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Y Goshima

Publications and source records attributed to Y Goshima.

At least 37 records · Page 2Linked to original sources
PubMed1999

The evidence for tonic GABAergic regulation of basal L-DOPA release via activation of inhibitory GABA(A) receptors in the nucleus tractus solitarii of anesthetized rats.

We have proposed that DOPA is a neurotransmitter of the primary baroreceptor afferents terminating in the rat nucleus tractus solitarii (NTS). GABA is a putative inhibitory neuromodulator for baroreflex inputs in the NTS. Thus, GABA may inhibit DOPAergic transmission in the NTS. We tried to clarify whether basal DOPA release is inhibited by muscimol, a GABA(A) agonist, and facilitated by bicuculline, a GABA(A) antagonist, during microdialysis of the NTS in anesthetized rats. DOPA release was consistently detectable. Muscimol 10-100 microM perfused via probes gradually inhibited concentration-dependently DOPA release. Peak 30% inhibition occurred 2 h after perfusion. Muscimol (30 microM)-induced inhibition was antagonized by non-effective 10 microM bicuculline. Bicuculline (30 microM) elicited peak 30% facilitation of DOPA release 2 h after perfusion. Endogenous GABA seems to regulate tonically basal DOPA release via activation of inhibitory GABA(A) receptors in the rat NTS. These findings further support the above proposal.

Anesthesia↗
PubMed1999

GABA may function tonically via GABA(A) receptors to inhibit hypotension and bradycardia by L-DOPA microinjected into depressor sites of the nucleus tractus solitarii in anesthetized rats.

We have proposed that DOPA is a transmitter of the primary baroreceptor afferents terminating in the rat nucleus tractus solitarii (NTS). GABA is a putative inhibitory neuromodulator for baroreflex inputs in the NTS. GABA may inhibit DOPAergic transmission. Drugs were microinjected into depressor sites of the NTS in anesthetized rats. DOPA (10-60 ng) elicited dose-dependent depressor responses. GABA (3-300 ng) elicited dose-dependent pressor responses. Nipecotic acid (100 ng) elicited pressor responses. Bicuculline (10 ng) elicited depressor responses. Responses to DOPA (30 ng) were inhibited by pretreatment with GABA and nipecotic acid, but potentiated by bicuculline, when vascular responses to pretreated drugs returned to basal levels. DOPA ME, a competitive DOPA antagonist, did not displace specific [3H]GABA binding. Prior DOPA ME (1 microg) inhibited by one-half pressor responses to 300 ng GABA. GABA seems to inhibit tonically via GABA(A) receptors depressor responses to DOPA and to elicit pressor responses partially by inhibition of tonic function of endogenous DOPA to activate depressor sites in the NTS. These findings further support the above proposal.

Anesthesia↗
PubMed1999

Some interactions of L-DOPA and its related compounds with glutamate receptors.

L-DOPA is probably a transmitter and/or modulator in the central nervous system (1). L-DOPA methyl ester (DOPA ME) is a competitive L-DOPA antagonist. However, it remains to be clarified whether there exist L-DOPAergic receptors. In Xenopus laevis oocytes injected with rat brain poly(A)+ RNA, L-DOPA induced small inward currents with ED50 of 2.2 mM at a holding potential of -70 mV. The currents were abolished by kynurenic acid or CNQX. Similar L-DOPA-currents were seen in oocytes co-injected with AMPA receptors, GluRs1,2,3 and 4. In brain membrane preparations, L-DOPA inhibited specific binding of [3H]-AMPA with IC50 of 260 microM. This inhibition was not modified by 200 microM ascorbic acid, an antioxidant. L-DOPA did not inhibit binding of [3H]-ligands of MK-801, kainate, DCKA and CGP39653. DOPA ME and L-DOPA cyclohexyl ester, a novel, potent and competitive antagonist (2), inhibited specific binding of [3H]-MK-801 with respective IC50 of 1 and 0.68 mM, but elicited no effect on that of the other [3H]-ligands. With low affinities, L-DOPA acts on AMPA receptors, while competitive antagonists act on NMDA ion channel domain. L-DOPAergic agonist and antagonist may not interact on ionotropic glutamate receptors. DOPA ME-sensitive L-DOPA recognition sites (1) seem to differ from glutamate receptors.

