Akemi Minegishi

Changes in the serotonin and 5-hydroxyindoleacetic acid contents in rat brain after ethanol and disulfiram treatments

Disulfiram (700 mg/kg, p.o.) significantly increased the brain levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in rats. Ethanol (1 g/kg and 2 x 1.5 g/kg, i.p.) did not affect the 5-HT level, but at the higher dose it significantly increased the 5-HIAA level. When disulfiram was given in combination with ethanol, the brain level of 5-HT was significantly higher and, conversely, the 5-HIAA level was significantly lower, as compared to the results with disulfiram alone. These results suggest that the biogenic aldehyde derived from 5-HT may influence 5-HT metabolism and the elimination of 5-HIAA from the brain.

Effect of disulfiram on turnover of 5-hydroxytryptamine in rat brain.

Abstract Effect of disulfiram on 5-hydroxytryptamine (5-HT) turnover was studied. Treatment with disulfiram caused increases in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in rat brain. Under the same condition, activity of brain mitochondrial aldehyde dehydrogenase was reduced, however, supernatant aldehyde dehydrogenase and monoamine oxidase activities remained unchanged. Disulfiram had no effect on synthesis rate of 5-HT, but decreased metabolism of 5-HT. Moreover, disulfiram impaired transport of 5-HIAA from brain tissue.

Susceptibility of brain aldehyde metabolizing enzymes to pargyline, disulfiram and diethylmaleate in vivo in rats

Abstract In vivo susceptibility of mitochondrial (m)- and soluble (s)-aldehyde dehydrogenase (AlDH) and aldehyde reductase (AIR) to three compounds, i.e., pargyline, diethylmaleate and disulfiram in rat brain was studied. In all experiments using the compounds tested, m-AlDH was more significantly inhibited when the low concentration of the substrate (50 μM) was used, as compared with the inhibition of the enzyme in use of high substrate concentration (3.3 mM). Under same condition, little or no inhibition of s-AlDH and AIR was observed. These findings strongly suggest that there are at least two forms of AlDH with different Kms and they have different susceptibility to AlDH inhibitors.

Synergistic effect of prostaglandin E1 and disulfiram on the prolongation of hexobarbital hypnosis

A possible role of a deaminated metabolite of 5-hydroxytryptamine (5-HT) on hexobarbital hypnosis was studied in rats. Pretreatment with either prostaglandin E1 (PGE1) or disulfiram prolonged hexobarbital hypnosis, and a combined administration of both drugs strongly prolonged hexobarbitai hypnosis and drastically reduced brain hexobarbital content on awakening. PGE1 was found to enhance 5-HT synthesis without altering the elimination of 5-hydroxyindoleacetic acid. The results suggest that elevation of steady state level of 5-hydroxyindoleacetaldehyde potentiates hexobarbital hypnosis. In 1973, Haubrich et al.~ suggested that the sleep induced by prostaglandin E1 (PGE1) may be related to the increased formation of deaminated metabolites of 5-hydroxytryptamine (5-HT) in brain. In addition, Bhattacharya et al. 1 demonstrated that the potentiation of hexobarbital hypnosis by PGE1 might be mediated by serotonergic system. On the other hand, disulfiram was shown to prolong barbiturate hypnosis without any inhibition of liver drug metabolizing enzymesT,XL Recently, we demonstrated that this effect of disulfiram might be related to the elevation of steady state level of 5-hydroxyindoleacetaldehyde (5-HIAAld), one of the deaminated metabolites of 5-HT 3,7. In the present study, we examined the effect of a combined administration of PGE1 and disulfiram on hexobarbital hypnosis, and investigated the possible role of a deaminated metabolite of 5-HT in the alteration of brain susceptibility to hexobarbital. Male, Wistar rats weighing 130-150 g were used in this study. PGE~ was dissolved in absolute ethanol and diluted with 0.2 M phosphate buffer (pH 6.5). This solution was administered intraperitoneally at a dose of 1 mg/kg 15 min before

Effect of tryptophol on pentylenetetrazol and picrotoxin induced convulsion in mice.

Abstract The effect of treatment of mice with tryptophol (TOL), a neutral metabolite of tryptophan, on drug-induced convulsion was studied. TOL effectively suppressed both pentylenetetrazol and picrotoxin induced convulsion. Diphenylhydantoin (DPH), a potent inhibitor of brain aldehyde reductase, significantly reduced the anticonvulsant effect of TOL, however, TOL level in brain of DPH-treated mice was rather higher than that of control one. These results strongly suggest that the manifestation of the anticonvulsant effect of TOL requires the conversion of TOL to its active metabolite, indoleacetaldehyde.

