Biomedical subjects

S J Siegel

Publications and source records attributed to S J Siegel.

At least 19 recordsLinked to original sources

PubMed2006

Mecamylamine blocks nicotine-induced enhancement of the P20 auditory event-related potential and evoked gamma.

Cigarette smoking is significantly more prevalent in individuals with schizophrenia than in non-affected populations. Certain neurocognitive deficits and disruptions common in schizophrenia may be altered by smoking, leading to the hypothesis that schizophrenics engage in smoking behavior to alleviate specific neurocognitive symptoms of the disorder. Additionally, research suggests that individuals with schizophrenia have altered auditory event-related potentials (ERPs) and abnormalities in evoked gamma oscillations which are both indices of sensory information processing. This study was conducted to examine the effect of acute administration of nicotine and the non-specific nicotinic antagonist mecamylamine on the P20 and N40 components of the ERP and evoked gamma oscillations in mice. Acute nicotine (1 mg/kg) significantly increased P20 amplitude, an effect that was blocked by pretreatment with mecamylamine (2 mg/kg). Additionally, acute nicotine increased the normal burst of evoked gamma following an auditory stimulus. The increase in evoked gamma was also blocked by mecamylamine pretreatment. Although acute nicotine decreased amplitude of the N40 component, this decrease was not attenuated by mecamylamine. These results replicate findings that nicotine may enhance early sensory information processing through the nicotinic acetylcholinergic receptor system in an established model (ERPs) and extend these findings in an emerging, novel model (evoked gamma oscillations) of sensory information processing. The results also support the hypothesis that nicotine may be beneficial to individuals with deficits in neurocognitive functions, such as those suffering from schizophrenia.

Acetylcholine↗

PubMed2006

Rolipram: a specific phosphodiesterase 4 inhibitor with potential antipsychotic activity.

Currently available antipsychotic medications work primarily by antagonizing D2 dopamine receptors, thus raising intracellular cAMP levels. We hypothesized that intracellular stimulation of cAMP levels in the CNS would have similar effects to treatment with antipsychotic medication. To test this hypothesis, we studied the effect of an acute treatment of rolipram, an inhibitor of type 4 phosphodiesterases that degrade cAMP, on acoustic startle and prepulse inhibition (PPI) of the acoustic startle response in C57BL/6J mice known to exhibit poor PPI. PPI is disrupted in schizophrenia patients, and the ability of a drug to increase PPI in mice is predictive of antipsychotic efficacy. We show here that acute treatment with rolipram significantly increases PPI at doses that do not alter the acoustic startle response (lowest effective dose 0.66 mg/kg). In addition, rolipram (0.66 mg/kg) blocks the disruptive effects of amphetamine (10 mg/kg) on PPI. At a slightly higher dose (1.0 mg/kg), rolipram also induces catalepsy. Thus, phosphodiesterase-4 (PDE4) inhibition has many of the same behavioral effects as traditional antipsychotic medications. In contrast to traditional antipsychotics, these effects are achieved through alteration of an intracellular second messenger system rather than antagonism of neurotransmitter receptors. Given previous reports showing rolipram improves cognition, we conclude that PDE4 represents an important novel target for further antipsychotic drug development.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2006

Mice expressing constitutively active Gsalpha exhibit stimulus encoding deficits similar to those observed in schizophrenia patients.

People with schizophrenia display sensory encoding deficits across a broad range of electrophysiological and behavioral measures, suggesting fundamental impairments in the ability to transduce the external environment into coherent neural representations. This inability to create basic components of complex stimuli interferes with a high fidelity representation of the world and likely contributes to cognitive deficits. The current study evaluates the effects of constitutive forebrain activation of the G(s)alpha G-protein subunit on auditory threshold and gain using acoustic brainstem responses and cortically generated N40 event-related potentials to assess the role of cyclic AMP signaling in sensory encoding. Additionally, we examine the ability of pharmacological treatments that mimic (amphetamine) or ameliorate (haloperidol) positive symptoms of schizophrenia to test the hypothesis that the encoding deficits observed in G(s)alpha transgenic mice can be normalized with treatment. We find that G(s)alpha transgenic mice have decreased amplitude of cortically generated N40 but normal acoustic brainstem response amplitude, consistent with forebrain transgene expression and a schizophrenia endophenotype. Transgenic mice also display decreased stimulus intensity response (gain) in both acoustic brainstem response and N40, indicating corticofugal influence on regions that lack transgene expression. N40 deficits in transgenic animals were ameliorated with low dose haloperidol and reversed with higher dose, suggesting dopamine D2 receptor-linked Gi activity contributes to the impairment. Consistent with this hypothesis, we recreated the G(s)alpha transgenic deficit in wild type animals using the indirect dopamine agonist amphetamine. This transgenic model of sensory encoding deficits provides a foundation for identifying biochemical contributions to sensory processing impairments associated with schizophrenia.

