Nitric oxide synthase inhibition blocks amphetamine-induced locomotor activity in mice (original) (raw)
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Neuropharmacology, 2008
Nitric oxide (NO) is associated with dopamine (DA) release. Previously, we demonstrated that rats treated with a non-selective nitric oxide synthase inhibitor, N-omega-nitro-L-arginine (L-NNA) at postnatal days 4-6 (PD4-6) show increased locomotion and disrupt neuronal cytoarchitecture after puberty (PD60). Here, we investigate whether the modulation of NO production in rats at PD4-6 causes long term changes of NO system, its impact on DA innervation, and schizophrenia-like behaviors. NO levels were measured in seven brain areas at PD35, PD60, PD90, and PD120. Autoradiographic studies explored the effect of L-NNA on the expression of D 1 and D 2 receptors in the caudate-putamen (CPu) and nucleus accumbens (NAcc) at PD60. Locomotor activity was assessed at PD60 using the non-selective DA agonists, amphetamine and apomorphine, and the selective DA receptor agonist [D 2 , quinpirole; D 3 , 7-hydroxy-N,N-di-n-propylaminotetralin ((AE)-7-OH-DPAT)]. L-NNA treatment produced decreases in NO levels in the frontal cortex, striatum, brainstem and cerebellum, while in the occipital cortex changes were observed at PD120. Hippocampus and temporoparietal cortex showed differential levels of NO. Receptor autoradiography revealed increases in D 1 receptor levels in the NAcc (shell), while decreases in D 2 receptor binding were observed in the CPu and NAcc (core). Amphetamine and quinpirole treatments resulted in increases in locomotion. In contrast, treatment with 7-OH-DPAT produced hypolocomotion at low doses, while increased locomotion was seen at the highest dose. These results show that modulation of NO levels early postnatally (PD4-6) produces long term alteration in NO levels, with possible consequences on DA transmission, and related behaviors relevant to schizophrenia.
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.
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
Nitric oxide synthase inhibitors cause motor deficits in mice
European Neuropsychopharmacology, 2001
We investigated possible motor effects of 7-nitroindazole (7-NI), an neuronal nitric oxide synthase (nNOS) inhibitor, and N -nitro-Larginine methyl ester (L-NAME), an non-selective NOS inhibitor in mice using catalepsy and pole tests in comparison with dopamine D 2 receptor antagonist, haloperidol. We also studied the change in dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) contents of these compounds. The administration of 7-NI and L-NAME (40-160 mg / kg, s.c.) dose-dependently induced motor deficit in both catalepsy and pole tests. The motor deficit induced by 7-NI was more pronounced than the one produced by L-NAME. In contrast, haloperidol showed a marked motor deficit in mice. Haloperidol showed a marked motor deficit as compared with 7-NI and L-NAME. For dopamine, DOPAC and HVA contents, haloperidol exhibited a significant decrease in dopamine content and a significant increase in DOPAC and HVA content in the striatum. In contrast, 7-NI showed a significant increase in the striatal dopamine content. However, 7-NI had no significant change in the striatal DOPAC and HVA contents. On the other hand, no significant change in the striatal dopamine, DOPAC and HVA contents was observed in L-NAME-treated mice. The present study also showed that the motor deficit induced by 7-NI or L-NAME was significantly attenuated by the treatment with L-arginine. These results demonstrate that NOS inhibitors as well as dopamine D receptor antagonist haloperidol can induce motor deficit in mice. The present study also suggests that 2 the mechanism in the motor deficit caused by NOS inhibitors may be different from that in the motor deficit induced by haloperidol. Furthermore, our findings suggest that nNOS may play some role in control of motor behavior.
