MAP2-mediated in vitro interactions of brain microtubules and their modulation by cAMP.

Microtubule-associated proteins (MAPs) are involved in microtubule (MT) bundling and in crossbridges between MTs and other organelles. Previous studies have assigned the MT bundling function of MAPs to their MT-binding domain and its modulation by the projection domain. In the present work, we analyse the viscoelastic properties of MT suspensions in the presence or the absence of cAMP. The experimental data reveal the occurrence of interactions between MT polymers involving MAP2 and modulated by cAMP. Two distinct mechanisms of action of cAMP are identified, which involve on one hand the phosphorylation of MT proteins by the cAMP-dependent protein kinase A (PKA) bound to the end of the N-terminal projection of MAP2, and on the other hand the binding of cAMP to the RII subunit of the PKA affecting interactions between MTs in a phosphorylation-independent manner. These findings imply a role for the complex of PKA with the projection domain of MAP2 in MT-MT interactions and suggest that cAMP may influence directly the density and bundling of MT arrays in dendrites of neurons.

Acute effect of some psychotropic drugs on low-frequency amygdaloid kindled seizures.

We assessed the acute effects of some psychotropic drugs on amygdaloid-kindled seizures produced by low-frequency stimulation. We used the number of stimulating pulses required for the induction of epileptic afterdischarge (pulse-number threshold, PNT) as an indicator for the seizure-generating threshold, and the duration of the epileptic afterdischarge (AD duration, ADD) as an indicator for the duration of the induced seizures. Methamphetamine and atropine elevated the PNT and reduced the ADD. Haloperidol reduced the PNT at all tested doses and reduced the ADD at high dosage. Imipramine elevated the PNT at low doses and reduced the PNT at high dosage. Imipramine also reduced the ADD. Reserpine at high dose elevated the PNT without affecting the ADD.

Comparative study of dopamine metabolism with local cerebral glucose utilization in rat brain following the administration of haloperidol decanoate.

The effects of haloperidol decanoate on dopamine (DA) metabolism in discrete regions of rat brain were investigated and compared with changes in local cerebral glucose utilization (LCGU). The concentration of DA and its metabolite, homovanillic acid, and the alpha-methyl-p-tyrosine (alpha-MT)-induced decline of DA were measured in 6 brain regions by a high-performance liquid chromatographic assay. LCGU in 26 brain regions were examined by [14C]2-deoxy-D-glucose autoradiography. At 24-hr after intramuscular injection of haloperidol decanoate (60 mg eq/kg to haloperidol), the concentration of homovanillic acid in the prefrontal cortex, caudate-putamen, accumbens nucleus, lateral amygdala, and medial thalamus showed significant increase compared with control values. On day 21, the increase in these regions was significantly attenuated with no significant difference from the controls. Furthermore, chronic haloperidol rats showed alpha-MT-induced decline of DA to a similar extent in the control rats. LCGU on day 21 showed significant decrease in the parietal cortex, and a tendency toward decrease in the prefrontal cortex, lateral amygdala and medial thalamus compared with the controls. There was no significant change in LCGU in the caudate-putamen or accumbens nucleus. Chronic haloperidol would thus appear to affect energy metabolism mainly in the cortico-thalamo-limbic circuits, and this may not correspond well to presynaptic DA metabolism.

Plasma homovanillic acid in the prodromal phase of schizophrenia.

BACKGROUND: Plasma levels of homovanillic acid (pHVA) have been used as a peripheral measure of central dopaminergic activity. Despite a large body of studies investigating pHVA in schizophrenia, little is known about pHVA in patients in the prodromal phase of the illness. METHODS: Plasma HVA levels of 12 male outpatients meeting DSM-III-R criteria for the prodromal phase of schizophrenia at the time of blood sampling (who later developed psychotic symptoms) were compared with those of 12 normal male healthy volunteers. Task amounts in the Kraepelin arithmetic test at the time of blood sampling were compared between the prodromal patients and normal controls and were correlated with pHVA levels. RESULTS: The prodromal patients had significantly higher pHVA levels compared with normal control subjects. The mean amount of the arithmetic task for the prodromal patients was significantly less than that for controls. In the patient group, a significant negative correlation was observed between pHVA levels and the task amounts. CONCLUSIONS: Data from the present study indicate the presence of dopaminergic dysfunction in the prodromal stage of schizophrenia that is associated with neuropsychological impairment. Increased pHVA levels in the prodromal patients may have implications for early detection of schizophrenia.