Acoustic Stimulation↗

PubMed2005

Monoamine reuptake inhibition and nicotine receptor antagonism reduce amplitude and gating of auditory evoked potentials.

BACKGROUND: Sensory encoding deficits have been extensively studied as endophenotypic markers of schizophrenia using auditory evoked potentials. In order to increase understanding of the neurochemical basis of such deficits, we utilized an animal model to test whether monoamine reuptake inhibition and nicotine receptor antagonism reduce the amplitude and gating of the P20 and N40 auditory components. METHODS: C57BL/6J mice received 12 days of chronic vehicle, bupropion, haloperidol or bupropion plus haloperidol. Auditory evoked potentials were then recorded in alert mice to measure the amplitude and gating of evoked components during a paired click paradigm similar to tasks used to measure the P50 and N100 auditory potentials in schizophrenia. Evoked potentials were recorded prior to and following acute nicotine. RESULTS: Bupropion reduced the amplitude and gating of the N40 evoked potential in mice, similar to the P50 and N100 endophenotypes associated with sensory encoding deficits in schizophrenia. This deficit was fully reversed only by the combination of haloperidol and nicotine, suggesting that dopamine reuptake inhibition and nicotine antagonism both contribute to the observed phenotype. Furthermore, nicotine increased P20 amplitude across all groups supporting a role for nicotine agonists in pre-attentive sensory encoding deficits. CONCLUSIONS: We propose that the combination of monoamine inhibition and nicotine receptor antagonism may serve as a useful model for preclinical screening of pharmaceutical compounds aimed at treating sensory encoding deficits in schizophrenia.

Animals↗

PubMed2004

Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications.

OVERVIEW: All current antipsychotic medications work by binding to Gi-coupled dopamine (DA) D2 receptors. Such medications are thought to affect cellular function primarily by decreasing DA-mediated regulation of intracellular cyclic adenosine monophosphate (cAMP).However, several studies indicate that cAMP signal transduction abnormalities in schizophrenia may not be limited to D2-containing cells. The current study examines the potential of using non-receptor-based agents that modify intracellular signal transduction as potential antipsychotic medications. METHODS: The indirect DA agonist amphetamine has been used to model the auditory sensory processing deficits in schizophrenia. Such pharmacologically induced abnormalities are reversed by current antipsychotic treatments. This study examines the ability of the phosphodiesterase-4 inhibitor, rolipram, to reverse amphetamine-induced abnormalities in auditory-evoked potentials that are characteristic of schizophrenia. RESULTS: Rolipram reverses amphetamine-induced reductions in auditory-evoked potentials. CONCLUSION: This finding could lead to novel approaches to receptor-independent treatments for schizophrenia.

Amphetamine↗

PubMed2001

Computerized neurocognitive scanning: I. Methodology and validation in healthy people.

Neuropsychological testing batteries are applied in neurobehavioral evaluations of brain disorders, including neuropsychiatric populations. They are lengthy, require expert administrators and professional scorers, and are prone to data handling errors. We describe a brief computerized neurocognitive "scan" that assesses similar domains with adequate reliability. The scan and a traditional battery were administered to a sample of 92 healthy individuals (44 men, 48 women) in a counterbalanced order. Both approaches showed a significant "sex-typical" gradient, with women outperforming men in verbal memory relative to spatial tasks. Both methods also yielded similar profiles of sex differences, with the additional computerized measure of face memory showing better performance in women. Age effects were evident for both methods, but the computerized scan isolated the effects to speed rather than accuracy. Therefore, the computerized scan has favorable reliability and construct validity and can be applied efficiently to study healthy variability related to age and gender.

Adult↗

PubMed2001

Computerized neurocognitive scanning: II. The profile of schizophrenia.

Cognitive dysfunction in schizophrenia is well established with neuropsychological batteries, which have assessed multiple domains indicating diffuse deficits especially in processing related to frontotemporal systems. Two studies are reported examining the feasibility of the computerized neurocognitive scan to assess differential deficits in schizophrenia. In Study 1, we tested 53 patients and 71 controls with the traditional and computerized assessments counterbalanced in order. Both showed comparable generalized impairment in schizophrenia with differential deficits in executive functions and memory. The profile was replicated in Study 2 in a new sample of 68 patients and 37 controls, receiving only the computerized scan. The combined sample showed robust correlations between performance on both speed and accuracy measures of the neurocognitive scan and clinical variables, including premorbid adjustment, onset age, illness duration, quality of life, and severity of negative symptoms. These correlations were higher and more prevalent in women than men, who showed correlations predominantly for speed rather than accuracy. Neuroleptic exposure was associated with poorer performance only for speed of memory processing, and in men, this association was seen only for typical neuroleptics. We conclude that the computerized neurocognitive scan can be applied reliably in people with schizophrenia, yielding data that support its construct and criterion validity.

