Specific cognitive deficits in neurologic and psychiatric disease: targets for treatment.
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Cognition Disorders↗
Biomedical subjects
S I Deutsch
Publications and source records attributed to S I Deutsch.
Stress and a glycinergic intervention interact in the modulation of MK-801-elicited mouse popping behavior.
The ability of D-cycloserine, a partial glycine agonist, to modulate mouse popping behavior elicited by MK-801, a noncompetitive NMDA receptor antagonist, was studied in unstressed and stressed mice. In unstressed animals, D-cycloserine (5.6 and 10 mg/kg) attenuated the ability of MK-801 (1.0 mg/kg) to elicit this behavior. However, the ability of D-cycloserine to attenuate MK-801-elicited mouse-popping behavior was not evident in stressed mice, 24 h after they were forced to swim for up to 10 min in cold water. Thus, the therapeutic value of glycinergic interventions may be limited by environmental factors, such as stress.
Animals↗
Visual scanning of facial expressions in schizophrenia.
The authors previously observed that schizophrenic patients generated fewer fixations of < or = 50.1 ms in response to faces than did a clinical control group. This study examined whether deficits in short-duration eye movements were related to patients' problems in gestalt perception of faces. Faces were presented in upright and inverted orientations to examine the effects of distorting facial gestalts on eye movements. Normal subjects generated more saccades of < or = 50.1 ms to upright than to inverted faces. Patients' saccades of < or = 50.1 ms did not differ between orientations. Patterns of fixations and of saccades > 50.1 ms did not differ between groups. The results may indicate deficits in these patients in search strategies that underlie perception of facial gestalts.
Adult↗
Both nicotine and mecamylamine block dizocilpine-induced explosive jumping behavior in mice: psychiatric implications.
Dizocilpine (MK-801) administration to an outbred strain of NIH Swiss mice elicits discrete episodes of explosive jumping behavior designated as "popping." This behavior may serve as a useful preclinical paradigm for the screening of potentially novel antipsychotic medications. Both nicotine and mecamylamine, a nicotinic antagonist, dose-dependently blocked dizocilpine-induced popping. The data suggest that nicotine may be of therapeutic benefit in the treatment of schizophrenia and that some of its effects may be mediated by non-nicotinic receptors.
Animals↗
Visual scanning of faces correlates with schizophrenia symptomatology.
1. The purpose of this study was to examine whether quantitative measures of visual scanning of faces correlated with the severity of symptoms in patients with schizophrenia. 2. Preattentive visual fixations (fixations less than or equal to 50.1 ms in duration) were measured while 16 subjects with chronic schizophrenia and 38 comparison subjects scanned slides of human faces. 3. A significant inverse correlation was found between the number of preattentive fixations exhibited during 10 seconds of facial scanning and total Brief Psychiatric Rating Scale (BPRS) scores. 4. This study suggests that measures that probe preattentive processing during scanning of faces could represent a novel paradigm for studying the symptoms of schizophrenia.
Adult↗
Scheduled intermittent hospitalization for psychiatric patients.
OBJECTIVE: The effect of scheduled intermittent hospitalization on the hospital utilization, community adjustment, and self-esteem of persons with serious and persistent mental illness was examined in an experimental study. METHODS: Fifty-seven male veterans, aged 65 or younger, with a primary axis I psychiatric diagnosis who were frequent utilizers of inpatient care over the previous two years were randomly assigned to two groups. Patients in the experimental group were prescheduled for four hospital admissions, each lasting nine to 11 days, per year for two years. Patients in the control group had traditional access to hospital care. Psychiatric bed days, community adjustment, and self-esteem were assessed during and after the intervention. RESULTS: No differences between the groups on demographic or clinical variables were detected at study entry. The experimental group showed improvement in self-esteem, affect, and complaints of physical symptoms at one year. No statistically significant differences between groups were found in hospital utilization, financial management, substance abuse, or psychological well-being at one year. CONCLUSIONS: Scheduled intermittent hospitalization may be an appropriate and promising alternative to traditional care for revolving-door patients. This intervention could maintain patients at a higher level of wellness than traditional care and reduce the recurrence of the crises that precipitate hospitalization.
Adult↗
The antiseizure efficacies of MK-801, phencyclidine, ketamine, and memantine are altered selectively by stress.
Adaptive changes in the NMDA receptor complex occur in response to exposure to stress. We have previously shown that the ability of MK-801, an uncompetitive NMDA receptor antagonist, to antagonize electrically precipitated tonic hind-limb extension is reduced 24 h after mice are forced to swim for up to 10 min in cold water. The stress-induced reduction of the antiseizure efficacy of MK-801 stimulated the proposal that mice exposed to swim stress may serve as "an intact animal model" of altered or diminished NMDA-mediated neural transmission. In the current investigation, the dose-dependent abilities for the antagonism of electrically precipitated seizures in mice were determined for MK-801, phencyclidine, ketamine, and memantine. Interestingly, a single session of cold water swim stress reduced the antiseizure efficacies of MK-801 and memantine without affecting phencyclidine and ketamine when tested 24 h later. The data do not suggest that stress results in a simple reduction in the number of activated or open channels, but rather alters their size or charge characteristics.
