PubMed Health⌕ Search

Biomedical subjects

H Mitsushio

Publications and source records attributed to H Mitsushio.

At least 19 recordsLinked to original sources
PubMed1996

An insertion/deletion polymorphism in the angiotensin converting enzyme gene is associated with both brain substance P contents and affective disorders.

Because of a potent action of angiotensin converting enzyme (ACE) to degrade substance P (SP) and an association of the insertion/deletion (I/D) polymorphism of the ACE gene with ACE activity, an association between the SP level and the ACE I/D polymorphism were examined using 20 human postmortem brain samples. The results showed a significant association between the polymorphism and SP levels in the basal ganglia and substantia nigra, where both ACE and SP concentrate, and a higher SP level in the subjects with the DD genotype than in those with the II genotype, with an intermediate level in heterozygotes. Associations of the polymorphism with schizophrenia and affective disorders were also investigated in 292 unrelated Japanese schizophrenics, 65 patients with affective disorders, and 579 controls. The D allele was significantly more frequent in the patients with affective disorders than in the controls (p < .02), and the DD genotype was significantly more frequent in the patients with affective disorders than in the controls (p < .002). There is no significant difference in the frequencies of the allele and the genotype between the controls and schizophrenics. These results suggest that the ACE I/D polymorphism is one of the genetic factors for an interindividual variability of brain SP levels, and that the ACE polymorphism may contribute to the susceptibility to affective disorders.

Adult↗
PubMed1996

Reduction of substance P after chronic antidepressants treatment in the striatum, substantia nigra and amygdala of the rat.

We investigated the effects of chronic treatment with food containing one of five antidepressants on substance P (SP) content in the rat brain using radioimmunoassay and enzyme-immunoassay. The antidepressants used were imipramine, desipramine, clomipramine, amoxapine and mianserin. Following 40 days of treatment, all the antidepressants decreased SP concentrations in the striatum, substantia nigra and amygdala. Only imipramine and desipramine reduced the peptide content in the hippocampus, and only mianserin reduced it in the septum. We further examined the acute effects of antidepressants one hour after a single intraperitoneal administration. Acute imipramine and desipramine treatment reduced SP in the striatum, whereas acute mianserin decreased it in the striatum and substantia nigra. These results demonstrate that all antidepressants on chronic treatment had a common effect, a reduction of SP content in the striatum, substantia nigra and amygdala. This raises the possibility that such a decrease may contribute to the therapeutic action of antidepressants in affective disorders.

Amoxapine↗
PubMed1993

Association between severity of alcoholism and the A1 allele of the dopamine D2 receptor gene TaqI A RFLP in Japanese.

The allelic association of TaqI A restriction fragment length polymorphism (RFLP) of the dopamine D2 receptor gene with alcoholism was examined in 78 Japanese alcoholics and compared with Japanese controls. A significantly higher frequency of the A1 allele (0.42) was found in 100 Japanese unscreened controls compared with those reported in white populations. Among 70 alcoholics whose severities were determined, the A1 allele was present in 77% of 43 more severe alcoholics and in 59% of 27 less severe alcoholics. The A1 allele was present significantly less frequently in the alcoholics at the age of 60 or older (42%), compared with those under the age of 60 (74%). In the subjects under the age of 60, the A1 allele was present in 83% of the 35 more severe alcoholics, being significantly more frequent than in 60% of the 35 nonalcoholic controls. All of the 7 alcoholics homozygous for the A1 allele were classified as severe. The average severity of alcoholism increased in the order A2/A2, A1/A2, and A1/A1 genotypes. These data suggest that the A1 allele is associated with severe alcoholism in the Japanese population and that the effect is related to or has a linkage disequilibrium with a genetic factor that has a small but not negligible additive effect on alcoholism.

Age Factors↗
PubMed1993

Substance P-immunoreactive astrocytes in gracile sensory nervous tract of spinal cord in gracile axonal dystrophy mutant mouse.