Adult↗

PubMed1996

Circuit-specific alterations of N-methyl-D-aspartate receptor subunit 1 in the dentate gyrus of aged monkeys.

Age-associated memory impairment occurs frequently in primates. Based on the established importance of both the perforant path and N-methyl-D-aspartate (NMDA) receptors in memory formation, we investigated the glutamate receptor distribution and immunofluorescence intensity within the dentate gyrus of juvenile, adult, and aged macaque monkeys with the combined use of subunit-specific antibodies and quantitative confocal laser scanning microscopy. Here we demonstrate that aged monkeys, compared to adult monkeys, exhibit a 30.6% decrease in the ratio of NMDA receptor subunit 1 (NMDAR1) immunofluorescence intensity within the distal dendrites of the dentate gyrus granule cells, which receive the perforant path input from the entorhinal cortex, relative to the proximal dendrites, which receive an intrinsic excitatory input from the dentate hilus. The intradendritic alteration in NMDAR1 immunofluorescence occurs without a similar alteration of non-NMDA receptor subunits. Further analyses using synaptophysin as a reflection of total synaptic density and microtubule-associated protein 2 as a dendritic structural marker demonstrated no significant difference in staining intensity or area across the molecular layer in aged animals compared to the younger animals. These findings suggest that, in aged monkeys, a circuit-specific alteration in the intradendritic concentration of NMDAR1 occurs without concomitant gross structural changes in dendritic morphology or a significant change in the total synaptic density across the molecular layer. This alteration in the NMDA receptor-mediated input to the hippocampus from the entorhinal cortex may represent a molecular/cellular substrate for age-associated memory impairments.

Aging↗

PubMed1995

Distribution of the excitatory amino acid receptor subunits GluR2(4) in monkey hippocampus and colocalization with subunits GluR5-7 and NMDAR1.

Ionotropic excitatory amino acid (EAA) receptors are divided pharmacologically into three categories termed NMDA, AMPA/kainate, and high affinity kainate receptors. Each of these receptor subtypes is composed of a specific subset of subunits termed GluR1-4 (AMPA/kainate), GluR5-7, KA1-2 (high affinity kainate), and NMDAR1, 2 A-D (NMDA). Although colocalization of NMDA and non-NMDA receptors has been previously demonstrated electrophysiologically in rat, comprehensive analyses of subunit specific colocalization patterns have not been possible until the advent of appropriate antibodies. The present study investigates such immunocytochemical colocalization of several EAA receptor subunits within individual cells as well as dendritic spines in the monkey hippocampus. Double-label immunohistochemical experiments using antibodies which are specific for GluR2(4), GluR5-7, and NMDAR1 demonstrated that virtually all projection neurons in each subfield of the hippocampus contain subunits from the AMPA/kainate, kainate, and NMDA receptor families. In addition, confocal microscopy has demonstrated that individual spines may contain subunits representative of multiple EAA receptor families. Furthermore, detailed regional, cellular, and ultrastructural distribution patterns of the EAA receptor subunits GluR2 and GluR4 in monkey hippocampus are presented based on the use of a monoclonal antibody (mAb), 3A11, which was generated against the putative extracellular N-terminal domain of GluR2. Since this antibody recognizes only GluR2 in Western blots, and GluR2 as well as GluR4 in fixed transiently transfected cells, it has been designated anti-GluR2(4). Immunocytochemical labeling with mAb 3A11 revealed pyramidal cell somata and dendrites in each field of the hippocampus, as well as granule cells and polymorphic hilar cells in the dentate gyrus. Small cells with the morphologic characteristics of astroglia were also immunolabeled for GluR2(4) within the alveus and fimbria. Immunoreactivity at the ultrastructural level was localized to postsynaptic densities on dendritic spines and shafts and within the somatodendritic cytoplasm in all major hippocampal regions, as well as in a subset of dentate granule cell axons within the mossy fiber projection.

Aging↗

PubMed1994

Regional, cellular, and ultrastructural distribution of N-methyl-D-aspartate receptor subunit 1 in monkey hippocampus.

