Ryuji Fukumori

Effect of methamphetamine on the locomotor activity in the 6-OHDA dorsal hippocampus lesioned rat

The present studies were carried out to examine a possible role of hippocampal dopamine in the hyperactivity induced by methamphetamine. For this purpose, 6-hydroxydopamine (6-OHDA) lesion of the dorsal hippocampus (D-HPC) was made in desmethylimipramine pretreated rats in order to specifically destroy dopamine neurons. D-HPC lesions produced a large (96%) and selective depletion of content of dopamine in the D-HPC. This lesion did not change spontaneous locomotion and rearing behavior. The 6-OHDA lesioned rat produced a blockade of the increase in locomotor activity induced by 1.0 and 2.0 mg/kg of methamphetamine. In contrast, the 6-OHDA lesion of the D-HPC failed to influence the methamphetamine-induced rearing activity. These results indicate that dopamine neurons in the D-HPC may have some role in methamphetamine-induced locomotion, but not in methamphetamine-induced rearing.

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.

Effect of p-chlorophenylalanine on diazepam withdrawal signs in rats

The effect of p-chlorophenylalanine (PCPA), a specific serotonin (5-HT) depleter, on diazepam withdrawal signs was studied. Rats were made dependent on diazepam by the chronic administration of this drug in the diet. At the time of diazepam withdrawal, the animals were treated with PCPA (200 mg/kg, IP) or the corresponding vehicle (control). After diazepam withdrawal, the maximal body weight losses of control and PCPA-treated animals were 4.1% and 9.0%, respectively. In naive animals, PCPA did not cause any change in body weight. These results suggest that depletion of central 5-HT by PCPA may potentiate the severity of diazepam withdrawal signs.

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.

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.

Effect of parachlorophenylalanine on the incidence of abnormal behaviors observed following diazepam withdrawal

Abstract 1. 1. Rats were rendered dependent on diazepam by administrating escalating dosages of diazepam in diet. 2. 2. At the time of diazepam withdrawal, the animals were treated with parachlorophenylalanine (PCPA), a potent serotonin (5-HT) depleter, or the corresponding vehicle. 3. 3. After diazepam withdrawal, PCPA-treated animals showed abnormal behaviors, such as aggression, irritability, vocalization and muscular rigidity. 4. 4. In contrast, little or no changes in behavior were observed in control animals. 5. 5. These results suggest that depletion of brain 5-HT by PCPA potentiates diazepam withdrawal signs.

Changes in tissue concentrations of sulfhydryl groups in relation to the metabolism of biogenic amines in vitro.

Abstract Quantitative changes in nonprotein sulfhydryl (NP-SH) and protein sulfhydryl (P-SH) contents of rat tissue homogenates after incubation in the presence and absence of serotonin and dopamine were investigated. According to the enzymic determination of NP-SH using partially purified rat liver formaldehyde dehydrogenase, 81.4% of NP-SH in rat brain could be considered as reduced glutathione (GSH). The decrease in GSH was significantly less with added NAD in liver homogenate, but not in brain. On the other hand, addition of pargyline to the incubation mixture resulted in a smaller decrease in GSH-lost. These facts revealed that the decrease in GSH in the presence and absence of serotonin or dopamine is dependent on both the activities of monoamine oxidase and aldehyde dehydrogenase of tissues, which are involved in formation of aldehyde derivatives of these amines. In addition, decrease of P-SH in the presence of serotonin or dopamine may be protected by addition of GSH as a scavenger of the aldehyde formed.