Biomedical subjects

Henry Szechtman

Publications and source records attributed to Henry Szechtman.

At least 19 recordsLinked to original sources

PubMed2006

Psychosis pathways converge via D2high dopamine receptors.

The objective of this review is to identify a target or biomarker of altered neurochemical sensitivity that is common to the many animal models of human psychoses associated with street drugs, brain injury, steroid use, birth injury, and gene alterations. Psychosis in humans can be caused by amphetamine, phencyclidine, steroids, ethanol, and brain lesions such as hippocampal, cortical, and entorhinal lesions. Strikingly, all of these drugs and lesions in rats lead to dopamine supersensitivity and increase the high-affinity states of dopamine D2 receptors, or D2High, by 200-400% in striata. Similar supersensitivity and D2High elevations occur in rats born by Caesarian section and in rats treated with corticosterone or antipsychotics such as reserpine, risperidone, haloperidol, olanzapine, quetiapine, and clozapine, with the latter two inducing elevated D2High states less than that caused by haloperidol or olanzapine. Mice born with gene knockouts of some possible schizophrenia susceptibility genes are dopamine supersensitive, and their striata reveal markedly elevated D2High states; suchgenes include dopamine-beta-hydroxylase, dopamine D4 receptors, G protein receptor kinase 6, tyrosine hydroxylase, catechol-O-methyltransferase, the trace amine-1 receptor, regulator of G protein signaling RGS9, and the RIIbeta form of cAMP-dependent protein kinase (PKA). Striata from mice that are not dopamine supersensitive did not reveal elevated D2High states; these include mice with knockouts of adenosine A2A receptors, glycogen synthase kinase GSK3beta, metabotropic glutamate receptor 5, dopamine D1 or D3 receptors, histamine H1, H2, or H3 receptors, and rats treated with ketanserin or aD1 antagonist. The evidence suggests that there are multiple pathways that convergetoelevate the D2High state in brain regions and that this elevation may elicit psychosis. This proposition is supported by the dopamine supersensitivity that is a common feature of schizophrenia and that also occurs in many types of genetically altered, drug-altered, and lesion-altered animals. Dopamine supersensitivity, in turn, correlates with D2High states. The finding that all antipsychotics, traditional and recent ones, act on D2High dopamine receptors further supports the proposition.

Animals↗

PubMed2006

Differential effects of clorgyline on sensitization to quinpirole in rats tested in small and large environments.

RATIONALE: Cotreatment with clorgyline shifts the development of sensitization to the D2/D3 dopamine receptor agonist quinpirole from locomotion to mouthing, an effect apparently unrelated to the monoamine oxidase inhibition property of clorgyline. This phenomenon was demonstrated in rats examined in small activity chambers. However, like with other psychostimulant drugs, sensitization to quinpirole is modulated by environmental context. It is not known whether the clorgyline cotreatment effect is likewise influenced by the environment. OBJECTIVE: To determine the generality of the clorgyline effect on behavioral sensitization by evaluating the effects of clorgyline cotreatment on sensitization to quinpirole in two different environments: a small activity chamber and a large open field. METHODS: Male rats received eight injections of quinpirole (0.5 mg/kg, twice weekly) in an open field or activity chamber; one group in each environment received a constant infusion of clorgyline (1 mg/kg/day via osmotic minipumps) while the other group served as the sham surgery control. For quinpirole injection 7 or 8, rats were tested in the alternate environment. RESULTS: In activity chambers, clorgyline cotreatment switched sensitization to quinpirole from locomotion to mouthing. In the open field, clorgyline cotreatment increased mouthing and expanded the explored space without a change in path stereotypy or the amount of locomotion compared to treatment with quinpirole alone. CONCLUSIONS: Structure of the environment can modulate the clorgyline cotreatment effect on behavioral sensitization to quinpirole. The behavioral profiles produced by clorgyline cotreatment in the two environments resembled the behavioral effects observed with quinpirole and D1 agonist cotreatment. It is suggested that clorgyline cotreatment produces a behavioral profile characteristic of enhanced dopamine D1 and D2 receptor costimulation.

Animals↗

PubMed2006

Development and temporal organization of compulsive checking induced by repeated injections of the dopamine agonist quinpirole in an animal model of obsessive-compulsive disorder.