Role of Nitric Oxide on Motor Behavior
Cellular and Molecular Neurobiology, 2005
1. The present review paper describes results indicating the influence of nitric oxide (NO) on motor control. Our last studies showed that systemic injections of low doses of inhibitors of NO synthase (NOS), the enzyme responsible for NO formation, induce anxiolytic effects in the elevated plus maze whereas higher doses decrease maze exploration. Also, NOS inhibitors decrease locomotion and rearing in an open field arena. 2. These results may involve motor effects of this compounds, since inhibitors of NOS, NG-nitro-L-arginine (L-NOARG), N G-nitro-L-arginine methylester (L-NAME), N Gmonomethyl-L-arginine (L-NMMA), and 7-Nitroindazole (7-NIO), induced catalepsy in mice. This effect was also found in rats after systemic, intracebroventricular or intrastriatal administration. 3. Acute administration of L-NOARG has an additive cataleptic effect with haloperidol, a dopamine D2 antagonist. The catalepsy is also potentiated by WAY 100135 (5-HT1a receptor antagonist), ketanserin (5HT2a and alfa1 adrenergic receptor antagonist), and ritanserin (5-HT2a and 5HT2c receptor antagonist). Atropine sulfate and biperiden, antimuscarinic drugs, block L-NOARG-induced catalepsy in mice. 4. L-NOARG subchronic administration in mice induces rapid tolerance (3 days) to its cataleptic effects. It also produces cross-tolerance to haloperidol-induced catalepsy. After subchronic L-NOARG treatment there is an increase in the density NADPH-d positive neurons in the dorsal part of nucleus caudate-putamen, nucleus accumbens, and tegmental pedunculupontinus nucleus. In contrast, this treatment decreases NADPH-d neuronal number in the substantia nigra compacta. 5. Considering these results we suggest that (i) NO may modulate motor behavior, probably by interfering with dopaminergic, serotonergic, and cholinergic neurotransmission in the striatum; (ii) Subchronic NO synthesis inhibition induces plastic changes in NOproducing neurons in brain areas related to motor control and causes cross-tolerance to the cataleptic effect of haloperidol, raising the possibility that such treatments could decrease motor side effects associated with antipsychotic medications. 6. Finally, recent studies using experimental Parkinson's disease models suggest an interaction between NO system and neurodegenerative processes in the nigrostriatal pathway. It provides evidence of a protective role of NO. Together, our results indicate that NO may
New and potent inhibitors of nitric oxide synthase reduce motor activity in mice
Behavioural Brain Research, 1997
Potent inhibitors of nitric oxide synthase (NOS), 3-bromo-7-nitro indazole, 1-(2-trifluoromethylphenyl)imidazole, S-methyl-Lthiocitrulline and 7-nitro indazole, reduced locomotion in mice. These results suggest that activity of NOS and corresponding NO release are of importance for normal locomotion. © 1997 Elsevier Science B.V.
Evidence for the role of nitric oxide in caffeine-induced locomotor activity in mice
Psychopharmacology, 2004
Rationale Nitric oxide (NO) is implicated in the acute locomotor activating effects of some addictive drugs such as amphetamine and cocaine, but has not been investigated in the case of caffeine. Objectives We investigated the effects of a nitric oxide synthase (NOS) inhibitor Nω-Nitro-l-arginine methyl ester (l-NAME) and a combination of l-arginine, a NO precursor, and l-NAME on caffeine induced locomotor activity in Swiss Webster mice. Methods Locomotor activity was recorded for 30 min immediately following caffeine (0.25–128 mg/kg) or saline administration. In a further study, l-NAME (15 and 30 mg/kg) was administered to another group of mice 30 min before caffeine (1 and 16 mg/kg) injections. Finally, l-arginine (1000 mg/kg), a nitric oxide precursor, was administered 20 min before the l-NAME (15 and 30 mg/kg) treatments and locomotor activities were again recorded immediately after caffeine (1 and 16 mg/kg) injections. Results Caffeine (0.5–16 mg/kg) significantly increased locomotor activity, while l-NAME (30 mg/kg) blocked caffeine (1 and 16 mg/kg)-induced locomotor activity. The low dose of l-NAME blocked only caffeine (1 mg/kg)-induced locomotor activity. l-Arginine reversed the inhibitory effects of l-NAME on caffeine-induced locomotor activity. l-NAME and l-arginine had no effect on the locomotor activity of the mice when given by themselves. Conclusions The results suggest that caffeine-induced locomotor activity might be modulated by NO in mice.
