Is L-DOPA a neurotransmitter of the primary baroreceptor afferents terminating in the nucleus tractus solitarii of rats?
Explore the source record for details and available documents.
Afferent Pathways↗
Biomedical subjects
Y Misu
Publications and source records attributed to Y Misu.
[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↗
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↗
Aripiprazole, a novel antipsychotic drug, inhibits quinpirole-evoked GTPase activity but does not up-regulate dopamine D2 receptor following repeated treatment in the rat striatum.
Aripiprazole, a quinolinone derivative, is a new dopaminergic agent which has been recently developed and demonstrated to be clinically useful as an antipsychotic drug with reduced extrapyramidal motor side effects. Here, we found that aripiprazole competed [3H]spiperone binding with a 100-fold higher affinity than [3H]SCH23390 binding, and inhibited the quinpirole-induced facilitation of high-affinity GTPase activity in rat striatal membranes. The effects of chronic administration of aripiprazole and haloperidol on dopamine D2 receptor binding and mRNA level in rat striata were examined by a [3H]spiperone binding assay and a ribonuclease protection assay. Haloperidol induced a significant rise in Bmax of [3H]spiperone binding at 1 mg/kg and in the level of dopamine D2L receptor mRNA at 4 mg/kg. A high dose of aripiprazole (100 mg/kg) only tended to increase the Bmax of [3H]spiperone binding non-significantly, and had no effect on the level of dopamine D2L receptor mRNA. These results indicated that aripiprazole had an antagonistic activity to dopamine D2 receptors with a high affinity, but that the potency of aripiprazole to up-regulate dopamine D2 receptors in the striatum was much smaller than that of haloperidol. This small up-regulation may be related to the ability to aripiprazole to act without side effects including tardive dyskinesia.
Animals↗
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↗
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↗
[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↗
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↗
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↗
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↗
L-DOPA induces concentration-dependent facilitation and inhibition of presynaptic acetylcholine release in the guinea-pig submucous plexus.
Neurotransmitter- or neuromodulator-like actions of L-DOPA were investigated with intracellular recordings from submucous plexus neurons of the guinea-pig caecum. L-DOPA at 30 nM augmented the amplitude of fast EPSPs, but did not affect depolarizations elicited by puff application of acetylcholine (ACh). The augmenting effect of L-DOPA on the fast EPSPs was counteracted by L-DOPA methyl ester. The fast EPSPs were depressed by 10 microM L-DOPA, but transiently augmented after rinsing the drug. L-DOPA methyl ester did not affect the inhibitory action of L-DOPA on the fast EPSPs, but antagonized the potentiation following the inhibition. The depolarization elicited by exogenously applied ACh was inhibited by 10 microM L-DOPA. Intracellular Ca2+ concentrations ([Ca2+]i) of the neuronal soma were measured with fura-2 microfluorophotometry. The transient increase in the [Ca2+]i evoked by the somatic action potential (delta[Ca2+]AP) was facilitated by 30 nM L-DOPA, but decreased by the drug at 10 microM. It is concluded that L-DOPA at low concentrations enhances the delta[Ca2+]AP, increasing the neurotransmitter release, but at high dose diminishes the delta[Ca2+]AP, inhibiting the neurotransmission.
Acetylcholine↗
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↗
Neurobiology of L-DOPAergic systems.