The effect of tandospirone, a serotonin(1A) agonist, on memory function in schizophrenia.

BACKGROUND: The purpose of this study was to test the hypothesis that the addition of tandospirone, a 5-HT(1A) partial agonist, to ongoing treatment with typical antipsychotic drugs, would improve memory function in patients with schizophrenia. METHODS: Eleven outpatients (male/female = 7/4) with schizophrenia who had been on stable doses of haloperidol and biperiden were given tandospirone, 30 mg/day, for 4 weeks. The Wechsler Memory Scale-Revised (WMS-R) was administered at baseline and 4 weeks after the addition of tandospirone. The Brief Psychiatric Rating Scale (BPRS; Total, Positive, and Negative subscale scores) and the Simpson-Angus Scale for Extrapyramidal Symptoms (SAS) were also completed on the two occasions. To exclude the possibility of a practice effect on the WMS-R test, 11 age-matched patients with schizophrenia (M/F = 7/4) were tested at baseline and after a 4-week interval. RESULTS: Repeated measures analysis of variance revealed a significant time by group (patients with or without tandospirone) effect for the Verbal-, but not the Visual Memory composite scores of the WMS-R test; no significant change was observed in patients without tandospirone, whereas improvement in the Verbal Memory score was noted in patients receiving tandospirone. Moreover, there was improvement in the Inclusion score, an index of memory organization as measured by the Logical Memory subtest of WMS-R, only in patients with tandospirone. Scores on the BPRS and SAS were improved during treatment with tandospirone, but the effects did not reach statistical significance. CONCLUSIONS: The results suggest that adjunctive treatment with 5-HT(1A) agonists may improve some types of memory function in schizophrenia.

Magnetic resonance imaging study of the cavum septi pellucidi in patients with schizophrenia.

OBJECTIVE: High-resolution magnetic resonance imaging was used to evaluate the prevalence of the cavum septi pellucidi (CSP) in 79 normal subjects and 86 patients with schizophrenia. METHOD: The CSP was assessed by counting the number of consecutive coronal 1-mm slices containing the CSP. A CSP equal to or greater than 6 mm in length was defined as large. RESULTS: The CSP was found in 74.4% of the patients and 74.7% of the normal subjects, a nonsignificant difference. No difference between groups was found in the prevalence of a large CSP. CONCLUSIONS: The findings support the idea that a small CSP is a normal anatomical variant. More cases of a large CSP are needed to elucidate the implications of this abnormality in schizophrenia.

Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment.

OBJECTIVE: The goal of this study was to evaluate the effects of the addition of tandospirone, a serotonin-1A (5-HT(1A)) agonist, to ongoing treatment with typical antipsychotic drugs, on two cognitive domains that are relevant to functional outcome in patients with schizophrenia. METHOD: Twenty-six patients with schizophrenia who were receiving stable doses of typical antipsychotics were randomly assigned to adjunctive treatment with 30 mg/day of tandospirone or placebo for 6 weeks. Executive function and verbal memory as well as psychopathology were assessed at baseline and after 6 weeks. RESULTS: Both cognitive measures improved significantly in the patients who received tandospirone; subjects who did not receive tandospirone showed no change. There was no significant change in psychopathology ratings in either group. CONCLUSIONS: The results suggest the usefulness of 5-HT(1A) agonists for enhancing some types of cognitive performance and possibly social and work function in patients with schizophrenia.

Effect of mental stress on plasma homovanillic acid in healthy human subjects.

