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.

Subtype diagnosis in schizophrenia and its relation to neuropsychological and computerized tomography measures.

We compared schizophrenic patients with a subtype diagnosis of paranoia (n = 14) to those with nonparanoid subtype diagnoses (n = 18) on the Wisconsin Card Sorting Test (WCST) and multiple computed tomography (CT) scan measures. The results showed that patients with nonparanoid diagnoses sorted fewer categories and made more perseverative errors on the WCST than did patients with the paranoid diagnosis. However, patients in the nonparanoid group could not be distinguished from those in the paranoid group on CT scan measures of brain structure. Additionally, a significant correlation was found between right frontal sulcal enlargement on CT scans and the number of perseverative errors made on the WCST.

Correlation between antisaccade and Wisconsin Card Sorting Test performance in schizophrenia.

In 27 patients with chronic schizophrenia, there was a significant correlation between performance on an antisaccade eye movement task and on the Wisconsin Card Sorting Test. A significant correlation was not obtained between antisaccade task performance and scores on the modified Mini-Mental State examination or the Schedule for the Assessment of Negative Symptoms in Schizophrenia. In addition, patients' antisaccade task performance was impaired compared with that of 12 normal subjects.

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.

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.

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.

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.

Depot testosterone attenuates the anticonvulsant effect of flurazepam in mice.

We examined whether pretreatment with depot testosterone produces a functional alteration in benzodiazepine receptor sensitivity. This was accomplished by testing the ability of flurazepam to increase the threshold voltage for seizure production in groups of mice given vehicle or testosterone cypionate (1 or 5 mg/kg) 21 days prior to testing in an electroconvulsive shock paradigm. Depot testosterone treatment reduced flurazepam's antiseizure potency in this paradigm. That testosterone altered the ability of flurazepam to protect mice from seizures is consistent with previous reports suggesting a complex interaction between steroids and the BDZ/GABAA system.

Baclofen treatment in a patient with tardive dystonia.

The use of baclofen, a structural analog of gamma-aminobutyric acid (GABA), is described in the treatment of a patient with tardive dystonia. The patient, a woman with a clinical diagnosis of Alzheimer's disease, developed tardive dystonia after 8 weeks of haloperidol therapy and experienced complete remission of her dystonia while taking baclofen 60 mg/day. This case suggests that baclofen may facilitate remission of tardive dystonia in some cases and provides a basis for further investigation.

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.

Profound stress-induced alterations in flurazepam's antiseizure efficacy can be attenuated.

A new procedure is described for assessing the sensitivity of the benzodiazepine receptor in intact animals. This procedure measures the ability of benzodiazepines to antagonize electrically-induced seizures precipitated by incremental increases in voltage. This functional measure detected stress-induced alterations in benzodiazepine receptor sensitivity, an alteration shown previously with in vitro and in vivo receptor binding techniques. In contrast, mouse rotorod performance, which has been proposed as a behavioral measure of benzodiazepine receptor sensitivity did not show stress-induced alterations. The mechanism of these stress-induced alterations was explored using this incremental electroconvulsive shock procedure (IECS). A 'GABA-negative' benzodiazepine mimicked the effects of swim stress, whereas treatment of animals prior to swim stress with Ro15-1788, a 'GABA-neutral' benzodiazepine, attenuated these stress-induced alterations. These data suggest both that these stress effects may be mediated by an endogenous ligand, and that Ro15-1788 may have a novel indication as a prophylactic intervention for individuals at risk for exposure to severe and unusual stress.

Interaction of cholinergic and glutamatergic transmission in the hippocampus: an in vitro autoradiographic receptor analysis.

Quantitative in vitro receptor autoradiography was used to examine the effect of acute scopolamine administration on specific binding to components of the N-methyl-D-aspartate (NMDA) receptor complex in four regions of mouse hippocampus. The binding of [3H]glycine to the strychnine-insensitive site was increased 1 h after administration of scopolamine hydrobromide (10 mg/kg) in the ventral dentate gyrus. The study suggests that rapid alterations in strychnine-insensitive glycine binding can occur in response to cholinergic perturbations. Moreover, these data suggest a delicate interaction between cholinergic and glutamatergic projections in the hippocampus.

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.

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.

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.

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.

Clock drawing in the screening assessment of cognitive impairment in an ambulatory care setting: a preliminary report.