The regional, cellular, and subcellular distributions of N-methyl-D-aspartate (NMDA) receptor subunit 1, NMDAR-1, were investigated in monkey hippocampus by using a monoclonal antibody directed against a fusion protein corresponding to aa 660-811 of NMDAR-1. The data indicate that many neurons in each subfield of the hippocampus contain NMDAR-1 protein, although the intensity and distribution of immunoreactivity varied across regions, strata, and cellular compartments. In stratum lucidum of CA3, mossy fiber axons were immunoreactive for NMDAR-1, which may correspond to previously hypothesized presynaptic receptors. NMDAR-1-labeled postsynaptic profiles were present in stratum radiatum of CA3 but were largely absent from stratum lucidum. Such intraneuronal segregation of glutamate receptor subunits or classes may be spatially correlated with afferent systems that exhibit laminar segregation and terminate in different portions of the postsynaptic dendritic tree. For example, in CA3 pyramidal cells, NMDA receptors are postsynaptic in distal apical dendrites (stratum radiatum) where NMDA-dependent long-term potentiation in rats is mediated by associational/commissural afferents, and are absent from proximal apical dendrites (stratum lucidum), where NMDA-independent long-term potentiation is mediated by the mossy fiber input.

Animals↗

PubMed1993

Effects of social deprivation in prepubescent rhesus monkeys: immunohistochemical analysis of the neurofilament protein triplet in the hippocampal formation.

Social deprivation during early postnatal life has profound and long-lasting effects on the behavior of primates, including prolonged and exaggerated responses to stress as well as impaired performance on a variety of learning tasks. Although the cellular changes that underlie such alterations in behavior are unknown, environmentally induced psychopathology may involve morphologic or biochemical changes in select neuronal populations. The hippocampal formation of both socially deprived and socially reared prepubescent rhesus monkeys was selected for immunocytochemical investigation because of its association with the behavioral stress response and learning. Immunocytochemical analysis using antibodies specific for the neurofilament protein triplet was performed since these proteins are modified within degenerating neurons in a variety of neurodegenerative disorders. Results from optical density measurements indicate an increase in the intensity of non-phosphorylated neurofilament protein immunoreactivity in the dentate gyrus granule cell layer of socially deprived monkeys in comparison with that of socially reared animals, suggesting that early social deprivation may result in an increase in the amount of non-phosphorylated neurofilament protein in these cells. This phenotypic difference in dentate granule cells between differentially reared monkeys supports the notion that specific subpopulations of neurons in brain regions that subserve complex behaviors may undergo long-term modifications induced by environmental conditions. Furthermore, the data suggest that constitutive chemical components related to structural integrity may be as susceptible to early environmental manipulations as the more traditionally viewed measures of cellular perturbations, such as neurotransmitter dynamics, cell density and the establishment of connectivity. The observed modifications may serve as an anatomical substrate for behavioral abnormalities that persist in later life.

Animals↗

PubMed1990

Interpersonal perceptions and consequences of depressive-significant other relationships: a naturalistic study of college roommates.

We investigated social perceptions and consequences of depression and anxiety in roommate relationships. Mildly depressed, anxious but nondepressed, and nondepressed-nonanxious students (targets) and normal, same-sex roommates (a) rated the interpersonal impact on themselves of typical associations with their roommates and (b) judged their own interpersonal impact. Only depressed men received negative evaluations and emotional reactions from their roommates. However, depressed women reported more negative reactions to their normal roommates than vice versa. Finally, depressed targets perceived their interpersonal impact negatively, whereas their normal roommates perceived their own interpersonal impact as overly positive. These findings suggest that negative relationships between depressives and nondepressed others may be attributable, at least in part, to both participants' misperceptions of their social behavior and its consequences.

Adolescent↗

PubMed1987

Elevated serum levels of soluble interleukin-2 receptors in active pulmonary sarcoidosis: relative specificity and association with hypercalcemia.

We have previously reported serum elevations of the soluble form of the interleukin-2 receptor (IL-2R), a marker of T-cell activation, in sarcoidosis. In the present study, an enzyme-linked immunosorbent assay for soluble IL-2R was employed to compare sera from normal controls with those from patients with active sarcoidosis or idiopathic pulmonary fibrosis (IPF). Sera from patients with active sarcoidosis and parenchymal lung disease (radiographic Stages II or III) had geometric mean values for soluble IL-2R of 1975 units/ml compared to 640 units/ml for normal controls (p less than 0.001, Student's t-test). By contrast, soluble IL-2R levels were lower (989 units/ml, p less than 0.05 compared to normals) in patients with active sarcoidosis but no radiographic evidence for parenchymal disease (Stages 0 or I). Soluble IL-2R levels were not elevated in patients with inactive sarcoidosis. Three of the 4 sarcoidosis patients with the highest levels of soluble IL-2R also manifested hypercalcemia. While levels of soluble IL-2R were elevated for the group of patients with IPF (1171 units/ml, p less than 0.05 compared to normals), the striking elevations of soluble IL-2R noted in active sarcoidosis were not seen and there was greater overlap with normal values. We conclude that marked serum elevations of soluble IL-2R are more suggestive of active pulmonary sarcoidosis than IPF.

Adrenal Cortex Hormones↗

PubMed1973