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Biomedical subjects

S I Deutsch

Publications and source records attributed to S I Deutsch.

At least 19 recordsLinked to original sources
PubMed1995

The effects of adenosine A3 receptor stimulation on seizures in mice.

We have previously shown that acute preischemic adenosine A3 receptor stimulation results in an increased postischemic damage, while chronic stimulation of this receptor diminishes it. Since several pathophysiological phenomena are common for both ischemia and seizures, we have explored the effect of acute and chronic administration of the adenosine A3 receptor selective agonist IB-MECA (N6-(3-iodobenzyl) adenosine-5'-N-methylcarboxamide) prior to seizures induced by N-methyl-D-aspartate (NMDA), pentamethylenetetrazole, or electric shock. At 100 micrograms/kg, acutely injected IB-MECA was protective in chemically but not electrically induced seizures. In chronic administration of IB-MECA, significant protection against chemically induced seizures was obtained in all studied measures, i.e., seizure latency, neurological impairment, and survival. Although threshold voltage was unchanged in electrically induced seizures, a chronic regimen of IB-MECA significantly reduced postepileptic mortality. Since the combination of an arteriole-constricting compound 48/80 and hypotension-inducing clonidine injected prior to NMDA results in a significant protection against seizures, and since acute stimulation of adenosine A3 receptor causes both arteriolar constriction and severe hypotension, there is a possibility that the protection obtained by the acutely administered drug may result from inadequate delivery of chemoconvulsants to the brain. It is, however, unknown whether the protective effect of chronically administered IB-MECA is related to the effect of the drug on blood flow, neuronal mechanisms, or both.

Adenosine↗
PubMed1995

Interference with nitric oxide production and action potentiates the antiseizure efficacy of flurazepam.

The effect of inhibiting "downstream" consequences of NMDA receptor stimulation with 7-nitroindazole, an inhibitor of the neuronal form of nitric oxide synthase (NOS), and methylene blue, an inhibitor of the nitric oxide (NO)-sensitive soluble guanylyl cyclase, on electrically precipitated tonic hindlimb extension in mice was studied. Moreover, the abilities of these compounds to potentiate the antiseizure efficacy of flurazepam were also examined. When administered alone, 7-nitroindazole (10.0-100 mg/kg) and methylene blue (1.0-100 mg/kg) did not share the ability of MK-801 (0.1 to 1.0 mg/kg) to antagonize electrically precipitated tonic hindlimb extension. However, doses of MK-801 (0.18 mg/kg), 7-nitroindazole (100 mg/kg), and methylene blue (10.0 and 100 mg/kg) that were devoid of apparent antiseizure efficacy by themselves potentiated the ability of flurazepam to antagonize electrically precipitated seizures. NMDA receptor antagonists cause neuronal toxicity, interfere with acquisition of spatial memory and induction of long-term potentiation in the hippocampal CA1 region, and precipitate psychoses in susceptible individuals. Thus, the development of both open-channel blockers of the NMDA receptor complex that can be administered in lower doses, and inhibitors of the "downstream" consequences of NMDA receptor-gated transient elevations of intraneuronal calcium ions as potential adjunctive antiseizure medications should be considered. Moreover, administration of these compounds with benzodiazepines may attenuate some of the neurotoxicity that may result from NMDA receptor antagonism.

Analgesics↗
PubMed1995

MK-801 alters the GABAA receptor complex and potentiates flurazepam's antiseizure efficacy.

