PubMed Health⌕ Search

Biomedical subjects

I Nukina

Publications and source records attributed to I Nukina.

At least 19 recordsLinked to original sources
PubMed1990

[Effect of flunarizine hydrochloride on striatal D-2 dopamine receptors].

Flunarizine hydrochloride (FZ) is used to improve cerebral circulation and possesses Ca antagonistic effects. In recent years, this drug has been reported to induce parkinsonism and depressive symptoms as side effects, particularly in the elderly. Effects of FZ on dopamine receptors of the rat striatum were studied by radiolabeled receptor assay to clarify the mechanism of onset of parkinsonism in response to FZ. FZ was found to directly and competitively affect D-2 receptors without affecting D-1 receptors. Furthermore, the effect of FZ on D-2 receptors was found to be antagonistic based on the finding that the displacement curve for FZ in the binding of [3H]spiperone to D-2 receptors remained unchanged even after the addition of GppNHp. The effect of FZ on the D-2 receptors in aged rats was more marked than that in young-adult rats. In addition, the tertiary structures of FZ and the anti-schizophrenic agents, pimozide and haloperidol, were examined using computer graphics. FZ was found to have a tertiary structure highly analogous to pimozide and haloperidol, and FZ also had an alkyl structure linking a fluorophenyl group and a nitrogen atom, believed to be particularly necessary for the binding of anti-schizophrenic agents to D-2 receptors. These results may contribute to clarifying the mechanism of onset of parkinsonism in response to FZ, especially in the elderly.

Age Factors↗
PubMed1989

Neuropeptides modulate beta-adrenergic agonist binding and receptor downregulation in slices of rat brain.

Displacement curves of the beta-adrenergic agonist (-)-isoproterenol, on the binding of [3H]-dihydroalprenolol (DHA) in homogenates from the brain of rat defined a two-site model of high (KH; 8.5 +/- 1.6 nM) and low (KL; 771 +/- 111 nM) affinity. The KL/KH ratio was 84.5 +/- 4.5. Somatostatin, ACTH, dynorphin and mastoparan, but not vasoactive intestinal peptide (VIP), substance P, met-enkephalin or leu-enkephalin, each at 1 microM, decreased the KL/KH ratio to 35.2 +/- 4.2, 43.0 +/- 5.0, 52.0 +/- 2.3 and 60.3 +/- 8.0, respectively, without significant effect on either the Kd or Bmax of antagonist binding. Calcium was required for this effect of the neuropeptides. In slices from whole brain of rat, incubated for 2 hr, ACTH attenuated the isoproterenol-induced downregulation of beta-adrenoceptors. For beta-adrenergic agonists, there appeared to be a close correlation between the KL/KH ratio and intrinsic activity. These results suggest that certain neuropeptides may influence beta-adrenergic neurotransmission by modulating the intrinsic activity of beta-agonists. This modulation is manifested, at least in part, by changes in both binding affinity and receptor down-regulation.

Adrenergic beta-Agonists↗
PubMed1987

Acute cold-restraint stress affects alpha 2-adrenoceptors in specific brain regions of the rat.

The effect of acute cold-restraint stress on binding of [3H]rauwolscine to alpha 2-adrenoceptors was investigated in 10 regions of rat brain. Acute stress: significantly decreased the density but had no significant effect on the affinity of binding sites in the hippocampus; decreased density and increased affinity in the amygdala; and increased density and decreased the affinity in the midbrain. Seven other brain regions showed no significant changes in binding parameters in response to stress. These results, together with previous findings in this laboratory showed that alteration by restraint stress of noradrenaline levels in amygdala and hippocampus, but not other regions, indicate an association between neurotransmitter turnover and receptor function.

Acute Disease↗
PubMed1987

Agonist-induced regulation of adrenoceptor subtypes in cerebral cortical slices.

