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1.
Clin Neuropharmacol ; 24(5): 290-4, 2001.
Article in English | MEDLINE | ID: mdl-11586114

ABSTRACT

Topiramate was shown to attenuate the severity of negative symptoms (e.g., emotional withdrawal) in a patient with schizophrenia when added to his stable regimen of antipsychotic medication. Topiramate was administered for a period of 12 weeks; during the first 4 weeks, dosage was adjusted to the maximal tolerated dose ( i.e., 175 mg/d), and, thereafter, this dosage was maintained for 8 weeks. Topiramate was studied because of recent data and hypotheses suggesting that N-methyl-D-aspartate receptor hypofunction, dampened GABAergic inhibition, and excessive stimulation of the kainic acid (KA)/alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) class of glutamate receptors occur in at least some patients with schizophrenia, especially those with persistent negative symptoms and progressive psychosocial deterioration. Topiramate is a recently approved and marketed medication for the treatment of seizure disorders, whose mechanism of action includes potentiation of GABAergic neurotransmission and antagonism of KA/AMPA glutamate receptors. This case is presented because of the dramatic response of negative symptoms to the addition of topiramate. The severity of negative symptoms was assessed formally with the Negative Scale of the Positive and Negative Syndrome Scale. The negative symptoms of schizophrenia are usually resistant to most behavioral and pharmacologic interventions.


Subject(s)
Anticonvulsants/therapeutic use , Antipsychotic Agents/therapeutic use , Fructose/analogs & derivatives , Fructose/therapeutic use , Schizophrenia/drug therapy , Schizophrenic Psychology , Drug Therapy, Combination , Humans , Male , Middle Aged , Topiramate
2.
Clin Neuropharmacol ; 24(1): 43-9, 2001.
Article in English | MEDLINE | ID: mdl-11290881

ABSTRACT

A revision of an "excitotoxic hypothesis" of schizophrenia is summarized. The hypothesis suggests that in, at least, a subtype of patients with schizophrenia, progressive excitotoxic neuronal cell death in hippocampal and cortical areas occurs via "disinhibition" of glutamatergic projections to these areas. Patients who have excitotoxic damage would be expected to have poor outcomes characterized, perhaps, by anatomic evidence of progressive neurodegeneration, pronounced negative symptoms and cognitive deficits, and profound psychosocial deterioration. Disinhibited glutamatergic activity could result from inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission and a consequent failure to stimulate inhibitory gamma-aminobutyric acid (GABA)-ergic interneurons, and/or anatomic degeneration of inhibitory GABAergic interneurons. The result of these hypothesized mechanisms is excessive stimulation of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate class of glutamate receptor complexes. In turn, this excessive stimulation of AMPA/kainate receptors could lead to disruption of ionic gradients, depletion of energy reserves expended in an attempt to restore and maintain the ionic disequilibrium across neuronal membranes, generation of reactive oxygen species, and cell death from apoptotic and other mechanisms. The postulated existence of disinhibited glutamatergic neurotransmission and the subsequent cascade of excitotoxic events resulting from NMDA receptor hypofunction (NRH), anatomic degeneration of inhibitory GABAergic interneurons, or a combination of the two has suggested a diverse variety of experimental therapeutic interventions for schizophrenia. These interventions include facilitation of NMDA receptor-mediated neurotransmission, potentiation of GABAergic neurotransmission, antagonism of AMPA/kainate receptors, and "quenching" of locally generated reactive oxygen species. In fact, several of these approaches have already been pursued or are proposed as part of a systematic clinical investigation of the revised excitotoxic hypothesis of schizophrenia.


Subject(s)
Neurotoxins/metabolism , Schizophrenia/drug therapy , Schizophrenia/metabolism , Animals , Dopamine/metabolism , Glutamic Acid/metabolism , Humans , Receptors, Glutamate/metabolism , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism , gamma-Aminobutyric Acid/metabolism
3.
Clin Neuropharmacol ; 23(4): 222-5, 2000.
Article in English | MEDLINE | ID: mdl-11020129