Plasma levels of homovanillic acid (pHVA) have been suggested to provide a measure of dopaminergic activity in the central nervous system. The present study investigated the effect of mental stress by the Kraepelin test, a test of continuous arithmetic addition of single-digit figures for 30 min, on pHVA levels in 13 male psychiatrically normal healthy volunteers. Following an overnight fast and restricted physical activity, plasma samples were collected immediately before and after the administration of the Kraepelin test. Plasma HVA levels following the administration of the Kraepelin test were significantly lower than the pretest pHVA levels. The percent change in pHVA levels by the Kraepelin test positively correlated with pretest pHVA levels. The observed reduction in pHVA levels by mental stress in normal subjects may reflect some aspects of a dopamine-dependent restitutive system in the brain.

Differential effects of mental stress on plasma homovanillic acid in schizophrenia and normal controls.

We previously reported that mental stress by Kraepelin's arithmetic test decreases plasma homovanillic acid (pHVA) levels in psychiatrically normal healthy human subjects. The present study was undertaken to determine whether this pattern of changes in pHVA concentrations resulting from mental stress is altered in patients with schizophrenia. Fourteen male patients with schizophrenia including those under ongoing neuroleptic treatment and 14 normal male volunteers participated in the study. Following overnight fast and restricted physical activity, the subjects performed Kraepelin's arithmetic test for 30 minutes. Plasma samples were collected immediately before and after the test for measurement of pHVA levels. A significant diagnosis by Kraepelin's test effect was observed due to a decrease in pHVA levels by the Kraepelin test in control subjects but not in patients with schizophrenia. Changes in pHVA levels during the Kraepelin test positively correlated with pre-test pHVA levels in control subjects, while this correlation was not observed in patients with schizophrenia. These results may be further support for the presence of a dopamine-dependent restitutive system in the brain. The absence of response of pHVA levels to mental stress in patients with schizophrenia may indicate that the dopamine restitutive system in these patients is disrupted or already down-regulated, as previously predicted.

The action of taurine on the response to glutamate in the motoneuron of the isolated frog spinal cord.

Using the sucrose gap method, the effect of taurine on the response to glutamate in the ventral root of the isolated frog spinal cord was investigated. The depolarization induced by glutamate was reduced by taurine and the inhibitory action of taurine was antagonized by strychnine, but not by picrotoxin or bicuculline. This action of taurine was also unaffected by tetraethylammonium, 4-aminopyridine and Ringer deficient in sodium ions, but was affected by chloride-free Ringer. Potassium-free Ringer abolished the effect of taurine on the amplitude of the response to glutamate, but not on the rising phase of the depolarization induced by glutamate. Taurine also abolished the after-hyperpolarization induced by glutamate and this was reduced by ouabain or lithium ions. These findings suggest that taurine acts on a glycine receptor to inhibit the response to glutamate, that the action of taurine partly depends on chloride ions, and that taurine inhibits the sodium pump.

Comparison of the effect of zopiclone and brotizolam on sleep EEG by quantitative evaluation in healthy young women.

We studied the effect of brotizolam (BRO) (0.25 mg) and zopiclone (ZPC) (7.5 mg) on the sleep electroencephalograms (EEG) of seven healthy young women (ages 20-21 years). In addition to conventional sleep scoring, we performed spectral analysis of EEG wave forms using the Fast Fourier Transformation (FFT) method. Four weeks following two consecutive polysomnographic recordings with placebo administration (for baseline data), polysomnography with BRO or ZPC administration was performed on the subjects who were then crossed over to polysomnography with ZPC or BRO, respectively, 1 week later. Total rapid eye movement (REM) time was decreased on the ZPC and BRO nights and REM latency was prolonged on the ZPC night compared with baseline (BL) night. Other parameters, however, were not significantly different between the drug nights and the BL night. There were also no differences in standard scoring results between both drug nights. FFT analysis revealed significant differences in total power density percentage and mean power density percentage in both nonrapid eye movement (NREM) and REM sleep between ZPC and BRO nights and between both drug nights compared to the BL night. Total power density and mean power density per epoch showed significant decreases in the theta band (6.0-8.0 Hz) and sigma band (12.0-14.0 Hz) on the ZPC night versus the BRO night or BL night during specific NREM periods. The results of this study corroborate previous reports that suggest computer-aided quantitative electroencephalography aids in differentiating specific effects of hypnotics and other central-nervous-system-acting agents on the sleep EEG.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of chronic haloperidol treatment on amygdaloid seizure generation in cats.