MK-801 is an uncompetitive allosteric antagonist that interferes with glutamate-gated calcium ion conductance through the NMDA receptor-associated ionophore. In an outbred strain of mouse, MK-801 elicits episodes of explosive "popping" behaviors that may serve as a preclinical screening paradigm for novel antipsychotic medications. This investigation examined the effects of MK-801, at doses associated with the elicitation of popping, on the GABAA receptor complex in cerebral cortex, and flurazepam's ability to antagonize electrically precipitated seizures. Twenty four hours after MK-801 administration, there was an increased density of the radiolabeled antagonist-preferring conformation of the central benzodiazepine binding site and a potentiation of flurazepam's antiseizure efficacy. The data show that interference with NMDA receptor-mediated calcium ion conductance is associated with a relatively selective change in the GABAA receptor complex in cerebral cortex, and has functional behavioral consequences. Moreover, the data provide additional evidence for a delicate balance between GABAergic and glutamatergic transmission. Disturbance of this balance can have behavioral consequences for the animal.

Animals↗
PubMed1995

Anxiety and pupil reactivity in cocaine dependent subjects endorsing cocaine-induced paranoia: preliminary report.

There has been the clinical impression that people with higher levels of anxiety and central arousal are more prone to develop cocaine-induced paranoia (CIP), but this notion has not been formally studied. In the current study, we examined the differences between 28 CIP-endorsing and 16 CIP-denying chronic cocaine users in their levels of state and trait anxiety as measured by the Spielberger State-Tait Anxiety Inventory. We also studied levels of central arousal and reactivity using pupil size measures both during exposure to neutral, abstract, non-drug cues, and after exposure to a cocaine cue. Levels of trait (but not state) anxiety were significantly higher in the CIP group than in the non-CIP group. Moreover, while there were no significant pupil size differences or changes between the two groups while viewing neutral, abstract video images, the CIP group had significantly greater pupillary dilation in response to a video image of crack cocaine than did the non-CIP group. These significant differences remained even after covarying for anxiety scores. The study findings seem relevant to studies of autonomic reactivity in response to drug cues in cocaine-dependent patients; such studies might remain attentive to potential cue reactivity differences between patients endorsing and those denying CIP. Finally, this is the first study showing higher trait anxiety in patients with CIP.

Adult↗
PubMed1994

A glycinergic intervention potentiates the antiseizure efficacies of MK-801, flurazepam, and carbamazepine.

Twenty four hours after mice were forced to swim for up to 10 minutes in cold water, there was a reduction in the ability of MK-801 to antagonize the electrical precipitation of tonic hindlimb extension. Milacemide, a lipophilic prodrug of glycine, restored the antiseizure efficacy of MK-801 to the same level observed in unstressed animals treated with milacemide and MK-801. Stimulation of the glycine-gated chloride ionophore subsequent to the liberation of free glycine could explain milacemide's pharmacologic action as an adjuvant to MK-801. Consistent with this interpretation, milacemide was able to potentiate the antiseizure effects of flurazepam, a benzodiazepine agonist, in stressed and unstressed mice and carbamazepine in unstressed animals. D-cycloserine, a partial glycine agonist with greater specificity for the strychnine-insensitive modulatory site on the NMDA receptor complex, was examined for its effect on MK-801's antiseizure efficacy. At a high dose (320 mg/kg), D-cycloserine alone had an anticonvulsant effect. Moreover, this dose of D-cycloserine administered with MK-801 showed a significantly greater anticonvulsant efficacy than MK-801 alone. The data support the development of glycinergic interventions as adjunctive agents in the pharmacotherapy of seizure disorders.

Acetamides↗
PubMed1994

Allosteric effects of a GABA receptor-active steroid are altered by stress.