In the gracile axonal dystrophy (GAD) mutant mouse, the dying-back type axonal dystrophy of the primary afferent neurons in the gracile tract of the spinal cord was marked by severe gliosis characterized by the hypertrophy and proliferation of the fibrous astrocytes. Immunocytochemical observation for substance P (SP) revealed that SP-positive cells increased in the lesioned sites, primarily in the gracile nucleus of the medulla and subsequently in the gracile fasciculus of the spinal cord. The combined immunostaining of both SP and glial fibrillary acidic protein (GFAP) indicated that a strong correspondence exists between GFAP-positive networks and SP-positive grains, suggesting that SP was accumulated in the cytoplasm of astrocytes. The networks of SP-positive astrocytes spread all over the gracile tract and were densest at the subpial membrane. Similar lesions and SP activity were detected along the marginal zone of the lateral and ventral funiculi. Using an electron microscope, in addition to SP-positive axonal terminals in the gracile nucleus, most SP-positive cells in the gracile tract were identified as reactive astrocytes whose processes surrounded myelinated and nonmyelinated axons, and extended their foot processes to the blood vessels. By in situ hybridization histochemistry of SP mRNA, we confirmed the synthesis of SP in the astrocytes. Although the functional significance of SP within astrocytes is not established here, these results imply that the astrocytes may play a role as a gliotransmitter through which the progress of axonal degeneration in the spinal cord was modified.

Animals↗
PubMed1992

Modulation of cerebral acetylcholine metabolism by the dorsal diencephalic conduction system in the rat.

We investigated the effects of interruption of the impulse flow in the habenulopeduncular pathways by local infusion of tetrodotoxin on the acetylcholine and choline content in selected dopamine rich regions in the forebrain and midbrain in rats. The tetrodotoxin infusion caused a marked increase in acetylcholine content in the medial frontal cortex, striatum and ventral tegmental area+interpenduncular nucleus, but not in the limbic area or the substantia nigra, whereas choline content was reduced only in both the striatum and ventral tegmental area+interpeduncular nucleus. There was an increase in 3,4-dihydroxyphenylacetic acid content in the striatum after the manipulation. These findings suggest that the dorsal diencephalic conduction system may be involved in the integration of the activity of cholinergic neurons in the forebrain and midbrain regions and striatal dopanine neurons may play a role in the modulation of cholinergic neurons.

Acetylcholine↗
PubMed1991

Muscimol injections into the median raphe nucleus increase serum ACTH and corticosterone concentrations via a nonserotonergic mechanism.

Midbrain raphe serotonin (5-HT) neurons can influence the pituitary-adrenal axis. The midbrain raphe nuclei also contain a number of non-5-HT neurons, including gamma-aminobutyric acid (GABA) interneurons which can modulate 5-HT neuronal activity. We investigated the effects of intraraphe injections of the GABAA agonist, muscimol, on serum adrenocorticotropin hormone (ACTH) and corticosterone concentrations. Rats were infused with muscimol (0, 25, 50, and 100 ng in 0.5 microliters saline) into the median raphe nucleus (MR). The animals were killed 30 min later, and trunk blood was collected for measurement of serum concentrations of ACTH and corticosterone by radioimmunoassay. Muscimol dose dependently increased plasma concentrations of these two pituitary-adrenal hormones. In order to determine the role of MR 5-HT neurons in these effects, separate groups of implanted animals were infused with either the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT) or ascorbic acid vehicle into the MR. Two weeks later, the animals were infused with muscimol (100 ng in 0.5 microliters) and sacrificed as above. Treatment with 5,7-DHT, which markedly reduced hippocampal concentrations of 5-HT (-83%) and 5-HIAA (-73%), did not block intra-MR muscimol-induced elevations in ACTH and corticosterone. Thus, 5-HT neurons within the MR apparently do not mediate the increased activity of the pituitary-adrenal axis produced by stimulation of MR GABAA receptors.

5,7-Dihydroxytryptamine↗
PubMed1991

Intra-midbrain raphe injections of the neurokinin-3 agonist senktide inhibit food and water intake in the rat.

