Alteration of 5-HIAA levels in frontal cortex and dorsal raphe nucleus in rats treated with combined administration of tryptophan and ethanol.

The present studies sought to investigate the effect of tryptophan alone or coadministration of tryptophan and ethanol on the interaction of central frontal cortex and dorsal raphe nucleus serotonergic functional activities by utilizing in vivo microdialysis. Tryptophan (50 mg/kg, i.p.) led to a significant increase in the levels of 5-HIAA, a metabolite of serotonin (5-HT), in the dorsal raphe nucleus, but not in the frontal cortex. Coadministration of tryptophan and ethanol caused very marked increases in 5-hydroxyindoleacetic acid (5-HIAA) levels in both the frontal cortex and the dorsal raphe nucleus, although ethanol (1.25 g/kg) did not change 5-HIAA levels in both areas. Moreover, the application of WAY100635 (10 muM), 5-HT(1A) antagonist, into the frontal cortex after coadministration caused a marked increase in 5-HIAA levels in the frontal cortex and a decrease in the levels in the dorsal raphe nucleus, although WAY100635 alone had no effect on these levels. This may suggest that WAY100635-induced increase of 5-HIAA levels in the frontal cortex resulted from negative feedback following the blockade of serotonergic 5-HT(1A) autoreceptors, and that this increase in 5-HIAA levels decreased 5-HIAA levels in the dorsal raphe nucleus by preventing the activation of dorsal raphe 5-HT(1A) autoreceptors. WAY100635 into the dorsal raphe nucleus did not significantly change 5-HIAA levels in both areas. This may indicate that the blockade of dorsal raphe 5-HT(1A) autoreceptors by WAY100635 resulted in unchanged 5-HIAA levels in the frontal cortex. Behavioral sign of teeth-chattering was markedly observed following the coadministration and in combination with WAY100635. These results may suggest that the increased 5-HIAA levels in both areas after coadministration are indicative of the interrelation via activation of serotonergic neurons, and that the increased levels are partly responsible for behavioral activation of rats.

Acute effect of simultaneous administration of tryptophan and ethanol on serotonin metabolites in the locus coeruleus in rats.

Using the microdialysis method, we investigated whether the levels of serotonin (5-hydroxytryptamine, 5-HT) and its metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTPL), in the locus coeruleus are influenced by tryptophan alone or simultaneous administration of tryptophan and ethanol. Tryptophan (50 mg/kg, i.p.) led to a significant increase in the levels of 5-HIAA, but not 5-HT in the locus coeruleus. However, ethanol (1.25 g/kg) had no effect on the levels of 5-HT and its metabolites. Combined administration of tryptophan and ethanol caused very marked increases in 5-HIAA and 5-HTPL levels in the locus coeruleus. A time lag in the increased 5-HIAA levels between tryptophan alone and tryptophan plus ethanol was observed. Moreover, 5-HIAA levels in the locus coeruleus induced by tryptophan were abolished by microinjection of 5,7-dihydroxytryptamine (150 microg/4 microl) into the dorsal raphe nucleus. Judging from the present results, the serotonergic afferents to the locus coeruleus may originate for about 20-30% from cell bodies located in the dorsal raphe nucleus. Teeth-chattering was significantly detected in the tryptophan plus ethanol-treated rats when compared with the tryptophan-treated rats, but not in the saline-treated controls. These results may suggest that the increased levels of 5-HIAA and 5-HTPL in the locus coeruleus induced by tryptophan are potentiated by ethanol, and that these levels are partly responsible for behavioral activation.

Effects of acute and short-term administration of tryptophan plus ethanol on noradrenaline and serotonin metabolites in the locus coeruleus.