Rats treated chronically with the dopamine D2/D3 receptor agonist quinpirole develop locomotor sensitization and exhibit compulsive checking of specific places in an open-field arena, a behavioral profile that may represent an animal model of obsessive-compulsive disorder. However, it is not known how compulsive checking develops across quinpirole injections nor whether checking behavior possesses a particular temporal structure. Male rats received quinpirole (0.5mg/kg, twice weekly x 10) or an equivalent regimen of saline and were placed in a large open field for 55 min where their behavior was digitally tracked for subsequent analysis of checking behavior using existing and newly developed computer software. Results showed that the measures of compulsive checking did not follow a singular profile across injections: some remained constant and others changed monotonically reaching their near-maximum levels after about 5-7 quinpirole injections. Moreover, results showed that checking behavior was organized into bouts of checking, with the number of bouts, as well as the rate of checking within a bout, increasing across injections to reach near maximal levels after about 5-7 administrations of quinpirole. Finally, quinpirole-treated rats showed a paucity of long inter-bout intervals. These results suggest that (a) compulsive checking emerges from the operation of at least two underlying processes: a regulated process and a process of sensitization that intensifies the performance of checking behavior; and (b) quinpirole treatment may attenuate a sense of satiety that could underlie the compulsive nature of checking. Finally, because key variables measured using the newly developed algorithms showed the expected profile, the present study provides validation for the use of this methodology for the analysis of checking behavior.

Analysis of Variance↗

PubMed2006

Antidepressants attenuate increased susceptibility to colitis in a murine model of depression.

BACKGROUND & AIMS: Psychiatric factors may determine gastrointestinal health outcomes. Here, we used a model of depression based on neonatal maternal separation (MS) to identify alterations in gut physiology and to assess its association with increased sensitivity to experimental colitis in adulthood. We also examined whether antidepressant therapy attenuates the increased susceptibility to colitis. METHODS: C57BL/6 mouse pups were separated from mothers for 3 hours per day at 1-21 days of age. Maternally unseparated (US) litters served as controls. At 8 weeks of age mice were examined for changes in behavior, intestinal permeability, and sensitivity to colitis. Separate sets of MS and US mice were given either saline or the antidepressant desipramine 15 mg/kg once daily at 23-36 days of age. Testing of mice occurred at 8 weeks of age. RESULTS: Adult MS mice showed evidence of depressive-like behavior and enhanced intestinal permeability but showed no evidence of spontaneous inflammation. A more severe colitis was seen in MS compared with US mice. Antidepressant therapy improved parameters of depressive-like behavior and reduced the vulnerability to dextran sulphate sodium colitis in MS mice but had no effect on colitis in US mice. CONCLUSIONS: MS may lead to depression and increased responsiveness to stress, to impaired intestinal barrier function, and to enhanced vulnerability to colitis in adulthood. This vulnerability is reversed by antidepressant therapy. Depression increases vulnerability to intestinal inflammation. We speculate that pre-existing depression may facilitate the expression of inflammatory bowel diseases.

Animals↗

PubMed2005

Rituals, stereotypy and compulsive behavior in animals and humans.

From a survey of the behavior of animals in the wild, in captivity, under the influence of psychoactive drugs and in a model of obsessive-compulsive disorder (OCD), we identify that the behavioral repertoire invariably includes motor rituals, and that such rituals are performed at a few specific locations/objects in the environment with an orderly transition amongst locations/objects. The concept and parameters of this stable organization of rituals in time and space were used to analyze rituals of OCD patients, compared with control individuals performing the same actions (e.g. car locking). It was found that human rituals also converged to a few places/objects where repetitive acts were performed in a regular order, with the acts in OCD patients overlapping with those of control individuals. Across a very diverse range of animals and conditions, motor rituals are thus characterized by their close linkage to a few environmental locations and the repeated performance of relatively few acts. Such similarity in form may reflect a similarity in the mechanisms that control motor rituals in both animals and humans.

Animals↗

PubMed2005

Kappa-opioid agonist U69593 potentiates locomotor sensitization to the D2/D3 agonist quinpirole: pre- and postsynaptic mechanisms.