2-Amino-5-phosphonovalerate↗
PubMed1999

An L-dopaergic relay from the posterior hypothalamic nucleus to the rostral ventrolateral medulla and its cardiovascular function in anesthetized rats.

We have proposed that L-3,4-dihydroxyphenylalanine (L-DOPA) is a neurotransmitter in the central nervous system [Misu Y. et al. (1996) Prog. Neurobiol. 49, 415-454]. Herein, we attempt to clarify whether lesions in the posterior hypothalamic nucleus decrease the tissue content of L-DOPA in the rostral ventrolateral medulla. We also attempt to clarify whether or not endogenous L-DOPA is evoked by electrical stimulation of the posterior hypothalamic nucleus. It is possible that evoked L-DOPA functions as a transmitter candidate to activate pressor sites of the rostral ventrolateral medulla in anesthetized rats. Electrolytic lesions were made in the bilateral posterior hypothalamic nucleus by a monopolar direct current of 2 mA for 10 s, 10 days before measurements. The effect of the lesions was to selectively decrease the tissue content of L-DOPA by one-half in the right rostral ventrolateral medulla. Decreases in the amounts of dopamine, noradrenaline or adrenaline were not observed. Decreases were also not evident in the right caudal ventrolateral medulla. During microdialysis of the right rostral ventrolateral medulla, extracellular basal levels of L-DOPA and three types of catecholamine were consistently detectable by high-performance liquid chromatography with electrochemical detection. Tetrodotoxin (1 microM) perfused into the right rostral ventrolateral medulla gradually decreased basal levels of L-DOPA by 25%; it decreased basal levels of noradrenaline and adrenaline by 25-30% and dopamine levels by 40%. Intensive electrical stimulation of the ipsilateral posterior hypothalamic nucleus (50 Hz, 0.3 mA, 0.1 ms duration, twice for 5 min at an interval of 5 min) selectively caused the release of L-DOPA in a repetitive and constant manner. The stimulation was accompanied by hypertension and tachycardia. However, catecholamines were not released. Tetrodotoxin suppressed the release of L-DOPA, but partially inhibited hypertension with only a slight inhibition of tachycardia evoked by stimulation of the posterior hypothalamic nucleus. L-DOPA methyl ester, a competitive L-DOPA antagonist, was bilaterally microinjected into pressor sites of the rostral ventrolateral medulla at 1.5 microg x 2 and 3 microg x 2. The antagonist dose-dependently and consistently antagonized pressor and tachycardiac responses to mild transient stimulation of the unilateral posterior hypothalamic nucleus (33 Hz, 0.2 mA, 0.1 ms duration, for 10 s). In addition, the antagonist alone (3 microg x 2) elicited hypotension and bradycardia. These results show that an L-DOPAergic relay may project from the posterior hypothalamic nucleus directly to pressor sites of the rostral ventrolateral medulla and/or indirectly to certain neurons near pressor sites in microcircuits of the same region. When released, L-DOPA appears to function tonically to activate pressor sites; it also appears to be involved in the maintenance and regulation of blood pressure and heart rate.

Animals↗
PubMed1999

L-dopaergic components in the caudal ventrolateral medulla in baroreflex neurotransmission.