Microinjection and lesion studies have implicated the midbrain dorsal (DR) and median raphe (MR) nuclei in behavioral arousal. This behavioral state is manifested as locomotor hyperactivity, hyperphagia, hyperdipsia and increases in plasma corticosteroid release. Intra-midbrain raphe injections of the GABAA agonist muscimol elicit this behavioral activation. We have demonstrated that similar infusions of tachykinins produce locomotor hyperactivity through activation of neurokinin-3 (NK-3) receptors located on serotonin cell bodies. The purpose of the present study was to determine the effects of intra-MR and DR infusions of senktide, an NK-3 agonist, on food and water consumption in nondeprived rats. Male Sprague-Dawley rats were implanted with indwelling intra-MR or intra-DR cannula. Infusions of muscimol (25 ng/0.5 microliters) into the MR increased water intake, while MR and DR infusions increased food consumption. In contrast, intra-MR injections of senktide decreased water intake and intra-MR and DR injections decreased food intake. The results suggest that the behavioral states induced by muscimol and neurokinin infusions into the raphe are distinct and that raphe/neurokinin pathways are involved in consummatory mechanisms.

Animals↗
PubMed1990

Neuronal sites mediating locomotor hyperactivity following central neurokinin agonist administration.

The stable substance P analog, DiMeC7, increases spontaneous locomotor activity after infusion into the lateral ventricles or median raphe nucleus (MRN). The elevated locomotion observed after intracerebroventricular (ICV) infusion of DiMeC7 was attenuated, but not blocked, by bilateral 6-hydroxydopamine (6OHDA) lesions of the ventral tegmental area (VTA). In contrast, bilateral 6OHDA lesions of the nucleus accumbens (NAS) blocked the motor activity induced by ICV administration of DiMeC7. Similar lesions did not affect the increases in motor behavior observed after MRN infusions of DiMeC7. However, the hyperactivity following MRN microinjections of DiMeC7 was attenuated by intraperitoneal administration of the dopamine (DA) antagonist, haloperidol. The results suggest that ICV infusions of DiMeC7 increase locomotor activity by acting directly on neurons in the NAS and in part by influencing, directly or indirectly, the activity of DA cells in the VTA. The increased motor activity seen after MRN administration of DiMeC7 appears to depend on DA neurons but not on projections to the NAS.

Animals↗
PubMed1989

Intra-raphe neurokinin-induced hyperactivity: effects of 5,7-dihydroxytryptamine lesions.

Rats were implanted with cannulae in the median raphe nucleus (MR). 5,7-Dihydroxytryptamine (5,7-DHT) or vehicle was infused either directly through the MR cannula, or bilaterally into the medial forebrain bundle (MFB). The MR 5,7-DHT lesions completely blocked the hyperactivity elicited by injections into the MR of the neurokinin (NK) 3 agonists, DiMe-C7 and senktide, and the NK-2 agonist, neurokinin A. In contrast, the MFB 5,7-DHT lesions did not affect the locomotor hyperactivity produced by intra-MR administration of DiMe-C7 and senktide, but appeared to attenuate the effects of NKA. The data indicate that intra-raphe neurokinin-induced hyperactivity is mediated by 5-HT neurons, and that 5-HT projections to the forebrain may be involved in the behavioral activation induced by intra-raphe neurokinin A administration, but not that induced by intra-MR NK-3 agonists.

5,7-Dihydroxytryptamine↗
PubMed1988

Chronic dietary treatment with antidepressants decrease brain Met-enkephalin-like immunoreactivity in the rat.

This report describes the effect of chronic dietary treatment with antidepressants or antimanic drugs on brain Met-enkephalin-like immunoreactivity in the rat. The chronic treatment was administered through food containing 250-1000 mg desipramine, imipramine or clomipramine, 200-800 mg amoxapine or mianserin, 750-1500 mg lithium chloride, or 50 mg haloperidol per 1 kg food for 40 days. In the striatum, each antidepressant decreased the enkephalin content, while lithium or haloperidol, having an antimanic effect, increased the enkephalin content. Following the chronic administration of each antidepressant tested, the concentration of the peptide was reduced in the nucleus accumbens, hypothalamus and thalamus. We further examined the acute effect of the antidepressant (10 or 20 mg/kg) on the striatal enkephalin content at 60 min after a single intraperitoneal injection. The striatal content was decreased after the acute treatment with each antidepressant tested. These results indicate that the antidepressants had an effect on the neuronal activity of Met-enkephalin not only after chronic treatment, but also after acute treatment. The reduction in Met-enkephalin-like immunoreactivity after prolonged treatment with the antidepressant may possible contribute to the mechanism of antidepressive action.