The role of nitric oxide on glutaminergic modulation of dopaminergic activation
Pharmacological Research, 2005
Biochemical studies have been demonstrated that N-methyl-d-aspartate (NMDA)-evoked dopaminergic (DAergic) activation can be modulated by nitric oxide (NO) systems. Therefore, behavioral study was performed to characterize the role of NO on NMDA modulation of DAergic activation. It is well known that apomorphine induces climbing behaviors in mice by the activation of DAergic receptors. Our previous studies showed that NMDA receptor antagonists reduced apomorphine-induced climbing behaviors. It was reported that nitric oxide synthase (NOS) inhibitors reduced the apomorphine-induced climbing behaviors. In this experiment, NO donor restored the apomorphine-induced climbing behavior, which was inhibited by NMDA receptor antagonist. NOS inhibitor inhibited the apomorphine-induced climbing behavior, which was enhanced by NMDA receptor agonist. These results suggest that DAergic activation is regulated by both NMDA receptors and NO systems, and NO in the down-stream of NMDA receptors play an important role on the glutaminergic NMDA modulation of DAergic function.
Possible role of nitric oxide in the locomotor activity of hypertensive rats
Behavioural Brain Research, 2006
We aimed to analyze whether hypertension and changes in nitric oxide (NO) generation are associated with alterations of locomotor activity in rats. Male Wistar rats treated with an inhibitor of NO synthase, N G-nitro-l-arginine methyl ester (L-NAME, 40 mg/kg/day) for 6 weeks, control Wistar rats, spontaneously hypertensive rats (SHR), and control Wistar Kyoto rats (WKY) aged 18 weeks were investigated. Locomotor activities were tested by the open field method. NO synthase activity (NOS), concentration of cGMP and conjugated dienes (CD) as well as protein expression of nuclear factor NF-B were determined in the cerebral cortex, cerebellum and brainstem. NOS activity in the brain parts investigated was not changed in SHR in comparison with the normotensive WKY. L-NAME treatment resulted in the decreased NOS activity in comparison with Wistar rats. The concentration of CD and expression of NF-B protein, markers of reactive oxygen species, were higher and the concentration of cGMP was lower in hypertensive animals and more pronounced in SHR as well. Thus, the concentration of NO in the brain parts of SHR might be lower than in the L-NAME treated rats. L-NAME treatment increased horizontal (by 28%) and vertical (by 80%) motor activity. Similarly, in SHR both locomotor activities were increased by 105% and 148%, respectively, in comparison with WKY. In conclusion, decreased level of NO was associated with increased locomotor activity indicating that in addition to genetic differences which may determine changes in locomotor activity in hypertensive rats, the role of a signalling pathway mediated by NO may be supposed.
Catalepsy induced by intra-striatal administration of nitric oxide synthase inhibitors in rats
European Journal of Pharmacology, 2004
Systemic administration of nitric oxide synthase (NOS) inhibitors induces catalepsy in a dose-dependent manner in male Albino-Swiss mice. The objective of the present work was to investigate if similar effects occur in rats and if these effects are centrally mediated. The results showed that systemic administration of N G-nitro-L-arginine (L-NOARG, 40-160 mg/kg, i.p.), a non-selective NOS inhibitor, induced catalepsy in rats. Similar effects were found after intracerebroventricular (i.c.v.) injection of L-NOARG (50-200 nmol) or N Gnitro-L-arginine methylester (L-NAME, 100-200 nmol). The dose-response curve of the former compound, however, had an inverted U shape. The effect of L-NOARG (100 nmol, i.c.v.) was completely prevented by pre-treatment with L-arginine (300 nmol, i.c.v.) but not by D-arginine (300 nmol, i.c.v.). Intra-striatal injection of N G-monomethyl-L-arginine (L-NMMA, 100 nmol), 7-nitroindazole (7-NIO, 100 nmol), L-NOARG (25-100 nmol) or L-NAME (50-200 nmol) also induced catalepsy. Similar to i.c.v. administration, the latter two compounds produced bell-shaped dose-response curves. The cataleptic effect of intra-striatal administration of L-NAME (100 nmol) was reversed by local treatment with L-arginine (100 nmol). These results suggest that interference with the striatal formation of nitric oxide may induce significant motor effects in rats.