To assess whether the development and expression of behavioral sensitization to the dopamine D2/D3 agonist quinpirole (QNP) is influenced by coadministration of the kappa opioid receptor agonist U69593, rats received every 3-4 days for a total of 10 treatments an injection of U69593 (0.3 mg/kg) together with an injection of either a postsynaptic (0.5 mg/kg) or a presynaptic dose of QNP (0.05 mg/kg); locomotor activity was measured after each treatment. Control rats were injected as appropriate with QNP, U69593, and vehicle/saline. Following chronic treatment, dose-response profiles to QNP were obtained to assess the expression of sensitization; the effect of U69593 on locomotor activity in animals already sensitized to QNP was also assessed. Results showed that cotreatment of U69593 with a postsynaptic dose of QNP doubled the speed and magnitude of sensitization to QNP, while U69593 cotreatment with a presynaptic dose of QNP switched the effects of QNP from locomotor depression to locomotor sensitization. However, U69593 cotreatment with a presynaptic dose of QNP changed a different set of measures of sensitization than did cotreatment with a postsynaptic dose of the dopamine agonist. Together, findings suggest that sensitization to QNP is not a unitary phenomenon but has components that are relatively independent, mediated by distinct pre- and postsynaptic mechanisms and modulated by kappa receptor activity.

Algorithms↗

PubMed2005

Proliferating brain cells are a target of neurotoxic CSF in systemic autoimmune disease.

Brain atrophy, neurologic and psychiatric (NP) manifestations are common complications in the systemic autoimmune disease, lupus erythematosus (SLE). Here we show that the cerebrospinal fluid (CSF) from autoimmune MRL-lpr mice and a deceased NP-SLE patient reduce the viability of brain cells which proliferate in vitro. This detrimental effect was accompanied by periventricular neurodegeneration in the brains of autoimmune mice and profound in vivo neurotoxicity when their CSF was administered to the CNS of a rat. Multiple ionic responses with microfluorometry and protein peaks on electropherograms suggest more than one mechanism of cellular demise. Similar to the CSF from diseased MRL-lpr mice, the CSF from a deceased SLE patient with a history of psychosis, memory impairment, and seizures, reduced viability of the C17.2 neural stem cell line. Proposed mechanisms of cytotoxicity involve binding of intrathecally synthesized IgG autoantibodies to target(s) common to different mammalian species and neuronal populations. More importantly, these results indicate that the viability of proliferative neural cells can be compromised in systemic autoimmune disease. Antibody-mediated lesions of germinal layers may impair the regenerative capacity of the brain in NP-SLE and possibly, brain development and function in some forms of CNS disorders in which autoimmune phenomena have been documented.

Age Factors↗

PubMed2005

Impaired response to amphetamine and neuronal degeneration in the nucleus accumbens of autoimmune MRL-lpr mice.

Spontaneous development of lupus-like disease in MRL-lpr mice is accompanied by a constellation of behavioral deficits, including blunted responsiveness to sucrose. Although autoimmunity-induced damage of limbic areas is proposed to underlie this deficit, the systemic nature of the disease precludes inference of a causal relationship between CNS damage and functional loss. Based on the stimulatory effects of d-amphetamine sulfate (AMPH) on sucrose intake, the present study pharmacologically probes the functional status of central dopaminergic circuits involved in control of behavioral reward. The response rates were compared between diseased MRL-lpr mice and congenic MRL +/+ controls tested in the sucrose preference paradigm. Neuronal loss was assessed by Fluoro Jade B (FJB) staining of nucleus accumbens and the CA2/CA3 region. While control mice significantly increased intake of sucrose solutions 60 min after administration of AMPH (i.p., 0.5 mg/kg), the intake in drugged MRL-lpr mice was comparable to those given saline injection. Increased FJB staining was detected in the nucleus accumbens and hippocampus of diseased mice, and AMPH treatment neither altered this nor other measures of organ pathology. The results obtained are consistent with previously observed changes in the mesolimbic dopamine system of MRL-lpr mice and suggest that the lesion in the nucleus accumbens and deficits in dopamine release underlie impaired responsiveness to palatable stimulation during the progress of systemic autoimmune disease. As such, they point to a neurotransmitter-specific regional brain damage which may account for depressive behaviors in neuropsychiatric lupus erythematosus.