In an exploratory study to assess the utility of clock drawing as a screening test for cognitive impairment in medical/surgical outpatients, clock drawing and the 6-item Orientation-Memory-Concentration Test (OMCT) were administered to over 400 randomly selected ambulatory patients over the age of 55 in a busy inner-city hospital. The clock drawing test was completed by 431 patients, and 471 completed the OMCT. Clock drawing errors suggestive of moderate-to-severe cognitive impairment were found in 42.7% of patients; OMCT errors suggestive of moderate-to-severe cognitive impairment were found in 35.4% of the population tested. The clock drawing test might represent a quick-screen for cognitive impairment in an older general medical/surgical outpatient population, and might help identify patients not otherwise recognized as potentially unable to fully understand treatment recommendations.

Neurodevelopmental consequences of early exposure to phencyclidine and related drugs.

In the early development of the central nervous system, stimulation of N-methyl-D-aspartate (NMDA) receptors may be critical for neuronal cell survival and differentiation, as well as the establishment of neural networks resulting from "experience-dependent plasticity." The trophic influence of NMDA receptor stimulation may be present only during a certain critical period of development. There are, therefore, major concerns associated with the administration of noncompetitive NMDA receptor antagonists (such as MK-801 [dizocilpine]) as neuroprotective and anticonvulsant agents to pregnant women, neonates, infants, and young children. Several studies showing disruptive effects of noncompetitive NMDA receptor antagonists on normal neurobehavioral development are reviewed in this article. This research has important public health implications because phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, is a frequently-abused drug that may disrupt brain development in utero when abused by pregnant women. The article also reviews studies of neonatal blockade of the NMDA receptor complex in animals; studies that may lead to useful models of human neurodevelopmental disorders. These models may even mimic the relevant neurodevelopmental aspects of at least some forms of schizophrenia, especially the early developmental disconnection of circuits between the hippocampus and frontal cortex.

Current status of NMDA antagonist interventions in the treatment of nonketotic hyperglycinemia.

Impairment of the catabolism of glycine caused by "failure" of the glycine cleavage enzyme complex results in an inability to oxidatively decarboxylate this amino acid. As a result of this inability, the alpha carbon of glycine does not enter the one-carbon pool, leading to its reduction or depletion, and toxic accumulation of this amino acid neurotransmitter occurs. Strategies for the treatment of the clinical condition known as nonketotic hyperglycinemia, an autosomal recessive disorder associated with absent or diminished glycine cleavage enzyme activity, include reduction of the glycine burden, replenishment of the one-carbon pool, and antagonism of the neurotransmitter effects of glycine. Until recently, antagonism focused on interference with the glycine-associated chloride ionophore that is enriched in the brain stem and spinal cord, using strychnine as a specific intervention. However, the recent recognition of a "strychnine-insensitive" binding site for glycine on the N-methyl-D-aspartic acid (NMDA) receptor complex, a glutamate-gated cationic channel, has led to some newer approaches. Also, the recognition of milder, atypical variants of classic nonketotic hyperglycinemia has stimulated efforts to evaluate the therapeutic efficacy of these strategies to antagonize the NMDA receptor complex.

Environmental stress-induced functional modification of the central benzodiazepine binding site.

The central benzodiazepine binding site mediates the therapeutically relevant pharmacologic actions of benzodiazepine agonists, including reducing anxiety, sedation, muscle relaxation, and antagonism of seizure production. Benzodiazepines potentiate the ability of gamma-aminobutyric acid (GABA) to promote membrane chloride ion conductance by binding reversibly to a distinct site on the GABAA receptor complex. Although the role of this central benzodiazepine binding site in mediating the pharmacologic actions of benzodiazepine agonists has been shown conclusively, its participation in an animal's response to stress is less certain. Data are reviewed consistent with an environmental stress-induced modification of the structure and function of the central benzodiazepine binding site. Modifications show brain anatomic regional selectivity. The mechanisms of these modifications include rapid enzyme-mediated phosphorylations of the GABAA receptor complex and the selective transcription of individual polypeptide subunits. The potential relevance of the data on environmental stress-induced functional modifications of the central benzodiazepine binding site to the development of newer medications and improved understanding of the pathophysiology of stress-related neuropsychiatric disorders is discussed.