated in control rats but not in quinpirole-treated rats. However, quinpirole reliably reduced respiratory quotient (CO2/O2). This suggests that enhanced utilization of body lipids could be a separate physiological consequence of quinpirole that might support in part the heightened locomotor activity characteristic of the behavioral sensitization it induces.

Animals↗
PubMed1998

Effects of quinpirole on central dopamine systems in sensitized and non-sensitized rats.

The present study examined post mortem changes in central dopaminergic terminal regions following acute or chronic treatment regimens with the dopamine D2/D3 receptor agonist quinpirole, a psychomotor stimulant which induces pronounced behavioural sensitization when given chronically. Drug-induced changes in nucleus accumbens, striatum and amygdala were bilateral in nature, while in prefrontal cortex (medial prefrontal and anterior cingulate combined), left and right brain regions responded differentially to quinpirole. Acute drug treatment increased dopamine tissue levels in nucleus accumbens and right prefrontal cortex, while the dopamine metabolite 3,4-dihydroxyphenylacetic acid, was decreased in amygdala. In contrast, sensitization to quinpirole was associated with decreased dopamine levels in left prefrontal cortex, and increases in 3,4-dihydroxyphenylacetic acid levels in subcortical structures, particularly striatum and amygdala. Additionally, the increase in striatal 3,4-dihydroxyphenylacetic acid in chronic quinpirole animals was independent of drug treatment on the final day of injections. In summary, quinpirole induces a variety of simultaneous, regional changes in dopaminergic function, with the sensitized condition being primarily associated with an up-regulation of subcortical dopamine activity. While the nucleus accumbens and striatum play a well known role in motor activation and sensitized behaviour, it is concluded that the amygdala and prefrontal cortex have significant modulatory influences on these processes, with the role of the prefrontal cortex being asymmetrical in nature. Given the suggested relevance of behavioural sensitization to psychopathological states in humans, parallels are drawn between the present data and clinical findings, particularly in relation to obsessive-compulsive disorder.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Quinpirole induces compulsive checking behavior in rats: a potential animal model of obsessive-compulsive disorder (OCD).

Rats treated chronically with the dopamine agonist quinpirole (0.5 mg/kg, twice weekly x 10) met 5 criteria for performance of compulsive checking. Specifically, in a large open-field with single small objects in 4 of 25 locales, quinpirole rats revisited two places/objects excessively often and rapidly, compared with other locations in the environment or saline controls. They performed a ritual-like set of behavioral acts at these two places/objects and stopped in relatively few locales before returning to the preferred places/objects. Finally, they shifted their behavior to a new location when the object was moved there. Clomipramine (10 mg/kg, daily) postponed but did not prevent the development of the quinpirole effect. Quinpirole-induced compulsive checking may be an exaggeration of normal checking of home site in rats. Results suggest an animal model of obsessive-compulsive disorder and a role for dopamine in this disorder.

Animals↗