L-3,4-Dihydroxyphenylalanine (L-DOPA) is probably a transmitter of the primary baroreceptor afferents terminating in the nucleus tractus solitarii; L-DOPA functions tonically to activate depressor sites of the caudal ventrolateral medulla, which receives input from the nucleus tractus solitarii [Misu Y. et al. (1996) Prog. Neurobiol. 49, 415-454]. We have attempted to clarify whether or not L-DOPAergic components within the caudal ventrolateral medulla are involved in baroreflex neurotransmission in anesthetized rats. Electrolytic lesions of the right nucleus tractus solitarii (1 mA d.c. for 10 s, 10 days before measurement) selectively decreased by 45% the tissue content of L-DOPA in the dissected ipsilateral caudal ventrolateral medulla. Electrolytic lesions did not decrease dopamine, norepinephrine and epinephrine levels. During microdialysis of the right caudal ventrolateral medulla, extracellular levels of L-DOPA, norepinephrine, epinephrine and 3,4-dihydroxyphenylacetic acid were consistently detectable using high-performance liquid chromatography with electrochemical detection. However, extracellular dopamine levels were lower than the assay limit. Baroreceptor activation by i.v. phenylephrine selectively evoked L-DOPA without increasing the levels of norepinephrine, epinephrine and 3,4-dihydroxyphenylacetic acid. This L-DOPA release was suppressed by acute lesion in the ipsilateral nucleus tractus solitarii. Intermittent stimulation of the right aortic depressor nerve (20 Hz, 3 V, 0.3 ms duration, for 30 min) repetitively and constantly caused L-DOPA release, hypotension and bradycardia, without increases in levels of norepinephrine, epinephrine and 3,4-dihydroxyphenylacetic acid. Local inhibition of L-DOPA synthesis with alpha-methyl-p-tyrosine (30 microM) infused into the ipsilateral caudal ventrolateral medulla gradually decreased basal levels of L-DOPA and 3,4-dihydroxyphenylacetic acid without decreasing norepinephrine and epinephrine. The inhibition of L-DOPA synthesis interrupted L-DOPA release and decreased by 65% depressor responses elicited by aortic nerve stimulation; however, it produced no effect on bradycardic responses. CoCl2 (119 ng), a mainly presynaptic inhibitory transmission marker, and L-DOPA methyl ester (1 microg), a competitive L-DOPA antagonist, when microinjected into depressor sites of the right caudal ventrolateral medulla, reduced by 60% depressor responses to transient ipsilateral stimulation of the aortic nerve (20 Hz, 3 V, 0.1 ms duration, for 10 s). No changes in bradycardic responses were observed. There may exist an L-DOPAergic relay from the nucleus tractus solitarii to the caudal ventrolateral medulla. L-DOPAergic components in the caudal ventrolateral medulla are involved in baroreflex neurotransmission via a baroreceptor-aortic depressor nerve-nucleus tractus solitarii-caudal ventrolateral medulla relay in the rat.

Animals↗
PubMed1999

[A DOPA antagonist, DOPA cyclohexyl ester inhibits transient brain ischemia-induced release of glutamate and delayed neuronal cell death in striatal and hippocampal region of in vivo rats].

We have previously obtained evidence that DOPA is probably involved in an upstream process of mechanisms for in vivo neuronal cell death in striatum. We attempted to clarify whether or not this is also the case in hippocampal region of conscious Wistar rats. Four vessels were occluded for 5 min during microdialysis of hippocampus. DOPA, dopamine and glutamate (Glu) in perfusates collected every 10 min were measured by HPLC-ECD and spectrophotometer. Delayed neuronal cell death in hippocampus was evaluated 96 hr after ischemia. Five-min transient brain ischemia induced Glu release, with the peak being 2.5-fold of a basal release at the fraction immediately after ischemia. The release of DOPA and dopamine was not consistently detectable, but an increase was sometimes observed during and after ischemia. Delayed neuronal cell death was slight to moderate with 5-min ischemia. Intrastriatal perfusion of DOPA cyclohexyl ester (DOPA CHE) at 100 nM, a novel stable potent competitive DOPA antagonist, almost completely inhibited the ischemia-induced glutamate release, and protected hippocampal neurons from delayed cell death. Endogenously released DOPA itself seems to act on its recognition site and to behave as a causal and/or deteriorating factor on glutamate release and resultant delayed neuronal cell death by transient ischemia in rats.