ABSTRACT

Compared to conventional antipsychotic medications, atypical antipsychotic medications demonstrate greater central serotonin (5HT2) receptor antagonism than dopamine type 2 (D2) receptor antagonism. Nefazodone, an antidepressant medication, exhibits 5HT2 receptor antagonism; we therefore wondered if its addition to stable regimens of antipsychotic medication would increase antipsychotic efficacy, independently of a primary effect on mood, through the mechanism of augmented 5HT2 receptor antagonism. In a pilot investigation, we administered nefazodone (400 mg/d) for 6 weeks as an open-label adjunct to antipsychotic medication in 10 patients with chronic schizophrenia. The patients were moderately depressed at baseline but did not meet criteria for major depressive episode. The Brief Psychiatric Rating Scale (BPRS) and Montgomery-Asberg Depression Rating Scale scores showed statistically significant and clinically robust improvements with nefazodone treatment, which were maintained at follow-up evaluation 2 weeks after the end of nefazodone treatment. There were no adverse events. These results suggest that nefazodone may be a safe and effective adjunct to antipsychotic medications in schizophrenia and that augmentation of 5HT2 antagonism may prove to be a viable strategy for "boosting" antipsychotic efficacy and for treating depressive symptoms in schizophrenia.


Subject(s)
Antidepressive Agents, Second-Generation/therapeutic use , Schizophrenia/drug therapy , Triazoles/therapeutic use , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Piperazines , Psychiatric Status Rating Scales , Psychotic Disorders/drug therapy , Psychotic Disorders/psychology , Schizophrenic Psychology
4.
Pharmacol Biochem Behav ; 62(2): 395-8, 1999 Feb.
Article in English | MEDLINE | ID: mdl-9972709

ABSTRACT

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.


Subject(s)
Cycloserine/pharmacology , Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Motor Activity/drug effects , Stress, Physiological/physiopathology , Animals , Antimetabolites/pharmacology , Mice , Phencyclidine/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism
5.
J Neuropsychiatry Clin Neurosci ; 11(1): 103-6, 1999.
Article in English | MEDLINE | ID: mdl-9990565

ABSTRACT

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.


Subject(s)
Eye Movements/physiology , Facial Expression , Schizophrenia/physiopathology , Adult , Analysis of Variance , Behavioral Symptoms/physiopathology , Case-Control Studies , Face , Humans , Middle Aged , Pattern Recognition, Visual/physiology , Schizophrenic Psychology , Social Behavior , Social Perception
6.
Psychopharmacology (Berl) ; 140(2): 202-5, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9860111

ABSTRACT

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.


Subject(s)
Dizocilpine Maleate/pharmacology , Mecamylamine/pharmacology , Nicotine/pharmacology , Schizophrenia/drug therapy , Animals , Dizocilpine Maleate/antagonists & inhibitors , Dose-Response Relationship, Drug , Male , Mice , Motor Activity/drug effects
7.
Clin Neuropharmacol ; 21(6): 320-32, 1998.
Article in English | MEDLINE | ID: mdl-9844787

ABSTRACT

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.


Subject(s)
Brain/drug effects , Excitatory Amino Acid Antagonists/adverse effects , Phencyclidine/adverse effects , Animals , Brain/embryology , Female , Hippocampus/drug effects , Hippocampus/embryology , Humans , Neurons/drug effects , Pregnancy , Prenatal Exposure Delayed Effects , Rats
8.
Clin Neuropharmacol ; 21(5): 312-5, 1998.
Article in English | MEDLINE | ID: mdl-9789712

ABSTRACT

The relationship between pupil size and subjective symptoms of opiate withdrawal during gradual opiate agonist detoxification has not yet been studied. In the current study, the authors sought to determine the relationship between pupil size and intensity of opiate withdrawal symptoms. To accomplish this, they examined 19 subjects meeting DSM-IV criteria for opiate dependence (304.00) on agonist therapy. All subjects were undergoing opiate detoxification with either methadone or the longer-acting 1-alpha acetylmethadol (LAMM). During two separate visits, subjects' pupil sizes were assessed in the dark using a pupillometer. At each visit, subjects completed two standardized assessment tools (the Subjective Opiate Withdrawal Scale [SOWS] and the Weak Opiate Withdrawal Scale [WOWS]) for measuring subjective symptoms of opiate withdrawal. It was found that changes in pupil size significantly correlated with WOWS, but not with SOWS, scores. Larger pupil sizes were associated with less withdrawal distress. The sensitivity of the pupillometric test to detect increases in opiate craving during opiate agonist medication reduction was 92%, with a specificity of 57%. The predictive value of a positive test was 79%, whereas the predictive value of a negative test was 80%. Pupillometry may provide an objective measure of the intensity of opiate withdrawal in subjects during gradual methadone detoxification.