We evaluated the effect of chronic haloperidol treatment (0.5-2 mg/kg/day, 21 day) on amygdala-generating seizures using a kindling procedure induced by low frequency electrical stimulations. The number of stimulating pulses required for triggering of epileptic afterdischarge (pulse-number threshold; PNT) is the indicator of the seizure generating threshold. A PNT decrease occurred, followed by a PNT increase toward the pre-treatment level during high-dose, chronic haloperidol treatment. A PNT increase occurred, followed by a PNT decrease toward the pre-treatment level during the withdrawal period after the high-dose treatment. A decrease of the triggered seizure duration occurred during the high-dose treatment. These results indicate that a transient decrease of seizure generating threshold occurs during chronic haloperidol treatment, and withdrawal of the drug is followed by what appears to be a rebound phenomenon. We suggest that this effect might be related to the antipsychotic potency and associated neurochemical changes known to be caused by chronic haloperidol treatment.

Effects of chronic lithium treatment on limbic seizure generation in the cat.

The effect of chronic lithium administration (2.2-8.7 mEq/kg/day, 17 days) to the cat on seizure initiation in the amygdala and hippocampus was assessed by the low-frequency kindling technique. Lithium 4.3 mEq/kg/day PO, producing a serum lithium level between 1.2 and 1.6 mEq/l, caused an elevation of the amygdala seizure threshold on treatment days 5-9. In contrast, the same dosage caused a transient reduction of the hippocampus seizure threshold on treatment days 13-17 and on withdrawal days 21-25. Lithium 2.2 mEq/kg/day PO caused no significant effect on the parameters of the two types of seizure. Lithium 8.7 mEq/kg/day PO caused severe behavioral changes and did not permit chronic treatment. These results indicate that the effect of chronic lithium treatment on limbic seizures is dependent on the location of epileptic focus.

Distribution of clomipramine in various brain regions of rats under steady-state serum concentrations.

The clomipramine (CMP) distribution in 12 regions of rat brain was investigated 2 and 7 days after subcutaneous minipump implantation. The results of serial blood samplings during 7 days indicated that steady-state CMP serum levels were achieved from experimental day 2. The regional CMP distributions in the brains were uneven on both the 2nd and 7th experimental days. On both test days the CMP concentrations were higher in the cerebral cortex and hippocampus than those in the other regions, and those in the cerebellum and bulbus olfactorius and septum were lower. When the serial fluctuations of the CMP levels were examined in 12 brain regions, there were significant differences between days 2 and 7 in the following four regions: the anterior basal ganglia, hypothalamus, bulbus olfactorius + septum and amygdala.

Neural correlates of memory organization deficits in schizophrenia. A single photon emission computed tomography study with 99mTc-ethyl-cysteinate dimer during a verbal learning task.

Regional cerebral blood flow (rCBF) during a verbal learning task was measured using 99mTc-ethyl-cysteinate dimer and single photon emission computed tomography in 10 patients with schizophrenia and nine normal controls. Verbal repetition was used as a control task. The schizophrenic patients showed failure to spontaneously utilize implicit category information to learn the word lists. In the normal controls, rCBF in the left inferior frontal and left anterior cingulate regions was significantly increased during the verbal learning task, compared with the verbal repetition task. In contrast, there was no significant frontal lobe activation by the verbal learning in the schizophrenic patients. The patients had lower rCBF during the verbal learning task than the controls in the bilateral inferior frontal, left anterior cingulate, right superior frontal, and bilateral middle frontal regions. Activation in the left inferior frontal region was significantly positively correlated with categorical clustering in the task in the controls, but no such correlation was found in the patients. These results indicate that memory organization deficits in schizophrenia may be related to dysfunction in the prefrontal areas, especially in the left inferior frontal region.