Amphetamine↗

PubMed2005

Induction of compulsive-like washing by blocking the feeling of knowing: an experimental test of the security-motivation hypothesis of obsessive-compulsive disorder.

BACKGROUND: H. Szechtman and E. Woody (2004) hypothesized that obsessive-compulsive disorder results from a deficit in the feeling of knowing that normally terminates thoughts or actions elicited by security motivation. To test the plausibility of this proposed mechanism, an experiment was conducted to produce an analog of washing in obsessive-compulsive disorder by eliciting a scenario of potential harm and using hypnosis to block changes in internally generated feelings that would normally occur during washing. RESULTS: Participants reacted with increased disgust, anxiety, and heart rate to their mental images of contamination and potential danger. As predicted, high but not low hypnotizable participants showed a significant prolongation of washing when change in feelings during washing was blocked hypnotically. CONCLUSION: Results show that blocking the affective signal that is normally generated during security-related behaviors, such as washing, leads to prolonged performance of these behaviors. This finding lends support to the plausibility of the proposed model of obsessive-compulsive disorder.

Journal Article↗

PubMed2005

Psychostimulant-induced behavior as an animal model of obsessive-compulsive disorder: an ethological approach to the form of compulsive rituals.

Rats treated chronically with the D2/D3 dopamine receptor agonist quinpirole show a pattern of behavior that meets a set of ethologically derived criteria of compulsive behavior in obsessive-compulsive disorder (OCD). Moreover, in both quinpirole-treated rats and OCD patients, the structure of compulsive rituals appear similar in being composed of relatively few motor acts that are organized in a flexible yet recurrent manner. In addition, the development of compulsive behavior in quinpirole-treated rats is attenuated by the OCD pharmacotherapeutic drug clomipramine. These similarities support the validity of quinpirole-treated rats as a psychostimulant-induced animal model of OCD. Considering that the induction of compulsive behavior in the rat model involves chronic hyperstimulation of dopamine receptors, this raises the possibility that dopaminergic mechanisms may play a role in OCD, at least in some subtypes of this disorder.

Animals↗

PubMed2004

A PET provocation study of generalized social phobia.

In an investigation of the neural circuits that may mediate the subjective experience of social phobia (SP), six male patients with a primary DSM-IV diagnosis of generalized social phobia watched, in the presence of a group of "communication experts," a videotape of themselves giving an impromptu talk (Exposure condition). In the control Baseline condition, they viewed a videotape of a socially competent stranger giving a talk. Regional cerebral blood flow was measured thrice under each condition. The study revealed significant deactivations from Baseline during Exposure in the right lingual gyrus (BA 18) and in the right medial frontal gyrus (BA 11); significant activations during Exposure were not observed. Deactivation of these regions may reflect a strategy of visual avoidance employed by the patients to dampen their phobic experience.

Adolescent↗

PubMed2004

Sex differences in functional activation patterns revealed by increased emotion processing demands.

Two [O(15)] PET studies assessed sex differences regional brain activation in the recognition of emotional stimuli. Study I revealed that the recognition of emotion in visual faces resulted in bilateral frontal activation in women, and unilateral right-sided activation in men. In study II, the complexity of the emotional face task was increased through tje addition of associated auditory emotional stimuli. Men again showed unilateral frontal activation, in this case to the left; whereas women did not show bilateral frontal activation, but showed greater limbic activity. These results suggest that when processing broader cross-modal emotional stimuli, men engage more in associative cognitive strategies while women draw more on primary emotional references.

Adult↗

PubMed2004

Presynaptic stimulation and development of locomotor sensitization to the dopamine agonist quinpirole.

To assess whether locomotor sensitization induced by repeated injections of the dopamine agonist quinpirole reflects tolerance of the drug's presynaptic depressive effects on locomotion, independent groups of rats were treated chronically (every 3 daysx10) with either a presynaptic dose of quinpirole (0.025 mg/kg; n=27), a postsynaptic dose (0.5 mg/kg; n=27), or saline (n=26). Following chronic treatment, a full dose-response profile was determined to assess the presence of sensitization. Results indicated that treatment with the postsynaptic, but not the presynaptic, dose of quinpirole induced locomotor sensitization. Moreover, chronic treatment with low-dose quinpirole did not yield tolerance of the drug's depressive effects. It is suggested that presynaptic dopamine receptors may require extensive spatial and/or temporal summation to become tolerant.