L-DOPA is proposed to be a neurotransmitter and/or neuromodulator in CNS. It is released probably from neurons, which may contain L-DOPA as an end-product, and/or from some compartment other than catecholamine-containing vesicles. The L-DOPA itself produces presynaptic and postsynaptic responses. All are stereoselective and most are antagonized by competitive antagonist. In striatum, L-DOPA is neuromodulator, mother of catecholamines, not only a precursor for dopamine but also a potentiator of children for presynaptic beta-adrenoceptors to facilitate dopamine release and postsynaptic D2 receptors, and ACh release inhibitor. All may cooperate for Parkinson's disease. Meanwhile, supersensitization of increase in L-glutamate release to nanomolar levodopa was seen in Parkinson's model rats, which may relate to dyskinesia or "on-off" during chronic therapy. In lower brainstem, L-DOPA tonically activates postsynaptic depressor sites of NTS and CVLM and pressor sites of RVLM. L-DOPA is probably a neurotransmitter of primary baroreceptor afferents terminating in NTS. GABA, the inhibitory neuromodulator for baroreflex in NTS, tonically functions to inhibit, via GABAA receptors, L-DOPA release and depressor responses to levodopa. Levodopa inversely releases GABA. L-DOPAergic monosynaptic relay from NTS to CVLM and from PHN to RVLM is suggested. Tonic L-DOPAergic baroreceptor-aortic nerve-NTS-CVLM relay seems to carry baroreflex information. Disturbance of neuronal activity to release L-DOPA in NTS, loss of the activity in CVLM, enhancement of the activity with decreased decarboxylation and increase in sensitivity to levodopa in RVLM may be involved in maintenance of hypertension in SHR. This is a story of "L-DOPAergic receptors" with extremely high affinity and low density.
Afferent Pathways↗
[Pulmonary tuberculosis manifesting predominantly as ileus secondary to peritoneal tuberculosis in a young man].
A 27-year-old man was admitted to our hospital because of abdominal pain and vomiting. A radiograph of the chest revealed widening of the right superior part of the mediastinum, and an abdominal radiograph showed many air-fluid levels. A computed tomographic scan of the chest revealed a solitary nodule in the right anterior lobe of the lung, and right paratracheal lymphadenopathy. Ileus was diagnosed and a nasogastric tube was inserted. The patient's condition gradually worsened, and on hospital day 17 a laparotomy was performed. Operative findings were significant for numerous, white nodules all over the peritoneum, omentum, and mesentery, which ranged from miliary to rice grain-sized. Examination of an omental specimen revealed noncaseating granulomas with Lang hans' giant cells. The polymerase chain reaction was used to examine fluid from the nasogastric tube used before surgery, and on hospital day 40 that fluid was found to be positive for Mycobacterium tuberculosis. M. tuberculosis was also cultured from the fluid. From these findings, we concluded that this was a case of pulmonary tuberculosis manifesting predominantly as ileus secondary to tuberculous peritonitis. Anti-tuberculosis therapy consisting of isoniazid, rifampin, and ethambutol was started postoperatively. On repeat laparoscopy 224 days later, no white nodules were seen. A computed tomographic scan of the chest revealed that the right paratracheal lymphadenopathy was markedly reduced, and the solitary nodule in the right anterior lobe of the lung was almost gone. Few cases of young people with pulmonary tuberculosis manifesting primarily as ileus have been reported. Tuberculosis should be included in the differential diagnosis in patients presenting with ileus.
Adult↗
Evidence for a metabostatic opioid kappa-receptor inhibiting pertussis toxin-sensitive metabotropic glutamate receptor-currents in Xenopus oocytes.
Glutamate evoked pertussis toxin-sensitive currents in Xenopus oocytes expressing metabotropic glutamate receptor subtype 1 (mGluR1) and exogenous Gi1 alpha. The mGluR1-currents were completely blocked by U-73122, a phospholipase C (PLC) inhibitor and by niflumic acid, a chloride channel blocker. In the oocyte further coinjected with poly(A)+ RNA from the guinea pig cerebellum, the mGluR1-currents were inhibited by U-50488H, an opioid kappa-agonist, and this inhibition was blocked by norbinaltorphimine, an opioid kappa-antagonist. These findings suggest that the mRNA encoding a novel subtype of opioid kappa-receptor which inhibits Gi1-PLC-mediated currents is present in guinea pig cerebellar poly(A)+ fractions.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
L-DOPA inhibits spontaneous acetylcholine release from the striatum of experimental Parkinson's model rats.