Animals↗
PubMed1998

[Is endogenously released DOPA itself an upstream factor for increase in glutamate release and delayed neuronal cell death induced by transient ischemia in rats?].

DOPA itself is a neuromodulator in striata. In rat striata, DOPA by itself released neuronal glutamate in slices and caused cell death via glutamate release in cultured fetal neurons, suggesting involvement of DOPA in an upstream process of mechanisms for in vivo neuronal cell death. We attempted to clarify whether or not this idea is truly the case in conscious Wistar rats. Four vessels were occluded for 10 min during microdialysis of striata. DOPA, dopamine and glutamate in perfusates collected every 10 min were measured by HPLC-ECD and spectrophotometer. Delayed neuronal cell death in striata and hippocampus was evaluated 96 hr after ischemia. DOPA was indeed evoked with dopamine and glutamate during and after ischemia, and peak increases by respective 6-, 210- and 8-fold of a basal level were seen at the fraction immediately after ischemia. Delayed neuronal cell death was slight to moderate in striata and severe in hippocampus. Intrastriatal perfusion of NSD-1015, a central DOPA decarboxylase inhibitor, at 30 microM 10 min before ischemia, markedly increased DOPA and glutamate release by ischemia with slight inhibition of dopamine release and exaggerated delayed neuronal cell death in striata. Meanwhile, intrastriatal perfusion of DOPA cyclohexyl ester (DOPA CHE) at 10-100 nM, a novel stable potent competitive DOPA antagonist, antagonized dose-dependently increases in glutamate release by ischemia without modification of dopamine release. DOPA CHE at 100 nM protected striatal neurons from delayed cell death. Hippocampal neuronal cell death was neither affected by NSD-1015 nor by DOPA CHE. Endogenously released DOPA itself seems to act on its recognition site and to be a causal factor for increase in glutamate release and resultant delayed neuronal cell death by transient ischemia in rats.

Animals↗
PubMed1997

L-DOPA neurotoxicity is mediated by glutamate release in cultured rat striatal neurons.

The exposure of cultured rat striatal neurons to L-DOPA caused marked cell death. The L-DOPA cytotoxicity was inhibited by the addition of Mg2+ to and by the removal of Ca2+ from the culture medium, and also by the application of tetrodotoxin. Moreover, prolonged application of L-DOPA increased the glutamate content in the culture medium. These results indicate that L-DOPA produces neurotoxicity by facilitating glutamate release.

Animals↗
PubMed1997

A novel action of collapsin: collapsin-1 increases antero- and retrograde axoplasmic transport independently of growth cone collapse.

Chick collapsin-1, a member of the semaphorin family, has been implicated in axonal pathfinding as a repulsive guidance cue. Collapsin-1 induces growth cone collapse via a pathway which may include CRMP-62 and heterotrimeric G proteins. CRMP-62 protein is related to UNC-33, a nematode neuronal protein required for appropriately directed axonal extension. Mutations in unc-33 affect neural microtubules, the basic cytoskeletal elements for axoplasmic transport. Using computer-assisted video-enhanced differential interference contrast microscopy, we now demonstrate that collapsin-1 potently promotes axoplasmic transport. Collapsin-1 doubles the number of antero- and retrograde-transported organelles but not their velocity. Collapsin-1 decreases the number of stationary organelles, suggesting that the fraction of time during which a particle is moving is increased. Collapsin-1-stimulated transport occurs by a mechanism distinct from that causing growth cone collapse. Pertussis toxin (PTX) but not its B oligomer blocks collapsin-induced growth cone collapse. The holotoxin does not affect collapsin-stimulated axoplasmic transport. Mastoparan and a myelin protein NI-35 induce PTX-sensitive growth cone collapse but do not stimulate axoplasmic transport. These results provide evidence that collapsin has a unique property to activate axonal vesicular transport systems. There are at least two distinct pathways through which collapsin exerts its actions in developing neurons.

Animals↗
PubMed1997

An L-DOPA-like depressor action of L-threo-dihydroxyphenyl-serine in the rat caudal ventrolateral medulla.