Cerebral cortical slices from rat brain were incubated at 37 degrees C for 2 h in the presence of isoproterenol, noradrenaline, or adrenaline, and binding affinities and densities of adrenoceptor subtypes were subsequently examined in homogenized tissue. The density of alpha 2- and total beta-adrenoceptors was estimated using the radioligands [3H]rauwolscine and [3H]dihydroalprenolol (DHA), respectively. The percentages of beta 1- and beta 2-adrenoceptors were defined by inhibiting the binding of [3H]DHA with the beta 1-selective antagonist metoprolol. Exposure of slices to noradrenaline and adrenaline significantly decreased the maximal number of binding sites (Bmax) of alpha 2-adrenoceptors (48 and 37% respectively) without significantly affecting affinity; isoproterenol had no effect. Exposure to isoproterenol, noradrenaline, and adrenaline significantly decreased the Bmax of beta-adrenoceptors (by 60, 34, and 24%, respectively) but did not affect the affinity. Isoproterenol and adrenaline significantly decreased the density of beta 1-adrenoceptors by 75 and 24% and beta 2-adrenoceptors by 23 and 28%, respectively. Noradrenaline significantly decreased the density of beta 1-adrenoceptors by 42% without affecting the number of beta 2-adrenoceptors. These findings indicate that subtypes of adrenoceptors in rat cerebral cortex are differentially regulated by adrenergic agonists.

Animals↗
PubMed1985

Up-regulation of thyrotropin-releasing hormone (TRH) receptors in rat spinal cord after codepletion of serotonin and TRH.

Immunohistochemical evidence indicates the coexistence of serotonin and TRH in many raphe neurons. We examined the biochemical changes in TRH receptors after destruction of the serotonergic pathways by 5,7-dihydroxytryptamine (5,7-DHT). 2 weeks after an intracerebroventricular injection of 5,7-DHT, rats were killed, and specific brain regions were dissected on ice. Serotonin levels in the CNS of lesioned rats was reduced by 50-85% in all regions, with the highest reduction in the spinal cord and hippocampus. Immunoreactive TRH was reduced in the spinal cord by 70%, but other brain regions contained normal levels of TRH. TRH receptor binding was increased by 40% in the spinal cord of lesioned rats, but appeared unchanged in rostral brain regions in which no decrease in TRH content was detected. Scatchard plots of TRH receptor binding in the spinal cord indicated that the increased binding after 5,7-DHT administration reflected an increased receptor number. These findings suggest that biochemical up-regulation of TRH receptors occurs in the spinal cord following depletion of TRH.

5,7-Dihydroxytryptamine↗
PubMed1985

Properties and distribution of vasoactive intestinal polypeptide receptors in the rat brain.

Vasoactive intestinal polypeptide (VIP) interaction with the rat brain synaptic membrane was examined using 125I-labeled VIP as a tracer molecule. Ion, pH and incubation time significantly influenced VIP receptor binding. Scatchard analysis suggested that the rat brain membrane had a single binding site with an apparent dissociation constant (Kd) of 9.8 X 10(-9) M. The receptor activity was sensitive to trypsin and phospholipase A digestion, and heating at 100 degrees C for 5 min completely destroyed the binding activity. This indicates that protein and phospholipid moieties are essential for VIP binding. Thiol reagents reduced receptor binding activity, suggesting that an intrachain disulfide bond might be an important constituent of the VIP binding site. High levels of binding were found in the hippocampus, striatum and cerebral cortex, and binding was very low in the medulla/pons and cerebellum. The receptor density did not always parallel the brain distribution of immunoreactive VIP (IR-VIP) concentration. The cerebral cortex had the highest ratio of IR-VIP-to-receptor, and the striatum had the lowest ratio of IR-VIP-to receptor. Although intra-nigral or intra-striatal injection of 6-hydroxydopamine had no effect on striatal VIP-binding, an intra-striatal injection of kainic acid resulted in a substantial lowering of striatal VIP receptors. The neurotoxic effects of kainic acid have been shown to be dependent on the corticostriatal tract, and this suggests that the striatum receives the VIPergic innervation from the cerebral cortex. Our findings indicate that endogenous VIP and VIP receptors might act as a neurotransmission modulator of extrapyramidal function in the striatum.

Animals↗
PubMed1985

Effects of calcium hopantenate on neurotransmitter receptors in the rat brain.