The effects of acute and short-term administration of tryptophan or tryptophan plus ethanol on serotonin [5-hydroxytryptamine (5-HT)] and two of its metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTPL), in the locus coeruleus were investigated in rats by using the microdialysis method. In addition, the acute effects of these drugs on noradrenaline and its metabolite 4-hydroxy-3-methoxymandelic acid (HMMA) were addressed. A single co-administration of tryptophan (50 mg/kg, i.p.) and ethanol (1.25 g/kg, i.p.) did not change the concentrations of either noradrenaline or its metabolite in the locus coeruleus. In contrast, administration of tryptophan (50 mg/kg, i.p.) for three consecutive days caused an increase in the concentration of 5-HIAA, but not that of 5-HT, in the locus coeruleus. Combined administration of tryptophan plus ethanol for 3 days resulted in marked increases in 5-HIAA concentrations in the locus coeruleus, but not in 5-HTPL concentrations. However, administration of ethanol (1.25 g/kg) for 3 days had no effect on the concentrations of 5-HT and its metabolites. The increased 5-HIAA concentration that resulted with combined tryptophan plus ethanol administration was remarkably suppressed by disulfiram. Moreover, in comparison with tryptophan-treated rats, the behavioral sign of teeth-chattering was significantly detected in tryptophan plus ethanol-treated rats, but the enhancement of behavioral signs with combined treatment was markedly suppressed by disulfiram. Results of the current study seem to indicate that the stimulation of 5-HT metabolism in locus coeruleus serotonergic neurons by tryptophan was strengthened by the simultaneous administration of ethanol in short-term experiments, and that the increased 5-HIAA concentrations in the locus coeruleus are responsible for behavioral activation.

[Community home healthcare in 6-year pharmacy education].

As we enter more and more into a super-aging society, the requirement for home healthcare will increase. Pharmacists must work along with doctors and nurses in the field of home healthcare. Within the 6-year pharmacy curriculum, we must educate students as medicinal professionals who will join a medical team to serve the community. The Good Practice (GP) program, which has been supported by the Ministry of Education, Culture, Sports, Science & Technology, continues to be offered in our university. As a part of this program, students learn home healthcare in the community in cooperation with Yubari Medical Center. In addition, our students (pharmacy) can study community medicine together with students from Tenshi College (nursing and nutrition) in an optional class made available in Yubari during their summer vacation. According to the results of our survey after these programs, students have achieved a deep recognition of the importance of community medicine and cooperation with other medical staff in contributing to community home healthcare. We carry out these programs under agreements of collaboration with Yubari Medical Center and Tenshi College. We will talk today about training for pharmaceutical care in the community and the effect of training through this class on pharmacy education.

Antioxidative potential of fluvastatin via the inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity.

We previously reported that fluvastatin, a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, a strong lipid lowering drug, exerted an anti-atherosclerotic effect at doses insufficient to lower serum lipids in cholesterol fed rabbits. The evidence demonstrated that the superoxide anions from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase plays a critical role in several steps in the development of atherosclerosis. This study was designed to determine the effects of HMG-CoA reductase inhibitors on the production of the superoxide anions of NADPH oxidase in isolated rat peritoneal neutrophils. Fluvastatin (1-10 microM) decreased phorbol 12-myristate 13-acetate (PMA, 10 nM)-dependent reactive oxygen species (ROS) generation in a concentration-dependent manner. It also (10 microM) decreased PMA-dependent O(2) consumption of the rat neutrophils. These effects were reversed by the addition of mevalonate, a metabolite in the HMG-CoA reductase pathway. Treatment with pravastatin did not show any significant changes. Fluvastatin (10 microM) decreased ROS, such as hydroxyl radicals and superoxide anions generated by the Fenton reaction, and by the xanthine-xanthine oxidase system. Rats were treated with either fluvastatin (5 mg/kg per day, p.o.) or pravastatin (5 mg/kg per day, p.o.) for 1 week. Treatment with fluvastatin decreased the PMA-dependent ROS generation. The fluvastatin induced effect on the PMA-dependent ROS generation was reversed by the combined administration with 40 mg/kg mevalonate per day. The antioxidative effect of fluvastatin was thought to have caused not only the scavenging action of the radicals but also to have inhibited ROS generation by inhibiting the NADPH oxidase activity. This antioxidative potential of fluvastatin via the inhibition of NADPH oxidase activity may be profitable in preventing atherosclerosis.