Animals↗

PubMed2004

Hypophysectomy does not block sensitization to the dopamine agonist quinpirole or its modulation by the MAOI clorgyline.

Repeated administration of the dopamine agonist quinpirole induces behavioral sensitization in rats that is characterized by a four- to eight-fold increase in the amount of locomotion compared to an acute dose of quinpirole, in the absence of any increases in mouthing behavior. The monoamine oxidase (MAO) inhibitor, clorgyline, switches behavioral sensitization to quinpirole from that of locomotion to self-directed mouthing. The mechanism by which clorgyline produces this switch in behavioral sensitization is unknown, but is independent of the known effects of clorgyline, namely, inhibition of MAO, inhibition of striatal dopamine uptake, or stimulation of sigma and I(2) receptors. Because clorgyline also inhibits hypothalamo-pituitary-adrenal (HPA) axis function, and increased HPA activity facilitates the behavioral effects of psychostimulant drugs, the effects of clorgyline on quinpirole sensitization are possibly due to an inhibition of HPA function. Therefore, the present study examined whether HPA activity is required for sensitization to quinpirole, and whether clorgyline exerts its effects on quinpirole sensitization via inhibition of HPA function. Control and hypophysectomized rats were administered clorgyline (1 mg/kg, s.c.) or vehicle 90 min before each injection of quinpirole (0.5 mg/kg x 8, twice weekly) or saline. To assess the level of sensitization reached by control and hypophysectomized rats, test injections of quinpirole (0.0, 0.07, and 0.2 mg/kg) were administered. Chronic quinpirole administration produced equivalent levels of locomotor sensitization in control and hypophysectomized rats. Clorgyline was equally effective in blocking the development of locomotor sensitization in control and hypophysectomized rats, and in sensitizing self-directed mouthing. The present study suggests that (1). HPA function is not necessary for the development of quinpirole sensitization and, (2). clorgyline does not produce its effects on behavioral sensitization to quinpirole via an inhibition of HPA activity. Moreover, the observation that quinpirole sensitization develops normally in the absence of any pituitary endocrine function suggests that pituitary-gonadal and pituitary-thyroid axes activity are also not necessary for quinpirole sensitization to occur.

Animals↗

PubMed2004

Obsessive-compulsive disorder as a disturbance of security motivation.

The authors hypothesize that the symptoms of obsessive-compulsive disorder (OCD), despite their apparent nonrationality, have what might be termed an epistemic origin--that is, they stem from an inability to generate the normal "feeling of knowing" that would otherwise signal task completion and terminate the expression of a security motivational system. The authors compare their satiety-signal construct, which they term yedasentience, to various other senses of the feeling of knowing and indicate why OCD-like symptoms would stem from the abnormal absence of such a terminator emotion. In addition, they advance a tentative neuropsychological model to explain its underpinnings. The proposed model integrates many previous disparate observations and concepts about OCD and embeds it within the broader understanding of normal motivation.

Affect↗

PubMed2003

Asymmetric modulation of a catecholamine-regulated protein in the rat brain, following quinpirole administration.

We previously reported a brain-specific 40 kDa catecholamine-regulated protein (CRP40) that binds dopamine (DA) and related catecholamines. CPR40 shares significant sequence homology with human heat shock protein (Hsp70), GRP78/BIP, and human #BQ24193 protein. Recent studies with the DA D(2) receptor antagonist, haloperidol, demonstrated a significant increase in expression of CRP40 in the striatum (STR). The objective of the present study was to investigate CRP40 expression in various brain regions following treatments with the DA D(2)/D(3) receptor agonist quinpirole (QNP) in rats and examine possible relationships between neurochemical parameters and locomotor activity. Rats received injections of either QNP (0.5 mg/kg, for 27 days every third day) or saline (SAL) and their locomotor activities were measured for 90 min after each injection. At injection 9, QNP-treated rats showed locomotor activity that was significantly greater than SAL controls (F(2,28) = 3.88, P < 0.05, Duncan's multiple range test, P < 0.05). Neurochemically, acute QNP-treated rats demonstrated significant differential expression of CRP40 in the left/right prefrontal cortex (PFC) relative to SAL-treated rats (-17.76 +/- 2.10%, -10.35 +/- 1.23%, P < 0.001). Chronic QNP significantly decreased CRP40 expression in the STR, ventral tegmental area (VTA), and left/right PFC (-24.85+/- 2.10%, -18.15 +/- 5.64%, -49.13 +/- 7.05%, -25 +/- 3.63%, P < 0.001). Finally, chronic QNP treatment resulted in a significant increase in CRP40 levels in the nucleus accumbens (NA) (+39.32 +/- 7.00%, P < 0.001). Heat shock protein (i.e., Hsp70 or Hsc70) expression remained unaltered following QNP treatment. Since QNP is a DA D(2)/D(3) agonist, alterations in CRP40 expression following QNP treatment suggest the protein's function in dopaminergic neurotransmission.

