Kiyofumi Kobayashi

Brain Monoamines in Seizure Mechanism (Review)

A majority of experimental studies have strongly suggested that catecholamine and/or 5‐HT play an important role for regulating the seizure susceptibility. As mentioned previously, however, the relative significance of individual monoamine has not yet been fully clarified. Since it is well known that the interaction between cate‐cholaminergic and serotonergic neuronal activity is quite complex, a causal relationship between each monoamine and seizure susceptibility cannot be easily established if results are obtained from the whole brain study on pharmacologic manipulation of experimental seizures. The extensive study, including the monoamine turnover rates and concentrations in specific brain regions, may help to delineate such a correlation in the future. Further, when an object of study is concerned in excitability of the central nervous system, it should be necessary to elucidate the mutual relationship of mono‐amines to the other putative neurotrans‐mitters (e.g., acetylcholine, amino acid).

Developmental changes in the activity and substrate specificities of mouse brain monoamine oxidase

Developmental changes in monoamine oxidase (MAO) activity in the mouse brain were investigated with the substrates β-phenylethylamine (PEA), tryptamine, and 5-hydroxytryptamine (5-HT). In the newborn brain, MAO activity towards PEA was found to be much lower than the adult and to be inhibited by clorgyline in a double-sigmoidal fashion. The inhibition curve shifted to a single-sigmoidal pattern with age. MAO activity towards 5-HT as substrate was inhibited by 90% and in a single-sigmoidal manner by clorgyline throughout the postnatal life. Lineweaver-Burk plots with PEA as substrate presented two linear lines (apparentKm: 28.6 and 4.1 μM) for the newborn and one line (apparentKm: 11.4 μM) for the adult, respectively. The plot with highKm value for the newborn brain disappeared in a clorgyline-treated preparation. These findings suggest that age-dependent alterations in the ratio of MAO-A/MAO-B activity affect the substrate specificity of the enzyme.

Determination of p-hydroxyphenylacetic acid in cerebrospinal fluid by high-performance liquid chromatography with electrochemical detection

Using reversed-phase high-performance liquid chromatography and electrochemical detection with a rapid one-step purification on a Sephadex G-10 column, we have developed a sensitive technique to measure p-hydroxyphenylacetic acid, the oxidatively deaminated metabolite of p-tyramine. The metabolite was measured in cerebrospinal fluid with high recovery and precision. Concentrations of p-hydroxyphenylacetic acid ranged from 4.2 to 17.0 ng/ml with a mean value of 7.8 ng/ml +/- 1.1 SEM in lumbar cerebrospinal fluid of 11 control patients. In a preliminary analysis, the concentrations in schizophrenic patients were significantly lower than those in controls. Since p-hydroxyphenylacetic acid in cerebrospinal fluid seems to be derived from the brain, this finding may indicate a decrease in brain formation. The present method should be useful in clinical investigations to clarify a functional role of p-tyramine in the brain.

Comparative study of sulpiride and haloperidol on dopamine turnover in the rat brain

The effects of the neuroleptics, sulpiride and haloperidol, on dopamine (DA) turnover were compared following the acute and chronic administration of these drugs alone or in combination with levodopa or apomorphine. In the acute treatment, the increase in DA metabolites in the striatum and nucleus accumbens was more marked in the haloperidol-treated rats than in the sulpiridetreated rats. Following the additional administration of levodopa, however, the potency of the neuroleptics in elevating DA metabolites was reversed. A low dose of apomorphine induced a marked reduction in the striatal DA metabolite levels by approximately 50%. When rats were pretreated with the neuroleptics, haloperidol was more effective in preventing an apomorphine-induced reduction in DA metabolites. On repeated administration of the neuroleptics, a tolerance occurred in the striatum and nucleus accumbens, but not in the prefrontal cortex. This differential development of tolerance was observed in the different brain regions and with the different drugs administered. These results suggests that the pharmacological mechanism of sulpiride on DA turnover differs from that of haloperidol.

Effect of temperature on human platelet monoamine oxidase

Effect of temperature on human platelet MAO activity was studied by using three different substrates at a temperature range of 12–44°C. The Arrhenius plot of ln Vmax versus 1T yielded a straight line when tryptamine was used as substrate. On the other hand, a nonlinear relationship was observed with both benzylamine and PEA as substrates. This suggests that there are multiple catalytic sites or multiple forms in human platelet MAO.

p -Hydroxyphenylacetic Acid Concentration in the CSF of Patients with Neurological and Psychiatric Disorders

In recent years substantial evidence suggesting that p-tyramine (p-TA) acts as a neurotransmitter or neuromodulator in the brain has been presented (Boulton, 1978; Boulton and Juorio, 1979; Juorio and Jones, 1981). Although the physiological roles of this amine in the central nervous system (CNS) are as yet unknown, it has been claimed that p-TA may be involved in the etiology of certain mental disorders (Boulton and Juorio, 1979; Boulton, 1980). However, there is little clinical evidence for this proposal. p-Hydroxyphenylacetic aid (p-HPAA), a major metabolite of p-TA in the brain (McQuade et al., 1981), has been detected and quantitated in the cerebrospinal fluid (CSF)(Karoum et al., 1975; 1977), but a comparison of p-HPAA concentrations in the CSF of patients with various CNS disorders has not yet been made. We have recently developed a sensitive high-performance liquid chromatographic (HPLC) method for the determination of p-HPAA in CSF (Kobayashi et al., 1982). In this communication we describe CSF levels of p-HPAA in patients with various neurological and psychiatric disorders with special reference to schizophrenia.

Effects of Antipsychotic Drugs on Regional Cyclic AMP Levels in the Rat Brain

ABSTRACT In the present study the effects of antipsychotic drugs on regional cyclic AMP content of the rat brain in vivo were examined. A single dose of chlorpromazine (CPZ) inhibited L-dopa-induced increase in cyclic AMP levels of all brain regions examined. Sulpiride had virtually no effect on cyclic AMP levels. In long-term treatment with CPZ for 13 days, L-dopa-induced increase in cyclic AMP levels of CPZ-treated rats was not significantly different from controls 24 hours after the last injection. In contrast, 7 days after cessation of CPZ, cyclic AMP levels in the striatum of CPZ-treated rats significantly elevated in response to L-dopa administration compared with vehicle-treated rats. At this time, L-dopa produced a marked increase in stereotyped behaviors of CPZ-treated rats, while locomotor activity was not different between control and CPZ groups. A similar result was obtained with apomorphine in both biochemical and behavioral measurements. These data suggest that dopaminergic receptor hypersensitivity occurs in the nigrostriatal system, but not in the mesolimbic or mesocortical system after chronic CPZ administration. This might be related to regional differences in the development of tolerance to long-term antipsychotic treatment.