Acetylcholine (ACh) release was measured by microdialysis. Addition of 10 nM L-DOPA to the perfusate significantly decreased ACh release, from the striatum of rats lesioned with 6-hydroxydopamine (6-OHDA), but not sham-operated rats. The L-DOPA-induced decrease was not affected by (-)-sulpiride which completely blocked D2- and D3-agonist-induced decrease in ACh release in lesioned rats. Neither 10 nM D-DOPA nor 100 nM dopamine caused by any change in ACh release. These findings suggest that L-DOPA-sensitive mechanisms are supersensitized in Parkinson's disease model rats.
Acetylcholine↗
Loss of tonic neuronal activity to release L-DOPA in the caudal ventrolateral medulla of spontaneously hypertensive rats.
Experiments were designed to clarify whether a tonic L-DOPA system is altered in the caudal ventrolateral medulla (CVLM) of adult spontaneously hypertensive rats (SHR), compared to age-matched Wistar-Kyoto rats (WKY). By microdialysis in CVLM, basal L-DOPA release was constantly detectable and was lower in SHR than that in WKY. This release was reduced by tetrodotoxin perfusion (1 microM) in WKY to a basal level in SHR, whereas no modification occurred with tetrodotoxin in SHR. No difference of tyrosine hydroxylase and DOPA decarboxylase activities in the CVLM region was seen between the two strains. By microinjections into depressor sites of CVLM, L-DOPA (10-300 ng) or L-glutamate (3-300 ng) elicited dose-dependent depressor and bradycardic responses and greater depressor responses to both amino acids were seen at high doses in SHR, compared to WKY. Tonic neuronal activity to release L-DOPA is lost in the CVLM of adult SHR and this loss may contribute to maintenance of hypertension in SHR.
Animals↗
L-DOPA systems for blood pressure regulation in the lower brainstem.
We have explored probable neurotransmitter roles of L-3,4-dihydroxyphenylalanine (L-DOPA) in baroreceptor reflex and blood pressure regulation in depressor sites of the nucleus tractus solitarii (NTS) and the caudal ventrolateral medulla (CVLM), and in pressor sites of the rostral ventrolateral medulla (RVLM) in anesthetized rats. During microdialysis of these three areas, the basal L-DOPA release is in part tetrodotoxin (TTX)-sensitive and Ca2(+)-dependent, high K+ Ca2(+)-dependently releases dL-DOPA. L-DOPA microinjected (10-300 ng) dose-dependently produces postsynaptic depressor responses in the NTS and CVLM and pressor responses in the RVLM, and a recognition site for L-DOPA functions tonically to activate depressor neurons in the NTS and CVLM and pressor neurons in the RVLM. It is highly probable that L-DOPA is a neurotransmitter of the baroreceptor afferents terminating in the NTS, which is based on further findings such as (1) antagonism by a competitive L-DOPA antagonist against depressor responses to aortic nerve stimulation, (2) TTX-sensitive L-DOPA release by aortic nerve stimulation, (3) abolition of baroreceptor-stimulated L-DOPA release by bilateral sino-aortic denervation and (4) decreases in tyrosine hydroxylase (TH)- and L-DOPA-immunoreactivities without modifications of dopamine- and DBH-immunoreactivities in the left NTS and ganglion nodosum 7 days after ipsilateral aortic nerve denervation peripheral to the ganglion. In the NTS, GABA tonically functions to inhibit via GABAA receptors L-DOPA release and depressor responses to L-DOPA, whereas L-DOPA induces GABA release. Impaired TTX-sensitive neuronal activity to release L-DOPA in the NTS and enhanced TTX-sensitive neuronal activity including a decrease in decarboxylation of L-DOPA to dopamine and an increase in sensitivity of the recognition site to L-DOPA in the RVLM are relevant to the maintenance of hypertension in spontaneously hypertensive rats. Decreases in the contents of L-DOPA in the right CVLM 10 days after electrical lesion of the ipsilateral NTS suggest a 'L-DOPAergic' and monosynaptic relay from the NTS to the CVLM. L-DOPA seems to play major roles as a neurotransmitter for baroreceptor reflex and blood pressure regulation in the lower brainstem of rats.
Animals↗