Animals↗
PubMed1988

Neurotransmitters, receptors and neuropeptides in post-mortem brains of chronic schizophrenic patients.

In the analysis of post-mortem brains of 14 chronic schizophrenic patients and 10 controls, biochemical evidence of a hyperdopaminergic state was found in the basal ganglia of schizophrenics; tyrosine hydroxylase activity was increased with a concomitant increase of homovanillic acid. Unusually high tyrosine hydroxylase activity was noted in 2 schizophrenic cases. The Bmax value of 3H-spiperone binding for schizophrenics was higher than the controls. We also found increased specific binding of 3H-kainic acid to the prefrontal cortex in schizophrenics. A negative correlation existed between 3H-kainic acid binding in the medial frontal cortex, and glutamic acid content in various brain areas. Increased immunoreactivity of substance P was found in more than ten brain areas. Methionine-enkephalin was also increased in three areas of the prefrontal cortex of schizophrenics. These results suggest that the hyperdopaminergic state co-existed with glutamatergic hypofunction and increased neuropeptides in various brain areas of chronic schizophrenic patients.

Adult↗
PubMed1988

Effects of chronic treatment with trihexyphenidyl and carbamazepine alone or in combination with haloperidol on substance P content in rat brain: a possible implication of substance P in affective disorders.

To assess the roles of substance P in neurologic or psychiatric illnesses, effects of acute or chronic (40- or 80-day dietary) treatment with trihexyphenidyl and carbamazepine alone or in combination with haloperidol on substance P content were investigated in the rat brain. Either acute or chronic trihexyphenidyl administration did not alter substance P content when administered alone and did not prevent the haloperidol-induced substance P decrease in the striatum and substantia nigra when coadministered with haloperidol. Chronic dietary carbamazepine administration dose-dependently increased substance P content in the striatum and substantia nigra, but not in the raphe area, in a haloperidol-reversible manner. Carbamazepine also dose-dependently increased gamma-aminobutyric acid levels in the substantia nigra without altering the striatal dopamine turnover rate. The lack of effect of trihexyphenidyl, an anticholinergic drug used to treat antipsychotic drug-induced extrapyramidal (Parkinson) syndromes, suggests that antipsychotic drug-induced reduction in substance P content is not involved in the extrapyramidal side effects. Since the effects of carbamazepine on substance P content are identical with previously described effects of lithium, an alteration in substance P neurotransmission may be one of the neurochemical bases of common clinical and behavioral effects of carbamazepine and lithium on affective disorders.

Animals↗
PubMed1984

Increased brain serotonin metabolism during rebound sleep in sleep-deprived rats.

Adult male Wistar rats were almost totally deprived of sleep by handling for 24 hr. 5-Hydroxyindolacetic acid concentrations in the dorsal raphe nucleus area and thalamus increased by 140-180%, immediately after sleep deprivation and when the rats had a 3- or 30-min rebound sleep. The higher levels of 5-hydroxyindolacetic acid were still observed after the rats were awakening from a 4-hr sleep. The concentrations of 5-hydroxytryptamine (serotonin) decreased after sleep deprivation and increased during and after sleep, but the differences were not significant. Tryptophan accumulated in the dorsal raphe area and thalamus after sleep deprivation, and an elevated level did not return to baseline concentrations until the rats were awakening. Tryptophan hydroxylase activity did not change in the dorsal raphe area during and after sleep deprivation. These results suggest that the release and synthesis of 5-hydroxytryptamine in the dorsal raphe area and thalamus increased when the rats had a sleep pressure or a rebound sleep after total sleep deprivation. An increased transport of tryptophan into the brain may be closely involved in sleep-inducing mechanisms.

Animals↗