Recently, ring A reduced metabolites of naturally occurring steroids have been shown to act as allosteric modulators of GABA-gated chloride ion conductance. Specifically, 5 alpha-pregnane-3 alpha,21-diol-20-one (allotetrahydrodeoxycorticosterone; 5 alpha-THDOC) was shown to be a positive allosteric effector. For example, 5 alpha-THDOC enhances the specific binding of [3H]flunitrazepam, a benzodiazepine receptor agonist, among other pharmacological actions. Swim stress has been shown to reduce the ability of flurazepam, a prototypic benzodiazepine agonist, to antagonize the electrical precipitation of tonic hindlimb extension in mice. This stress-induced reduction in flurazepam's antiseizure efficacy persists for up to 72 h and is associated with alterations in the specific binding of ligands to the GABAA receptor complex. In the current study, the potentiation of [3H]flunitrazepam binding by 5 alpha-THDOC was greater in cerebral cortical membranes prepared from stressed mice compared with unstressed controls. Moreover, nanomolar concentrations of 5 alpha-THDOC that were ineffective in potentiating the specific binding of [35S]TBPS in cerebral cortical membranes prepared from unstressed control mice were capable of potentiating this binding in membranes prepared from stressed animals. Specifically, 50 nM 5 alpha-THDOC caused a 23% increase in the specific binding of [35S]TBPS in membranes from stressed mice, whereas it was without any significant effect in unstressed controls. This apparent ability of 5 alpha-THDOC to distinguish between the binding of [35S]TBPS to crude membranes prepared from stressed and unstressed control mice was eliminated in the presence of a 5 microM concentration of GABA.(ABSTRACT TRUNCATED AT 250 WORDS)

Allosteric Regulation↗
PubMed1994

Saccadic distractibility in cocaine dependent patients: a preliminary laboratory exploration of the cocaine-OCD hypothesis.

Epidemiologic Cachment Area Survey (ECAS) results suggest that cocaine abusing patients are at increased risk for the later development of Obsessive Compulsive Disorder (OCD), and a need for attention in laboratory and clinical research to the 'cocaine-OCD hypothesis' has been described. Analysis of the ECAS data, however, could not rule out the possibility of a 'distinctive OCD-like syndrome' related to cocaine use. Such an OCD-like syndrome in cocaine dependent individuals has been recently described, where some cocaine dependent patients compulsively forage for cocaine, especially after a cocaine binge. To further explore a possible relationship between cocaine dependence and OCD, the performance on an antisaccade task of 32 cocaine dependent individuals was compared to a group of 15 individuals without neuropsychiatric or substance abusing histories. OCD patients have been described as having a greater frequency of reflexive glances (i.e., increased saccadic distractibility) during the antisaccade task than normals. No statistically significant differences in antisaccade performance were observed between the cocaine dependent patients and a normal comparison group. However, when the cocaine using group was divided into those endorsing and those not endorsing significant cocaine-induced compulsive foraging, statistically significant differences emerged. Cocaine-induced compulsive foragers had the poorest antisaccade performance. While the small sample sizes and the lack of an OCD control group limit the conclusions that can be drawn from the present study, the results seem to suggest that a cocaine-OCD link might be particularly relevant for those cocaine addicts endorsing compulsive foraging.

Adult↗
PubMed1994

Molecular, functional and biochemical characteristics of the dopamine transporter: regional differences and clinical relevance.

The carrier molecule that transports dopamine (DA) across the synaptic membrane is known as the dopamine transporter (DAT). Depending on the ionic conditions, DAT may function as a mediator of both the inward directed DA transport known as the "reuptake" and the outward directed DA transport known as the "release." The functional significance of DAT is in the regulation of DA neurotransmission by terminating the action of DA in the synapse via reuptake. With use of DAT binding as a presynaptic marker to measure altered DA innervation, abnormalities of the DAT binding have been demonstrated in idiopathic Parkinson's disease, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity, and progressive supranuclear palsy. Moreover, the identification of DAT as the neuronal element that mediates the addictive properties of cocaine highlights its significance in cocaine addiction. Cocaine binding in the brain is heterogeneous, and there is an uneven distribution of the high- and low-affinity binding sites across the anatomical regions. Regional differences in ligand binding are observed by using both [3H]cocaine and the diphenyl-substituted piperazine derivatives known as the "GBR series" of ligands. The identification of compounds that inhibit the binding of medications for cocaine abuse. Furthermore, clarification of the various binding domains that may be relevant to transporter function in human neuropsychiatric disorders may lead to the development of new medications for schizophrenia, Tourette's disease, and drug addiction.