We have proposed that L-3,4-dihydroxyphenylalanine (L-DOPA) is a neurotransmitter and/or neuromodulator in the central nervous system (1). In this study, we investigated whether or not L-threo-dihydroxyphenylserine (L-threo-DOPS), a synthetic amino acid structurally related to L-DOPA, microinjected into the caudal ventrolateral medulla (CVLM) and the rostral ventrolateral medulla (RVLM) shows cardiovascular actions similar to those of L-DOPA in anesthetized rats. When L-threo-DOPS was microinjected into CVLM, it produced dose-dependent (0.01-3 ng) depressor and bradycardic responses. D-threo-DOPS (3 ng) produced no effect. The responses to L-threo-DOPS (1 ng) were almost completely blocked by L-DOPA methyl ester (1 microg), a competitive antagonist for L-DOPA, supporting the existence of an L-threo-DOPS-sensitive recognition site for L-DOPA in CVLM. Microinjection of L-threo-DOPS into RVLM, however, showed no effect (0.001-100 ng), which contrasted with the cardiopressor action of L-DOPA applied in RVLM. In RVLM, there may exist an L-threo-DOPS-insensitive recognition site for L-DOPA.

Animals↗
PubMed1997

[Studies on novel, stable and potent competitive antagonists against L-DOPA].

DOPA has been proposed to be a neurotransmitter of the primary baroreceptor afferents terminating in the NTS and a neuromodulator in striata of rats. Pre- and post-synaptic recognition sites for DOPA itself may exist. DOPA methyl ester (DOPA ester), a potent competitive antagonist for DOPA in continuously superfused slices or within a several min when microinjected in the NTS has some limitation in in vivo use because of its unstableness as a prodrug for DOPA. We have explored to find stable and potent antagonists for DOPA. At first, we tried to clarify whether or not newly synthesized DOPA esters with bulky structure such as DOPA cyclohexyl ester (CHE), DOPA cyclopentyl ester (CPE) and DOPA cyclopentyldimethyl ester (CPDME) antagonize depressor responses to DOPA microinjected into the NTS, and to what degree these analogues 1 microM perfused via probes are converted to DOPA during striatal microdialysis in urethane-anesthetized rats. Then, we analyzed mode of antagonism of some candidate in the NTS system. During striatal microdialysis, DOPA ester 1 microM increased extracellular levels of DOPA to an 100 fold higher level at a peak of the 1st 20 min sample after the perfusion. Conversion ratio of CHE, CPE and CPDME, compared to DOPA ester, was less than 1/5 at the peak of the 3rd sample, 1/3.3 at the peak of the 2nd, and 1/2.7 at the peak of the 3rd, respectively. In the NTS, all analogues 1 microgram microinjected abolished depressor responses to DOPA 60 ng. Time required to recover a base was 20 min for CHE and 10 min for DOPA ester, CPE and CPDME. At 100 ng, CHE inhibited peak depressor responses to DOPA 60 ng by 53%, CPE by 40%, and CPDME by 24%, compared to DOPA ester by 22%. Then, DOPA 10-300 ng microinjected produced dose-dependent hypotension. DOPA ester 300 ng, microinjected 1 min previously, shifted a dose-response curve for DOPA 30-300 ng to the right without reduction of the maximum response, showing a competitive mode of antagonism. CHE 30 ng competitively antagonized depressor responses to DOPA 18-300 ng without reduction of the maximum response. CHE 100 ng further shifted the dose-response curve for DOPA 18-100 ng to the right with 25% reduction of the maximum response. Antagonistic activity of CHE 100 ng was equipotent with DOPA ester 300 ng. CHE is a competitive antagonist including partially some noncompetitive components. A possible component might be related to NMDA receptors, since high concentrations of CHE displaced selective binding of [3H]-MK-801, an antagonist. In conclusion, CHE is suitable for the purpose.

Animals↗
PubMed1997

L-DOPA cyclohexyl ester is a novel stable and potent competitive antagonist against L-DOPA, as compared to L-DOPA methyl ester.