Animals↗
Pupillary changes associated with the development of stimulant-induced mania: a case report.
A 30-year-old cocaine-dependent man who was a subject in a study evaluating the anticraving efficacy of the stimulant medication diethylpropion (DEP) became manic during his second week on the study drug. Pupillometric changes while on DEP, especially changes in the total power of pupillary oscillation, were dramatically different than those observed in the eight other study subjects who did not become manic. The large changes in total power of pupillary oscillation occurred a few days before the patient became fully manic. Such medication-associated changes in the total power of pupillary oscillation might be of utility in identifying persons at risk for manic-like adverse effects during the medical use of psychomotor stimulants or sympathomimetic agents.
Adult↗
Methylene blue adjuvant therapy of schizophrenia.
There is growing interest in the role of the nitric oxide (NO) pathway in idiopathic psychotic disorders such as schizophrenia. In this preliminary study, we examined the therapeutic efficacy of methylene blue (MB), a "downstream" inhibitor of one of NO's actions, administered orally as an adjuvant to conventional neuroleptic medications. Specifically, MB blocks NO's activation of soluble guanylyl cyclase. MB has previously been reported to have therapeutic effects in the treatment of psychosis and mania. Preclinical data also suggest that MB might possess antipsychotic potential. Participants in the current study were eight patients with schizophrenia who had incomplete responses to conventional antipsychotics (as evidenced by a Brief Psychiatric Rating Scale [BPRS] total score of 35 or more). These patients completed a 4-week open-label study with a 1 week "off", 2 week "on", and one final week "off" design. Measures of treatment efficacy were the BPRS, Schedule for the Assessment of Negative Symptoms, and Clinical Global Improvement Scale administered weekly. Final scores for each outcome measure item were based on the consensus of at least two trained raters present during each rating interview. A statistically significant, albeit modest, decrease in the severity of psychopathology was observed while the subjects were taking MB, and psychopathology significantly worsened when MB was discontinued. The results suggest a need for further study with MB or perhaps other NO-dependent guanylyl cyclase-inhibiting medications.
Adult↗
Effects of nifedipine, a calcium channel antagonist, on cognitive function in schizophrenic patients with tardive dyskinesia.
We examined whether nifedipine, a calcium channel antagonist, added to a stable regimen of neuroleptic medication would affect cognition in patients with chronic schizophrenia or schizoaffective disorder who had tardive dyskinesia. Fifteen patients with tardive dyskinesia were treated with nifedipine (60 mg daily) or matching placebo for 4 weeks and then were crossed over from nifedipine to placebo or from placebo to nifedipine for another 4 weeks. At the end of each 4-week phase of the study, the patients performed a rotary pursuit test of procedural learning and a dementia scale assessing general cognitive abilities. Nifedipine improved performance in the rotary pursuit test and conceptual abilities in the dementia scale compared with placebo, but only for patients who first were exposed to the tests during the placebo condition. These results provide preliminary evidence that calcium channel antagonists might enhance learning and memory in schizophrenic patients with tardive dyskinesia.
Aged↗
Behavioral approaches to the functional assessment of NMDA-mediated neural transmission in intact mice.
Altered neurotransmission mediated by L-glutamate at the level of the N-methyl-D-aspartic acid (NMDA) receptor complex has been implicated in the pathophysiologic mechanisms of several major neuropsychiatric disorders. Moreover, strategies for the pharmacologic manipulation of NMDA-mediated neural transmission have been discussed for the treatment of disorders as diverse as schizophrenia, seizures, stroke, and traumatic brain injury, MK-801, an uncompetitive allosteric antagonist of the NMDA receptor complex, was shown to antagonize electrically precipitated seizures in a dose-dependent manner and elicit popping behavior in mice. Changes in the ability of MK-801 to antagonize electrically precipitated seizures or elicit popping behavior caused by stress or pharmacologic manipulations may reflect alterations in the populations of NMDA-associated channels responsible for these behavioral actions (e.g., the number of them in the open configuration or their size, shape, and charge characteristics). We used these paradigms to study the pharmacologic actions of an allosteric glycinergic intervention (i.e., milacemide), inhibitors of the "nitric oxide cascade" (i.e., 7-nitroindazole and methylene blue), and conventional (i.e., haloperidol) and atypical (i.e., clozapine) antipsychotic medications on NMDA-mediated neurotransmission in the intact mouse. Also, marked differences in the ability of MK-801 to elicit popping behavior in inbred mouse strains suggest that they differ in their populations of NMDA receptor complexes responsible for mediating this behavior. This latter observation could lend itself to the identification of specific genetic loci contributing to this behavior. In view of the ability of phencyclidine (PCP) to precipitate a schizophreniform psychosis and the action it shares with MK-801 on NMDA-mediated neurotransmission, the characterization of these genetic loci in mice may inform the search for human loci responsible for the susceptibility to "PCP-psychosis" and schizophrenia.