Effects of calcium hopantenate (HOPA) on neurotransmitter and neuropeptide receptors in the central nervous system (CNS) were investigated. In the radioreceptor assay (RRA), HOPA inhibited the [3H]-gamma-aminobutylic acid (GABA) receptor binding in a dose-dependent manner with a cross-reactive potency of 0.2%. On the other hand, radiolabeled ligand binding to CNS receptors in the benzodiazepine (BDZ)-, muscarinic cholinergic (mACh)-, methionine-enkephalin (ENK)- and thyrotropin releasing hormone (TRH)-RRA systems was not inhibited even by the addition of HOPA up to 100 microM. Repeated injection of HOPA (250 mg/kg/day for 7 consecutive days) increased GABA receptor binding by 53% in the cerebral cortex, while GABA binding in the rest of the forebrain did not change. The increased GABA receptor binding in the cerebral cortex of HOPA treated rats was due to the increased affinity of the binding sites. BDZ-, mACh-, ENK- and TRH-receptor bindings were not affected in either the cerebral cortex or the rest of the forebrain by repeated injection of HOPA. These results suggest that at least a part of the therapeutic efficacy of HOPA is due to sensitization of the GABA receptor in the cerebral cortex.

Animals↗
PubMed1985

Binding differences between nicotine and alpha-bungarotoxin in the rat brain.

Radioreceptor assay (RAA) results in rat brain with 3H-nicotine were compared with those obtained using 125I-alpha-Bungarotoxin (BTX). Scatchard analysis showed that the 3H-nicotine binding site had an average Kd and Bmax of 5.31 nM and 0.047 p moles/mg protein, respectively, and that the corresponding 125I-alpha-BTX binding site values were 0.092 nM and 0.044 p moles/mg protein. Cotinine, which is a nicotine metabolite and has a nicotine-like effect in vivo, inhibited 3H-nicotine binding but did not inhibit 125I-alpha-BTX binding. This result suggests that 3H-nicotine is a more useful ligand than 125I-alpha-BTX for investigating the pharmacological action of nicotine in the brain.

Animals↗
PubMed1984

An endogenous inhibitor of GABA receptor binding.

An endogenous inhibitor of GABA receptor binding was prepared from synaptic membrane of rat brain with 0.05% Triton X-100. The endogenous inhibitor was competitive with GABA for GABA binding sites. The inhibition of GABA receptor binding by the endogenous inhibitor was blocked by the allosteric effect of diazepam. In the presence of diazepam, specific [3H]GABA binding was greater in a medium containing the endogenous inhibitor than in one containing an equal inhibitory potency of GABA, whereas there was no difference in the absence of diazepam. This indicated that the endogenous inhibitor was not GABA itself.

Animals↗
PubMed1984

Improvement in freezing phenomenon of Parkinson's disease after DL-threo-3, 4-dihydroxyphenylserine.

A 77-year-old man with Parkinson's disease of long standing, under treatment with L-DOPA and benserazide, was administered DL-threo-3, 4-dihydroxyphenylserine (DL-threo-DOPS), a precursor of norepinephrine, for 10 days. With this administration the patient's freezing phenomenon was remarkably improved, and his dysarthria also showed improvement. When DL-threo-DOPS was suspended, the frozen gait returned on the third day to almost the former level, even though he continued to receive L-DOPA and benserazide. After administration of DL-threo-DOPS, the CSF level of 3-methoxy-4-hydroxyphenylglycol (MHPG), a major metabolite of norepinephrine, was 127.5% of the pretreatment level. These observations suggest that DL-threo-DOPS can pass through the blood-brain barrier and change to norepinephrine, and that DL-threo-DOPS may be beneficial in the treatment of the freezing phenomenon of Parkinson's disease.

Aged↗
PubMed1983

Chronic thyrotropin releasing hormone (TRH) administration on TRH receptors and muscarinic cholinergic receptors in CNS.

Intraperitoneal injections of thyrotropin releasing hormone (TRH, 6 mg/kg/day) to rats for 14 days resulted in a significant loss (20 25%) of TRH binding sites in the hippocampus, hypothalamus and cerebral cerebral cortex. The TRH-mediated loss was reversible and reflected a decrease in binding sites but no change in affinity. On the other hand, this TRH treatment did not affect the specific brain binding of [3H]QNB. The results suggest that TRH participates in regulating CNS-TRH receptors.

Animals↗
PubMed1983

Characteristics of muscarinic acetylcholine receptors in rat brain.