Animals↗
PubMed1994

L-tyrosine pharmacotherapy of schizophrenia: preliminary data.

The utility of L-tyrosine (10 g/day in four divided doses) as an adjuvant to molindone (150 mg/day) in the treatment of schizophrenia was investigated using a placebo-controlled, double-blind crossover design (3 weeks on L-tyrosine, 3 weeks on placebo). The objective of this inpatient study was to increase dopaminergic neural transmission along mesocortical projections in patients by increasing the precursor availability of L-tyrosine for dopamine biosynthesis. Theoretically, this approach might lessen both negative and positive symptoms of schizophrenia and improve frontal lobe-mediated neuropsychological performance. There was no evidence of statistically significant improvement conferred by L-tyrosine as measured by weekly Brief Psychiatric Rating Scale (BPRS), Schedule for the Assessment of Negative Symptoms (SANS), or Clinical Global Impressions (CGI) scales. The 12-h trough plasma level of L-tyrosine was significantly higher in all patients during the L-tyrosine phase of the study (t = -3.9, df = 20, p = 0.0009). At the end of each 3-week study period, no significant differences could be found in Wisconsin Card Sorting Test (WCST) or memory test performance. Smooth-pursuit eye movement (SPEM) performance had significantly more saccadic intrusions during the L-tyrosine supplementation phase compared to the placebo period. This increase in saccades during SPEM suggests that the tyrosine supplementation might have had some central effect.

Adult↗
PubMed1994

The relationship between cocaine-induced paranoia and compulsive foraging: a preliminary report.

Two prominent behavioral syndromes associated with chronic cocaine use that have been described in the literature are cocaine-induced paranoia (CIP) and cocaine-induced compulsive foraging (CICF) for cocaine. To help to clarify the relationship between the two cocaine-induced syndromes, the concordance and sequence of onset of the two cocaine-induced behaviors over the course of the patients' lifetime use of cocaine and during the course of a binge was examined in 62 crack cocaine-dependent men. Thirty-four (54.8%) reported experiencing both CIP and CICF. In 18 (29%) of the patients, only one of these cocaine-induced behavioral syndromes was reported. Ten (16.1%) of the subjects reported neither CIP nor CICF. Patterns of cocaine or other substance use and degrees of tolerance to cocaine were not significantly different between the groups endorsing different patterns of cocaine-induced behaviors. CIP typically preceded the onset of CICF both over the course of the patients' lifetime use of cocaine and over the course of a binge. The study results suggest varying thresholds for the expression of these behaviors in chronic cocaine-abusing individuals.

Adult↗
PubMed1994

Gaze discrimination in patients with schizophrenia: preliminary report.

The authors administered a gaze discrimination task to 24 patients with chronic schizophrenia and 25 subjects with no psychiatric history. Each subject was shown slides and asked, "Is the person in the slide looking directly at you?" Patients with schizophrenia were more likely than comparison subjects to perceive the person in the slide as looking at them when the person was looking away. Because there is evidence that gaze discrimination performance involves the superior temporal sulcus region of the brain and this region has been implicated in theories about the pathogenesis of schizophrenia, further study of the gaze discrimination task seems indicated.

Adult↗
PubMed1993

Discriminative stimulus properties of midazolam are shared by a GABA-receptor positive steroid.

3-Alpha-5-alpha-tetrahydrodeoxycorticosterone (alloTHDOC) is a 3-alpha ring A-reduced metabolite of deoxycorticosterone that has been shown to act via nongenomic mechanisms to modulate the GABAA receptor complex allosterically in vitro. Moreover, there are behavioral data consistent with the anxiolytic actions of GABA-receptor positive steroids. The drug discrimination paradigm was used in rats to demonstrate that effects of alloTHDOC are mediated by the GABAA receptor complex in the intact animal. In rats trained to discriminate 1.8 mg/kg of midazolam from saline, alloTHDOC substituted for the training stimulus.