We explore stable potent competitive antagonists against L-DOPA. In anesthetized rats, DOPA cyclohexyl ester (DOPA CHE) (30-100 ng) microinjected in depressor sites of the nucleus tractus solitarii dose-dependently shifted the dose-response-curve for L-DOPA (18-300 ng) to the right, with DOPA CHE (100 ng)-induced slight reduction of the maximum response. DOPA methyl ester (DOPA ME) at 100 ng also produced competitive antagonism. Antagonistic activity of DOPA CHE (100 ng) was similar to that of DOPA ME (300 ng). DOPA CHE is suitable for the purpose of screening.

Animals↗
PubMed1996

Differential neurotoxicity induced by L-DOPA and dopamine in cultured striatal neurons.

The neurotoxicity of L-DOPA and dopamine (DA) on striatal neurons was examined by using primary cultures of rat striatum. Exposure to L-DOPA and DA at concentrations of 30-300 microM induced dose-dependent cell death in both younger cultures (3 days in culture, 3 DIC) and elder cultures (10 days in culture, 10 DIC). The cytotoxicity of L-DOPA and DA was also dependent on the exposure time (6-24 h). Ascorbic acid (200 microM) inhibited both L-DOPA- and DA-induced cytotoxicity in 3 DIC cultures, whereas it provided significant protection against DA- but not L-DOPA-induced cytotoxicity in 10 DIC cultures. The L-DOPA cytotoxicity in 10 DIC cultures was prevented by a non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and by an NMDA receptor antagonist, MK-801. Neither antagonist prevented DA cytotoxicity. D-DOPA did not affect the viability of 10 DIC cultures, though it elicited marked toxicity in 3 DIC cultures. These results suggest that there are two components in the mechanisms that mediate the L-DOPA neurotoxicity on striatal neurons: one is autoxidation-relevant and the other is autoxidation-irrelevant. With respect to the latter, glutamate receptor stimulation may be involved. In contrast, autoxidation plays an important role in DA neurotoxicity.

Animals↗
PubMed1996

Ventral tegmental injection of nicotine induces locomotor activity and L-DOPA release from nucleus accumbens.

Effects of nicotine systemically or locally on locomotor activity and L-3,4-dihydroxyphenylalanine (L-DOPA) release were studied using microdialysis in the nucleus accumbens of freely moving rats. The basal L-DOPA release was Ca2(+)-dependent and tetrodotoxin-sensitive. Systemic nicotine (1 mg/kg s.c.) increased locomotor activity and L-DOPA release preferentially in the nucleus accumbens as compared with the striatum. Injection of nicotine (30 micrograms) into the ventral tegmental area increased locomotor activity and L-DOPA release from the nucleus accumbens. These increases were antagonized by prior injection of mecamylamine into the ventral tegmental area. Nicotine induces locomotor activity and L-DOPA release from the nucleus accumbens via nicotinic receptors in the ventral tegmental area. The release may be relevant to behavioral actions of nicotine.

Animals↗
PubMed1996

Depressor action of L-threo-dihydroxyphenylserine in the rat nucleus tractus solitarii.

Microinjections of L-threo-dihydroxyphenylserine (L-threo-DOPS, 0.1-3 ng), a synthetic precursor amino acid of noradrenaline, into the medial area of the nucleus tractus solitarii produced dose-dependent depressor and bradycardic responses in anesthetized rats treated with or without i.p. 3-hydroxybenzylhydrazine, a central inhibitor of L-aromatic amino acid decarboxylase. D-threo-DOPS (3 ng) produced no effect. L-Dihydroxyphenylalanine (L-DOPA) methyl ester (1 microgram), a competitive antagonist of L-DOPA, microinjected into the nucleus tractus solitarii, blocked the depressor and bradycardic responses to L-threo-DOPS itself produces vasodepressor actions without its conversion to noradrenaline, probably via a recognition site for L-DOPA in the rat nucleus tractus solitarii.

Animals↗