The role of nitric oxide on glutaminergic modulation of dopaminergic activation (original) (raw)
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Nitric Oxide-Induced Blockade of NMDA Receptors
Neuron, 2013
Westudied theeffectsof nitricoxide(NO)groducingagents on N-methyl+-aspartate (NMDA) receptor activation in cultured neurons. 3-Morpholino-sydnonimine (SIN-l) blocked both NMDA-induced currents and the associated increase in intracellular Ca*+. The actions of SIN-l were reversible and suppressed by hemoglobin. A degraded SIN-1 solution that did not release NO was unable to block NMDA receptors. This showed that the SIN-1 effects were due to NO and not to another breakdown product. Similar results were obtained with l-nitrosopyrrolidine(an NO-containingdrug) and with NO released from NaN02. Pretreatment with he moglobin potentiated NMDA-induced effects, demonstrating that endogenous NO modulates NMDA receptors. Since NMDA receptor activation induces NO synthesis, these re sults suggest a feedback inhibition of NMDA receptors by NO under physiological condition.
N-Metfayl-D-aspartate increases the excitability of nigrostriatal dopamine terminals
European Journal of Pharmacology, 1991
The terminal excitability of nigrostriatal dopamine cells was measured before and after i.v. administration of N-methyl-Daspartate (NMDA, 1 or 4 mg/kg), the competitive NMDA antagonist AR-7 (2-amino-7-phosphonoheptanoic acid) (4 mg/kg) or saline. NMDA produced a dose-dependent increase in terminal excitability, in the absence of an effect on the somal membrane, whereas AR-7 and saline were without effect. These data provide convergent in vivo evidence that glutamate can enhance striatai dopamine release via the NMDA receptor.
Nitric oxide synthase inhibition blocks amphetamine-induced locomotor activity in mice
Drug and Alcohol Dependence, 1999
Effects of N G-nitroarginine methyl ester (L-NAME), a nonspecific inhibitor of nitric oxide (NO) synthase, on amphetamine-induced locomotor activity were investigated in Swiss-Webster mice. Locomotor activity was measured for 30 min immediately following amphetamine (1, 2 and 4 mg/kg, i.p.) or saline treatments. L-NAME (15 and 30 mg/kg) and a combination of L-arginine (1000 mg/kg) and L-NAME (30 mg/kg) were injected 30 min before amphetamine (2 mg/kg) to other groups of the mice. L-Arginine was injected 30 min before L-NAME treatment when they were combined. L-NAME (30 mg/kg) and L-arginine (1000 mg/kg) were also tested for ability to depress or stimulate locomotor activity in the absence of amphetamine. Amphetamine caused a dose-dependent increase in locomotor activity of the mice. L-NAME blocked the amphetamine-induced locomotor stimulation dose dependently. L-Arginine pretreatment prevented the inhibitory effects of L-NAME on amphetamine-induced locomotor stimulation. L-NAME and L-arginine did not cause any significant change in locomotor activity in mice not treated with amphetamine. These results suggest that amphetamine-induced locomotor stimulation in mice is modulated by NO.
Neuroscience, 1987
Abstrac-This study examines the proposal that striatonigral pathways support circling mediated by dopamine D, receptors, but not D, receptors, in unilaterally dhydroxydopamine-treated rats. In this model the D,/D* agonist apomorphine, the D, agonist 2,3,4,5-tetrahydro-7,8_dihydroxy-1-phenyl-lH-3-benzazepine hydrochloride and the D, agonists N-n-propyl-N-phenylethyl-P-(3-hydroxyphenyl) ethylamine hydrochloride, truns-( -)-4aR, 4,4a,5,6,7,8,8a,9-octahydro-5-propyl-lH-pyrazolo-(3,4-g) quinolino monohydrochloride and lisuride evoked a characteristic spectrum of motor responses when administered systemically. In addition apomorphine, 2,3,4,5-tetrahydro-7,8-dihydroxy-l-phenyl-lH-3-benzazepine hydrochloride and lisuride replicated their systemic effects following stereotaxic injection into the supersensitive caudate nucleus. Three months after injecting the pars reticulata of the dopamine-denervated nigra with kainic acid (1 pg in 1 PI), all motor responses to intracaudate dopamine agonists were reduced or abolished. Systemic responses were modified differentially, often as early as one day post-kainate. Contraversive circling and posturing were reduced, or even reversed (apomorphine only), grooming was attenuated (all drugs) and 2,3,4,5-tetrahydro-7,8-dihydroxy-l-phenyl-lH-3-benzazepine hydrochlorideinduced forepaw nibbling and dyskinesia were abolished. By contrast, sniffing, movements of the head and locomotion were either unaffected, or significantly potentiated, suggesting these components of behaviour arose from dopamine receptors outside the denervated striatum. These behavioural changes showed no signs of recovery three months after kainate, and were not produced by partial lesions of the reticulata (1 pg kainate in 0.2~1).