Characteristics of muscarinic acetylcholine (ACh) receptors were studied in the rat central nervous system (CNS) using 3H-quinuclidinyl benzilate (QNB), an antagonist of muscarinic ACh receptors. Scatchard analysis indicated that the rat CNS had a single 3H-QNB binding site with an apparent dissociation constant (Kd) of 5.0 X 10(-10) M. Li+, Zn++ and Cu++ had strong effects on 3H-QNB binding which indicates that these metal ions might play important roles at muscarinic ACh receptor sites in the brain. Since antidepressants and antischizophrenic drugs displaced the binding of 3H-QNB, the anticholinergic effects of these drugs need to be taken into account when they are applied clinically. The muscarinic ACh receptor was successfully solubilized with lysophosphatidylcholine. By gel chromatography, with a Sepharose 6B column, the solubilized muscarinic ACh receptor molecule eluted at the fraction corresponding to a Stokes' radius of 6.1 nm. With the use of sucrose-density-gradient centrifugation, the molecular weight of the solubilized muscarinic ACh receptor was determined to be about 90,000 daltons. The regional distribution of 3H-QNB binding in rat brain was examined, and the highest level of 3H-QNB binding was found to be in the striatum followed by cerebral cortex and hippocampus, indicating that muscarinic ACh mechanisms affect CNS function mainly through these areas.

Animals↗
PubMed1982

Cerebrospinal fluid GABA levels in various neurological and psychiatric diseases.

Cerebrospinal fluid gamma-aminobutyric acid (CSF-GABA) was analysed by radioreceptor assay in 16 normal controls and 84 patients with various neurological and psychiatric diseases. In patients with spinocerebellar degeneration, neuro-Behçet's syndrome and Parkinson's disease, CSF-GABA levels were decreased. On the other hand, increased CSF-GABA levels were detected in patients with meningitis.

Adult↗
PubMed1981

Differentiation of agonist conformation and antagonist conformation in multiple opioid receptors.

To differentiate the opiate (naloxone) receptor and the enkephalin receptor in rat brain, we solubilized the receptor molecules by detergent and determined the molecular weights by gel filtration. The receptor preparation was bound to [3H] naloxone or [3H] Met5-enkephalin, and was solubilized by Triton X-100. On gel chromatography with a Sepharose 6B column, the agonist and the antagonist conformation of opioid receptors eluted as molecules with the molecular weights of 240,000, and 120,000 and with Stokes' radii of 5.5 nm and 4.3 nm, respectively. Further, it was also disclosed that Na+ was bound to the antagonist conformation of opioid receptors but not to the agonist conformation.

Animals↗
PubMedDate not supplied

Characteristics of thyrotropin releasing hormone (TRH) receptors in rat brain.

Characteristics of TRH-receptors were studied in the rat central nervous system (CNS). Ion species, pH and temperature importantly influenced TRH-receptor binding. Subcellular distribution of TRH-receptor binding revealed that synaptic membranes had the greatest percentage of total sites. Scatchard analysis suggested that the rat CNS had two distinct TRH binding sites with apparent dissociation constants (Kd) of 5 X 10(09) M and 13 X 10(-8) M. Receptor activity is sensitive to trypsin and phospholipase A digestion, suggesting that protein and phospholipid moieties are essential for the binding of [3H]TRH. Thiol reagents reduced the binding activity of the receptor, suggesting that an intrachain disulfide bond may form an important constituent of the binding site for TRH. The TRH-receptor in the rat brain was successfully solubilized with non-ionic detergent Triton X-100. On gel chromatography with Sepharose 6B column, the solubilized TRH-receptor molecule eluted at the fraction corresponding to an apparent molecular weight of 300,000 daltons, with Stokes' radius of 5.8 nm. The regional distribution of TRH-receptor binding was examined to clarify the site of TRH action. The highest level of binding was in the hypothalamus, cerebral cortex and hippocampus, indicating that TRH affects the CNS function mainly through the limbic system, cerebral cortex and hypothalamus. Moreover, tricyclic anti-depressants and Li+ decreased the binding of [3H]TRH. These findings suggest that endogenous TRH and TRH receptor may play the role of a neurotransmission modulator in the brain to control emotional and mental functions.

Animals↗