Animals↗
PubMed1993

Swim stress selectively alters the specific binding of a benzodiazepine antagonist in mice.

The ability of flurazepam to antagonize the electrical precipitation of tonic hindlimb extension is reduced 24 h after mice are forced to swim for 10 min in cold water (6 degrees C). Presumably, this reduction in flurazepam's antiseizure efficacy reflects an environmental stress-induced modification of the GABAA receptor complex. The current study employed a variety of complementary in vitro approaches to characterize the delayed effects of cold-water swim stress on binding parameters of the GABAA receptor complex that may be associated with flurazepam's reduced antiseizure efficacy. The specific binding of [3H]flunitrazepam and the potentiation of this binding by chloride ions did not change after stress in the cerebral cortex, hippocampus, and cerebellum. Moreover, swim stress did not alter the ability of GABA to inhibit the binding of [35S]t-butylbicyclophosphorothionate (TBPS), a ligand that is a specific biochemical marker of the GABA-associated chloride ionophore, to crude membranes prepared from the cerebral cortex and cerebellum. Swim stress was associated with alterations of the specific binding of [3H]Ro 15-1788, a benzodiazepine receptor antagonist, to crude hippocampal and cerebellar membranes. The results are considered in the context of new insights derived from molecular cloning studies of the GABAA receptor complex.

Animals↗
PubMed1993

Differentiation between MK-801- and apomorphine-induced stereotyped behaviors in mice.

The ability of phencyclidine (PCP) to model schizophreniform psychosis is believed to be related to its ability to produce both hypoglutamatergia and hyperdopaminergia. As such, identification of PCP-stimulated behaviors may be important for the development of animal models of schizophrenia. In this study, MK-801 [(+)-5-methyl-10,11-dihydro-5H- dibenzo[a,d]cycloheptane-5,10-imine maleate], a high-affinity PCP analogue, was administered to mice in order to stimulate "PCP behaviors." These PCP behaviors were compared with behaviors stimulated by apomorphine, a dopamine agonist. Stereotyped behavior was assessed by both visual observations and automated measurements. Visual observations showed highly intense gnawing and sniffing in apomorphine-treated mice and the absence of gnawing in MK-801-treated mice. Automated stereotypic measures showed that, compared with vehicle-treated controls, there were frequent dissociations between MK-801 and apomorphine. Conceivably, a compound that attenuates PCP-stimulated behaviors while sparing apomorphine-stimulated behaviors would possess both antipsychotic efficacy and be devoid of undesirable side effects associated with dopamine blockade.

Analysis of Variance↗
PubMed1993

Measurement of an explosive behavior in the mouse, induced by MK-801, a PCP analogue.

MK-801, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor complex that binds with high-affinity to the phencyclidine (PCP) binding site, stimulated an outbred strain of NIH Swiss mice to display discrete episodes of explosive jumping behavior, designated as "popping." The episodes of this behavior were characterized with respect to their dose dependency, latency, and duration. The number of mice displaying this behavior increased with increasing doses of MK-801. The intensity of the popping behavior was sensitive to dose-dependent inhibition by haloperidol, a conventional antipsychotic medication, and clozapine, an atypical antipsychotic medication. In view of PCP's ability to precipitate a schizophreniform psychosis in humans, the behavior may serve as a useful preclinical paradigm for the screening of potentially novel antipsychotic medications.

Analysis of Variance↗
PubMed1993

Transient compulsive foraging behavior associated with crack cocaine use.

Compulsive foraging behavior associated with use of crack cocaine involves compulsively searching the environment for possibly misplaced pieces of crack. Of 41 crack cocaine addicts evaluated, 33 (80.5%) reported at least some compulsive foraging associated with use of crack; 21 (51.2%) reported such behavior as always associated with crack use. The mean length of time spent in compulsive foraging was 90 minutes. Cocaine-induced foraging may represent a drug-induced model of a type of compulsive behavior.

Adult↗