Animals↗

PubMed2003

Clorgyline-induced switch from locomotion to mouthing in sensitization to the dopamine D2/D3 agonist quinpirole in rats: role of sigma and imidazoline I2 receptors.

RATIONALE: 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. Clorgyline has a high affinity for imidazoline I(2) and sigma receptors, which could account for its effects on quinpirole sensitization. OBJECTIVES: To examine whether the effect of clorgyline on quinpirole sensitization is attributed to stimulation of either I(2) or sigma receptors. METHODS: In one experiment, rats received injections of the I(2) receptor agonist 2-BFI (0.2 mg/kg, IP) or vehicle, 90 min prior to each injection of quinpirole (0.5 mg/kg, SC, x 8, twice weekly) or saline. A similar protocol was used to examine the effects of the MAOI Ro 41-1049 (10 mg/kg, SC) on quinpirole sensitization. Unlike clorgyline, Ro 41-1049 has no affinity for sigma or I(2) sites. An initial experiment demonstrated that intermittent injections of clorgyline (1 mg/kg, SC) are as effective as a continuous clorgyline administration (1 mg/kg per day via osmotic mini-pump) on quinpirole sensitization. RESULTS: Like clorgyline, Ro 41-1049, but not 2-BFI, blocked the development of quinpirole-induced locomotor sensitization and induced instead sensitization of self-directed mouthing. CONCLUSIONS: Because Ro 41-1049 produced the same effects as clorgyline, and 2-BFI had no effects on quinpirole sensitization, it is unlikely that clorgyline exerts its effects via an action at sigma or I(2) receptors. Our results are consistent with the suggestion that clorgyline and Ro 41-1049 affect the behavioral response to quinpirole via the MAOI-displaceable quinpirole binding (MQB) site, and the hypothesis that the MQB site selects what motor output becomes sensitized to repeated injections of quinpirole.

Animals↗

PubMed2003

Taste responsiveness and diet preference in autoimmune MRL mice.

One of the most profound behavioural deficits in lupus-prone MRL-lpr mice is blunted responsiveness to sweet solutions. Given the systemic nature of autoimmune/inflammatory disease, it was not clear whether impaired taste sensitivity or motivated response to palatable food underlie this deficit. The present study compares response rates of MRL-lpr mice (which develop disease early), congenic MRL +/+ mice (which develop disease later in life) and non-autoimmune Swiss Webster (SW) mice to different tastes and diets. Healthy SW mice showed the highest responsiveness to palatable stimulation throughout the study. Conversely, the preference for palatable solutions progressively declined in MRL-lpr mice as the disease developed. No differences between the two MRL substrains were seen in responsiveness to quinine or saline, suggesting that blunted responsiveness to palatable solutions cannot be accounted for by reduced taste sensory function (hypogeusia). In addition, changes in response rates to palatable solutions were associated with systemic upregulation of pro-inflammatory cytokines. With a new cohort of mice fed on carbohydrate-rich and fat-rich diets, we also examined whether reduced sucrose intake in MRL-lpr mice can be accounted for by a reduced craving for carbohydrates. Contrary to this expectation, diseased MRL-lpr mice preferred carbohydrate-rich food while consuming a food mass comparable to controls. These results further support the hypothesis that the onset of lupus-like disease alters motivated behaviour, independent of changes in neurologic function and food metabolism.

Animals↗