Subject(s)
Narcotics/adverse effects , Opioid-Related Disorders/physiopathology , Opium/adverse effects , Pupil/physiology , Reflex, Pupillary/physiology , Substance Withdrawal Syndrome/diagnosis , Adult , Analgesics, Opioid/therapeutic use , Humans , Image Processing, Computer-Assisted , Male , Methadone/therapeutic use , Methadyl Acetate/therapeutic use , Middle Aged , Opioid-Related Disorders/psychology , Opioid-Related Disorders/rehabilitation , Personality Inventory/statistics & numerical data , Pupil/drug effects , Reflex, Pupillary/drug effects , Substance Withdrawal Syndrome/physiopathology , Substance Withdrawal Syndrome/psychology
9.
Article in English | MEDLINE | ID: mdl-9789881

ABSTRACT

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.


Subject(s)
Face , Schizophrenia/classification , Visual Perception , Adult , Eye Movements , Female , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Schizophrenia/pathology , Sensitivity and Specificity , Severity of Illness Index
10.
Clin Neuropharmacol ; 21(4): 255-7, 1998.
Article in English | MEDLINE | ID: mdl-9704168

ABSTRACT

The ability of MK-801 to antagonize the electrical precipitation of tonic hindlimb extension was studied in four inbred mouse strains (BALB/c, C57BL/6, AKR, and DBA/2) and the outbred NIH Swiss strain, using an incremental electroconvulsive shock (IECS) procedure. Strains differed in the threshold voltages required for the electrical precipitation of tonic hindlimb extension. They also differed in their sensitivity to antagonism of electrically precipitated tonic hindlimb extension by MK-801. The BALB/c, C57BL, and DBA strains required a significant elevation of the threshold voltage for the elicitation of tonic hindlimb extension in response to 0.18 mg/kg of MK-801, the lowest dose tested; whereas the AKR and NIH Swiss strains did not respond to this dose with an increase of threshold voltage for the elicitation of tonic hindlimb extension. Moreover, a higher percentage of BALB/c mice were maximally protected against seizure elicitation by MK-801 over a dosage range of 0.18 to 0.56 mg/kg, compared to the other strains. The demonstration of strain differences suggests that genetic factors influence the anticonvulsant properties of MK-801.


Subject(s)
Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Neuroprotective Agents/pharmacology , Analysis of Variance , Animals , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred Strains , Predictive Value of Tests , Receptors, N-Methyl-D-Aspartate/physiology , Sensitivity and Specificity , Species Specificity
11.
Clin Neuropharmacol ; 21(2): 71-9, 1998.
Article in English | MEDLINE | ID: mdl-9579291

ABSTRACT

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.


Subject(s)
Glycine/blood , Metabolic Diseases/drug therapy , N-Methylaspartate/antagonists & inhibitors , Tryptophan/administration & dosage , Electroencephalography , Excitatory Amino Acid Agonists/therapeutic use , Excitatory Amino Acid Antagonists/therapeutic use , Humans , Hyperglycemic Hyperosmolar Nonketotic Coma/drug therapy , Ketamine/therapeutic use , Metabolic Diseases/blood , N-Methylaspartate/therapeutic use , Tryptophan/therapeutic use
12.
Pharmacol Biochem Behav ; 58(3): 709-12, 1997 Nov.
Article in English | MEDLINE | ID: mdl-9329063

ABSTRACT

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.


Subject(s)
Anticonvulsants/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Stress, Psychological/physiopathology , Animals , Cold Temperature , Dizocilpine Maleate/pharmacology , Dose-Response Relationship, Drug , Ketamine/pharmacology , Male , Memantine/pharmacology , Mice , Phencyclidine/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors
13.
Clin Neuropharmacol ; 20(5): 375-84, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9331513

ABSTRACT

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.


Subject(s)
Behavior, Animal/physiology , N-Methylaspartate/physiology , Synaptic Transmission/physiology , Animals , Glutamic Acid/physiology , Humans , Mice , Mice, Inbred Strains , Receptors, N-Methyl-D-Aspartate/physiology
14.
Clin Neuropharmacol ; 20(4): 357-63, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9260734

ABSTRACT

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.


Subject(s)
Enzyme Inhibitors/therapeutic use , Methylene Blue/therapeutic use , Nitric Oxide/antagonists & inhibitors , Schizophrenia/drug therapy , Adult , Guanylate Cyclase/antagonists & inhibitors , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Schizophrenic Psychology
15.
Clin Neuropharmacol ; 20(4): 364-70, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9260735

ABSTRACT

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.