Tryptophol-induced change in brain 5-hydroxytryptamine metabolism

The effects of tryptophol (TOL) on brain 5-hydroxytryptamine (5-HT) metabolism were studied. After TOL injection (200 mg/kg IP), brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were increased, 5-HT synthesis rate was decreased, and monoamine oxidase (MAO) activity remained unchanged. Pretreatment of mice with p-chlorophenylalanine (PCPA), a potent inhibitor of 5-HT synthesis, did not affect the anticonvulsant action of TOL. These results suggest that alteration of 5-HT metabolism after TOL injection is not directly related to the anticonvulsant action of TOL.

Effect of disulfiram in combination with L-tryptophan and lithium on pentylenetetrazol-induced seizure

Disulfiram prolonged the latency to clonic seizure caused by pentylenetetrazol (PTZ, 100 mg/kg SC). The effect of disulfiram was augmented by combination with tryptophan plus lithium, although neither tryptophan or lithium prolonged the latency to clonic seizure. The latency to tonic seizure was also prolonged in disulfiram-treated animals in parallel with the prolongation of the latency to clonic seizure. Lithium treatment completely prevented the incidence of tonic seizure, while this effect was cancelled in disulfiramtreated animals. Disulfiram acts on the clonic and tonic seizures in different ways.

Changes in seizure susceptibility after successive treatments of mice with tryptophol and ethanol

Changes in leptazol (pentetrazol) seizure susceptibility after successive treatments of mice with tryptophol, a neutral metabolite of indoleamine, in combination with ethanol have been examined. Mice treated with tryptophol plus ethanol became highly susceptible to convulsions. There was little or no difference in seizure susceptibility in mice treated with tryptophol or ethanol alone, compared with the corresponding controls. In the mice treated with tryptophol plus ethanol, a much higher brain tryptophol level was observed, compared with that in mice treated with tryptophol alone. There appeared to be a good correlation between the reduction of the length of the seizure latency time and the time for which the brains were exposed to high levels of tryptophol. These results suggest that elevation of the levels of neutral indoleamine metabolites in the brain may have resulted in the increase in the seizure susceptibility.

Disulfiram-like effect of diethyl maleate on barbiturate-induced hypnosis and 5-hydroxytryptamine metabolism.

Diethyl maleate (DEM, 600 mg kg−1 i.p.) significantly potentiated hexobarbitone hypnosis and lowered plasma hexobarbitone level on awakening. Sleeping time following intra‐cerebroventricular (i.c.v.) injection of phenobarbitone was also prolonged by DEM treatment. When administered to DEM‐treated rats, L‐tryptophan (50 mg kg−1 i.p.) significantly potentiated hexobarbitone hypnosis, although alone it had no effect in control rats. DEM markedly diminished the activity of brain low‐Km aldehyde dehydrogenase (AlDH) and the formation of 5‐hydroxyindoleacetic acid from 5‐hydroxytryptamine (5‐HT) without affecting MAO activity in various areas of the brain. Conversely, the protein‐bound radioactivity derived from i.c.v. [14C]‐5‐HT was increased by DEM treatment. These results showed that DEM is comparable with disulfiram, a brain AlDH inhibitor, in terms of its effect on 5‐HT metabolism and barbiturate hypnosis.

Compensatory increase in synaptosomal aldehyde reductase activity in rat brain after chronic barbital treatment.

Abstract The changes in brain aldehyde reductase (AIR) activities during long-term treatment of rats with barbital were studied. NADH-linked AIR activity in the synaptosomal fraction increased rapidly, and supernatant AIR activity rose later during barbital treatment. With respect to NADPH-linked AIR, two distinct K m values were observed for p -nitrobenzaldehyde. The low- K m enzyme had a higher K i value than the high- K m enzyme. Although the elevation of NADPH-linked AIR activity under the routine assay conditions was less remarkable, V max values of the low- K m enzyme were greatly increased in both the synaptosomal and the supernatant fractions by chronic barbital treatment. In addition, the K i value of low- K m AIR in synaptosomes was greater in barbital-treated animals than in control animals. K m values were unchanged in either fraction by chronic barbital treatment. These data suggest that chronic barbital treatment resulted in a compensatory increase in the activity of AIR with low K m , which is less sensitive to barbital and utilizes either NADH or NADPH, in synaptosomes.