Nitric oxide involvement in regulating the dopamine transport in the striatal region of rat brain
Neurochemistry International, 1997
dopamine ([3H]DA) overflow was measured from striatal slices in the presence of different glutamate (Glu) receptor agonists such as N-methyl-D-aspartate (NMDA), kainate (KA) and quisqualate (QA) and their corresponding antagonists, Dizocilpine maleate (MK-801), D-7-glutamylaminomethanesulfonic acid (GAMS) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), respectively. [3H]DA uptake and release in the presence of L-Arginine (L-Arg) and N6-nitro-arginine (L-N-Arg), an inhibitor of nitric oxide (NO) synthesis were also evaluated. L-N-Arg alone or combined with L-Arg significantly reduced [3H]DA uptake at 10 and 100#M from 33% to 44% from striatal slices. Whereas, in brain synaptosomal fractions L-Arg induced a biphasic effect on that [3H]DA uptake in a dose dependent manner, and L-N-Arg showed an absolute inhibition in 80°90% of this [3H]DA uptake at 1-500 #M. The amino acids, lysine, valine and histidine (100#M) had a little effect inhibitory on [3H]DA uptake from synaptosomal fractions. Glu agonists, NMDA (10/~M) and KA (10 #M) importantly increased the spontaneous [3H]DA overflow, which was blocked by MK-801 (10 #M) and GAMS (10/~M), respectively. QA had no effect on [3H]DA release. L-Arg (100200#M) potentiated the spontaneous [3H]DA overflow in a dose dependent fashion from striatal slices, being reverted by 10/~M L-N-Arg alone or in combination with all other compounds; whereas, lysine, histidine and valine did not modify that spontaneous [3H]DA overflow. Results support the hypothesis related to the participation of NO on DA transport possibly synthesized at the dopaminergic (DAergic) terminals in the striatum; also that L-Arg concentration may determine alternative mechanisms to regulate the DAergic activity at the striatum. © 1997 Elsevier Science Ltd
Role of nigral dopamine in amphetamine-induced locomotor activity
Brain Research, 1983
Dopamine ( 11)0 ug) injected into the substantia nigra pars reticulata of rats pretreatcd with the monoamine oxidase inhibitor, pargyline, resulted in a stimulation of locomotor activity. Bilateral injection of the dopamine antagonist haloperidol (5 ug) into the substantia nigra pars rcticulata resulted in a reduction of the locomotor activity evoked by a low dose of amphetamine ( 1.25 mg/kg s.c.). These results suggest that the release of dopamine from nigral dendrites is involved in amphetamine-induced locomotor activity.
Impact of dopamineglutamate interactions on striatal neuronal nitric oxide synthase activity
Psychopharmacology, 2010
RationaleIt is known that dopamine (DA) D1 receptor activation stimulates striatal nitric oxide (NO) synthesis, whereas D2 receptor activation produces the opposite effect. However, the mechanisms involved in the dopaminergic modulation of NO synthase (NOS) are unknown.ObjectivesWe hypothesized that the effects of DA on striatal NO signaling are dependent on ongoing glutamatergic activation of NOS. Therefore, the current study examined whether intact NMDA receptor activation is required for the dopaminergic modulation of NOS activity.MethodsWe assessed the impact of pharmacological manipulations of D1, D2 and NMDA receptors on NOS activity in the dorsal striatum and motor cortex using nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry. Drugs were administered systemically to conscious animals and NADPH-d staining was quantified in these regions using ex vivo measurements of tissue optical density.ResultsAdministration of the neuronal NOS inhibitor NG-propyl-L-arginine (NPA), the D1 receptor antagonist SCH 23390, and the NMDA receptor antagonist 3-phosphonopropyl-piperazine-2-carboxylic acid (CPP) all attenuated staining selectively in the striatum. Administration of the D2 receptor agonist quinpirole decreased NADPH-d staining in both the striatum and cortex. Striatal NADPH-d staining elicited by administration of the D1 receptor agonist SKF 81297 or the D2 receptor antagonist eticlopride was attenuated by NPA, SCH 23390, and CPP pretreatment. Quinpirole pretreatment also abolished the facilitatory effect of SKF 81297.ConclusionsThese studies show for the first time that ongoing NMDA receptor activation is necessary for modulation of striatal NOS activity by both facilitatory (D1 receptor activation) and inhibitory (D2 receptor activation) dopaminergic signaling mechanisms.