Subject(s)
Calcium Channel Blockers/therapeutic use , Cognition/drug effects , Dyskinesia, Drug-Induced/drug therapy , Nifedipine/therapeutic use , Schizophrenia/complications , Aged , Cross-Over Studies , Double-Blind Method , Dyskinesia, Drug-Induced/complications , Female , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Psychomotor Performance/drug effects , Schizophrenic Psychology
16.
Clin Neuropharmacol ; 20(3): 270-5, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9197951

ABSTRACT

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.


Subject(s)
Appetite Depressants/adverse effects , Bipolar Disorder/chemically induced , Cocaine , Diethylpropion/adverse effects , Pupil Disorders/physiopathology , Substance-Related Disorders/drug therapy , Adult , Appetite Depressants/therapeutic use , Diethylpropion/therapeutic use , Humans , Male
17.
Pharmacol Biochem Behav ; 57(1-2): 315-7, 1997.
Article in English | MEDLINE | ID: mdl-9164588

ABSTRACT

We examined possible genetic contributions to MK-801-elicited "popping" behavior in mice. MK-801-elicited "popping" behavior may represent a preclinical screening paradigm for identifying novel antipsychotic medications. Specifically, we studied the sensitivity of four inbred strains of mice (BALB/c, C57BL/6, AKR, and DBA/2) to MK-801-elicited "popping" behavior and compared their response to the outbred NIH Swiss strain in which the behavior was first characterized. The BALB/c strain was most sensitive to the elicitation of MK-801 induced popping behavior, whereas the other inbred strains were less sensitive than the outbred strain. The identification of strain differences in MK-801-elicited "popping" behavior suggests an important role for genetic factors in the elicitation of MK-801 "popping" behavior in mice.


Subject(s)
Chromosome Mapping , Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Motor Activity/drug effects , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Analysis of Variance , Animals , Drug Resistance/genetics , Male , Mice , Mice, Inbred Strains , Species Specificity
18.
Article in English | MEDLINE | ID: mdl-9144110

ABSTRACT

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).


Subject(s)
Alcoholism/diagnosis , Atrophy/pathology , Frontal Lobe/pathology , Parietal Lobe/pathology , Adolescent , Adult , Chronic Disease , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Severity of Illness Index
19.
Article in English | MEDLINE | ID: mdl-9017534

ABSTRACT

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.


Subject(s)
Attention/physiology , Cocaine , Eye Movements/physiology , Opioid-Related Disorders/psychology , Visual Perception/physiology , Adult , Crack Cocaine , Cues , Fixation, Ocular/physiology , Humans , Male , Psychiatric Status Rating Scales , Saccades/physiology
20.
Pharmacol Biochem Behav ; 55(3): 323-6, 1996 Nov.
Article in English | MEDLINE | ID: mdl-8951972

ABSTRACT

The development of neuroactive steroids as anticonvulsant medications may be useful both as a primary treatment and as an adjuvant to other anticonvulsants. They may be limited, however, by sedative and ataxic side effects. In the current study, 3 alpha-hydroxy-5 beta-pregnan-20-one and alfaxalone, two prototypic neuroactive steroids, were shown to potentiate the ability of flurazepam to antagonize electrically precipitated tonic hindlimb extension in mice at doses that by themselves had little antiseizure efficacy. While alfaxalone alone lacked motor incoordinating effects at a dose (18.0 mg/kg) that potentiated the antiseizure efficacy of flurazepam, the same dose of 3 alpha-hydroxy-5 beta-pregnan-20-one possessed both the ability to potentiate flurazepam's anticonvulsant effect and disrupt mouse rotorod performance. The data suggest that allosteric interactions that have been described in vitro between neuroactive steroids and other modulators of the GABAA receptor complex may have relevance for the intact animal. Finally, the data also suggest that neuroactive steroids could be developed as short-lived adjuvant antiseizure medications in certain critical situations (e.g., medication-refractory status epilepticus). However, the motor incoordinating effects resulting from the combination of neuroactive steroids and flurazepam suggest that their usefulness as adjuvant medications in the chronic therapy of seizure disorders may be limited.


Subject(s)
Anticonvulsants/pharmacology , Flurazepam/pharmacology , Hypnotics and Sedatives/pharmacology , Pregnanediones/pharmacology , Pregnanolone/pharmacology , Seizures/prevention & control , Animals , Behavior, Animal/drug effects , Drug Interactions , Electric Stimulation , GABA Modulators/pharmacology , Male , Mice , Motor Activity/drug effects , Receptors, GABA-A/physiology
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