Animals↗
Preattentive and attentive eye movements during visual scanning of a cocaine cue: correlation with intensity of cocaine cravings.
The visual scanning of 19 recently abstinent crack cocaine-dependent men was assessed while they viewed a picture of a cocaine cue and a picture of a neutral cue. Cocaine craving scores were inversely correlated with the number of preattentive fixations and saccades and were positively correlated with the number of attentive fixations.
Adult↗
Frontal cortical atrophy and negative symptoms in patients with chronic alcohol dependence.
It has been suggested that frontal lobe pathology is associated with negative symptoms in patients with chronic alcoholism. In his exploratory study, the authors examined 19 chronic alcoholic inpatients on an alcohol treatment unit and found a significant relationship between severity of frontal atrophy (as measured by CT) and negative symptoms (as measured by the Scale for the Assessment of Negative Symptoms).
Adolescent↗
Selective effects of MAO inhibition on peripheral benzodiazepine receptor binding in the mouse.
Monoamine Oxidase (MAO) and the peripheral benzodiazepine binding site (PBR) share a close physical proximity to each other in the outer mitochondrial membrane. Furthermore, MAO activity and the density of PBR sites are affected by stress; benzodiazepines may influence stress-induced changes in MAO activity. In view of the close physical association between MAO and the PBR, we examined the effects of chronic administration of selective and nonselective MAO inhibitors to mice on the specific binding of 3H-Ro5-4864 and 3H-PK-11195 to crude membranes prepared from kidney, heart and liver. Chronic MAO inhibition was associated with alterations in PBR binding in all three tissues; however, in heart and liver changes were not detectable with 3H-PK-11195. Perhaps, the ability to discern changes with 3H-Ro5-4864 that are not detectable with 3H-PK-11195 reflects a functional change in the "activity" of the PBR site in heart and liver that is elicited by chronic MAO inhibition and mediated by a change in the "conformation" of the protein that is detected with 3H-Ro5-4864. Importantly, iproniazid, the nonselective MAO inhibitor, caused changes in PBR binding in all three of the tissues.
Animals↗
[Glucocorticoid resistance syndrome].
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Adrenal Cortex Diseases↗
Impaired motor skill learning in schizophrenia: implications for corticostriatal dysfunction.
We assessed skill learning in young and older schizophrenic patients using the rotary pursuit task. Schizophrenic patients displayed impaired learning on this task compared with normal control subjects, but older patients were not more impaired than young ones. The patients' rotary pursuit learning was not correlated to the severity of abnormal movements or to their treatment with medication, but it was associated to conceptual abilities assessed on the Dementia Rating Scale (Mattis 1988). An impairment in acquiring motor procedures in this task might reflect neuropsychological deficits associated with corticostriatal pathology.
Adult↗
7-Nitroindazole and methylene blue, inhibitors of neuronal nitric oxide synthase and NO-stimulated guanylate cyclase, block MK-801-elicited behaviors in mice.
We examined the abilities of 7-nitroindazole and methylene blue, inhibitors of the neuronal isoform of nitric oxide synthase (NOS) and nitric oxide-stimulated guanylate cyclase activity respectively, to attenuate explosive episodic jumping behavior(s) ("popping") elicited by MK-801 in mice. MK-801, like phencyclidine (PCP), is a high-affinity, noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. We have postulated that MK-801-elicited popping behavior in mice represents an animal model of schizophrenia, because popping behavior is markedly inhibited/antagonized by both typical and atypical antipsychotic drugs. In the present study, popping behavior induced by MK-801 was measured using an automated detection system that quantifies vertical displacements on the testing platform. 7-Nitroindazole (100 mg/kg) and methylene blue (32 and 100 mg/kg) significantly reduced the number and force of MK-801-elicited popping behavior. Mouse rotorod performance did not differ between animals receiving 7-nitroindazole, methylene blue, or their respective vehicles, suggesting that attenuation of MK-801-elicited popping behavior was not due to either sedation or ataxia caused by 7-nitroindazole or methylene blue. Our findings suggest that nitric oxide may, in part, mediate behaviors induced by NMDA receptor antagonists, like MK-801, and that inhibitors of NOS may have antipsychotic actions.
Animals↗
The competitive NMDA antagonist CPP blocks MK-801-elicited popping behavior in mice.
In the current investigation, the ability of CPP (3-(2-carboxypiperazine-4-yl) propyl-1-phosphate) to elicit mouse popping behavior in a manner similar to that of MK-801 was studied. Unlike MK-801, CPP (3.2-32 mg/kg) did not elicit any popping. The data show that a reduction in NMDA-mediated neural transmission alone is not sufficient to elicit popping behavior in mice. Moreover, pretreatment of mice with CPP attenuated MK-801's ability to elicit popping. These results suggest that popping requires the channel to be in the "active", or open, configuration and that it depends on MK-801's access and binding to its unique site in the hydrophobic channel domain.
Animals↗