D1-like dopamine receptor activation and natriuresis by nitrocatechol COMT inhibitors
Kidney International, 2001
D 1-like dopamine receptor activation and natriuresis by nitroproximal tubule, the overall increase in sodium excretion catechol COMT inhibitors. produced by dopamine and D 1-like receptor agonists Background. In recent years, several nitrocatechol derivaresults from inhibition of main sodium transport mechatives (tolcapone, entacapone, and nitecapone) have been develnisms at the basolateral and apical membranes, respecoped and found to be highly selective and potent inhibitors of tively, Na ϩ ,K ϩ-ATPase [2, 3] and Na ϩ /H ϩ exchanger [4]. catechol-O-methyltransferase (COMT). More recently, natriuretic properties were described for two of these compounds (en-The proximal tubules, but not distal segments of the tacapone and nitecapone), although this was not accompanied by nephron, are endowed with a high aromatic L-amino enhanced urinary excretion of dopamine. We hypothesized that acid decarboxylase (AADC) activity, and epithelial cells nitrocatechol derivatives stimulate D 1-like dopamine receptors. of proximal tubules have been demonstrated to synthe-Methods. Adult male Wistar rats were treated with a nitrocatsize dopamine from circulating or filtered L-3,4-dihyechol COMT inhibitor (entacapone, tolcapone, or nitecapone, 30 mg/kg, orally), and the urinary excretion of dopamine and droxyphenylalanine (L-DOPA) [3, 5, 6]. One of the most sodium was quantitated. The interaction of nitrocatechol derivimportant factors in determining the synthesis of dopaatives with D 1-like receptors was evaluated by their ability to mine is the amount of sodium delivered to the kidney displace [ 3 H]-Sch23390 binding from membranes of rat renal [3, 5, 6]. However, high levels of enzymes involved in the cortex and cAMP production in opossum kidney (OK) cells. metabolic degradation of renal dopamine, such as types Results. Urinary excretion of sodium (mol/h) was markedly A and B monoamine oxidases (MAO-A and MAO-B) increased by all three nitrocatechol derivatives: vehicle, 55.0 Ϯ 5.6; entacapone, 98.4 Ϯ 9.3; tolcapone, 97.5 Ϯ 9.3; and nitecaand catechol-O-methyltransferase (COMT) [7-10], may pone, 120.5 Ϯ 12.6. Pretreatment with the selective D 1 antagodetermine the overall availability of the amine. nist Sch 23390 (60 g/kg) completely prevented their natri-More recently, the administration of a new class of uretic effects. Nitecapone and tolcapone were equipotent (IC 50s COMT inhibitors (the nitrocatechol derivatives nitecaof 48 and 42 mol/L) and more potent than entacapone and dopone and entacapone) was shown to be accompanied by pamine (IC 50s of 107 and 279 mol/L) in displacing [ 3 H]-Sch23390 binding. In OK cells, all three nitrocatechol derivatives signifimarked natriuresis and a parallel reduction of Na ϩ ,K ϩcantly increased cAMP accumulation and reduced Na ϩ /H ϩ ex-ATPase activity [11-13]. These effects were prevented change and Na ϩ ,K ϩ-ATPase activities, this being prevented by by selective blockade of dopamine D 1 receptors, but were a blockade of D 1-like receptors. not accompanied by parallel increases in the urinary Conclusion. Stimulation of D 1-like dopamine receptors and excretion of dopamine. An increase in the urinary excreinhibition of Na ϩ /H ϩ exchange and Na ϩ ,K ϩ-ATPase activities by nitrocatechol COMT inhibitors may contribute to natri
Role of nitrergic system in behavioral and neurotoxic effects of amphetamine analogs
Pharmacology & Therapeutics, 2006
Several amphetamine analogs are potent psychostimulants and major drugs of abuse. In animal models, the psychomotor and reinforcing effects of amphetamine, methamphetamine (METH), 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy), and methylphenidate (MPD; Ritalin) are thought to be dependent on increased extracellular levels of dopamine (DA) in mesocorticolimbic and mesostriatal pathways. However, amphetamine analogs that increase primarily serotonergic transmission, such as p-chloroamphetamine (PCA) and fenfluramine (FEN), have no potential for abuse. High doses of METH, MDMA, PCA, and FEN produce depletions of dopaminergic and serotonergic nerve terminal markers and are considered as potential neurotoxicants. The first part of this review briefly summarizes the behavioral and neurotoxic effects of amphetamines that have a different spectrum of activity on dopaminergic and serotonergic systems. The second part discusses evidence supporting involvement of the nitrergic system in dopamine-mediated effects of amphetamines. The nitrergic system in this context corresponds to nitric oxide (NO) produced from neuronal nitric oxide synthase (nNOS) that has roles in nonsynaptic interneuronal communication and excitotoxic neuronal injury. Increasing evidence now suggests cross talk between dopamine, glutamate, and NO. Results from our laboratory indicate that dopamine-dependent psychomotor, reinforcing, and neurotoxic effects of amphetamines are diminished by pharmacological blockade of nNOS or deletion of the nNOS gene. These findings, and evidence supporting the role of NO in synaptic plasticity and neurotoxic insults, suggest that NO functions as a neuronal messenger and a neurotoxicant subsequent to exposure to amphetamine-like psychostimulants. D