Scanning eye movements in schizophrenic patients. Relationship to clinical symptoms and regional cerebral blood flow using 123I-IMP SPECT.

Eye movements during the Benton Visual Retention Test were examined using an eye-mark recorder in 32 schizophrenic patients and 32 normal controls. The patients had significantly fewer eye fixations, longer mean duration of fixation and shorter length of mean scan path than the controls. In the patients, these eye movement parameters were significantly correlated with the negative symptom score but not with the positive symptom score on the Positive and Negative Syndrome Scale. These parameters had a significant correlation with the composite score on the Scale for the Assessment of Negative Symptoms (SANS). In particular, they were highly correlated with avolition-apathy and affective flattening or blunting scores on SANS subscales. Thus, examination of scanning eye movements seemed to be a good objective index of negative symptoms. Secondly, regional cerebral blood flow (rCBF) was examined using N-isopropyl-p-[123I]iodoamphetamine (123I-IMP) and single photon emission computer tomography in 17 of 32 patients. With regard to the relationship between the eye movement parameters and rCBF, the mean duration of fixation was negatively correlated with 123I-IMP uptake in the left superior frontal area and left basal ganglia. The mean length of the scan path was correlated with uptake in the left superior frontal area. These findings suggest that the characteristic eye movements of schizophrenic patients are likely to be related with dysfunction of the frontal-basal ganglia neural circuit.

Limited visual search on the WAIS Picture Completion test in patients with schizophrenia.

The Wechsler Adult Intelligence Scale was examined in 39 patients with schizophrenia, the visual cognitive task of Picture Completion showing the most impairment. In order to clarify the role of eye movements in Picture Completion, searching eye movements in 12 schizophrenic patients and 12 normal controls were recorded using an infrared eye-mark recorder. Schizophrenic patients as a group showed fewer eye fixations, and shorter total length of scan path than normal controls during the last 10 s of exposure to the picture. However, the patients who responded correctly, did so with a similar number of fixations and similar length of total scan path to those of normal controls. The patients who failed in the task took a significantly longer time for the first survey of the picture than the successful patients and normal controls. The less efficient strategy of visual search seen in the patients who failed might be a manifestation of poor reality testing and be related to frontal lobe dysfunction.

Two types of neuroplasticities in the kindling phenomenon.

We stimulated the dorsal hippocampus of the rat with 2 Hz electrical stimulation to induce kindling seizures. As we reported previously using cats, pulse-number threshold (PNT), the number of stimulating-pulses required for the triggering of epileptic afterdischarge, decreased profoundly in the initial stage of the kindling process and the behavioral seizure stage (BSS) developed in the later stage. After the completion of kindling, a 4 week interval elevated PNT significantly compared to the value at the completion of kindling, whereas BSS showed no regression. These results suggest that there are two types of neuroplasticities which are independent of each other in the kindling phenomenon, one is the early-short type which is involved in the susceptibility of epileptic focus in hippocampus and the other is the late-long type which is involved in the full propagation of kindled seizures to the extra-limbic area.

An evidence of 'post-seizure excitation' in feline-kindled seizures.

We assessed the post-seizure effects on the seizure threshold and the seizure duration using low-frequency kindling technique. The number of stimulating pulses required for a triggering of epileptic afterdischarge (pulse-number threshold; PNT) was used for the indicator of seizure threshold. PNT increased significantly at 2 and 4 h inter-stimulation intervals, whereas it decreased significantly with an increase of seizure duration at 16 and 24 h intervals. It appears from these data that a post-seizure excitation occurs after a post-seizure inhibition.

A biphasic change of afterdischarge threshold during the kindling process.

Cats were stimulated in the ventral hippocampus with low-frequency (about 3 Hz) square wave pulses. All subjects were kindled until generalized convulsion occurred. During the kindling process, the number of stimulating pulses required for the provocation of afterdischarge (AD), which was used as an indicator of AD threshold, decreased suddenly in the initial stage and increased gradually in the late stage. We consider this phenomenon to be important in deepening the understanding of seizure generation.