Serotonergic mediation of the antidepressant-like effects of nitric oxide synthase inhibitors

Harkin, Andrew; Connor, Thomas J.; Walsh, Martin P.; John, Nejimol; Kelly, John

doi:10.1016/s0028-3908(03)00030-3

Cited by 139 publications

(105 citation statements)

References 28 publications

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“…The behavioural profile of NOS inhibitors in the adapted FST for rats parallels that obtained with the SSRI, fluoxetine. Moreover, depletion of endogenous 5-HT blocks the antidepressant-like activity associated with NOS inhibitors in the test (Harkin et al, 2003). From these observations it was proposed that NOS inhibitors may elicit their antidepressant-like activity in the FST through a 5-HT dependent mechanism.…”

Section: Accepted M Manuscriptmentioning

confidence: 98%

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A role for serotonin in the antidepressant activity of NG-Nitro-L-arginine, in the rat forced swimming test

Gigliucci

Buckley

Nunan

et al. 2010

Pharmacology Biochemistry and Behavior

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Section: Accepted M Manuscriptmentioning

confidence: 98%

“…Previously we reported that the NOS inhibitors, N G -nitro-L-arginine (L-NA) and 7-nitroindazole (7-NI), dose dependently reduce immobility and increase swimming behaviour in the rat and mouse forced swimming test (FST), a test predictive of antidepressant activity (Harkin et al, 1999(Harkin et al, , 2003.…”

Section: Introductionmentioning

confidence: 99%

A role for serotonin in the antidepressant activity of NG-Nitro-L-arginine, in the rat forced swimming test

Gigliucci

Buckley

Nunan

et al. 2010

Pharmacology Biochemistry and Behavior

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“…As NMDA-R antagonists possess antidepressant properties, targets downstream of the receptor, such as nNOS may represent targets for antidepressant activity. In this regard, L-arginine-derived inhibitors of NOS, produce antidepressant activity in the forced swimming test (FST), a preclinical behavioural screening procedure sensitive to antidepressant activity (Gigliucci et al, 2010;Harkin et al, 2003;Harkin et al, 1999;Dhir and Kulkarni, 2011;Wegener and Volke, 2010). Genetic deletion of nNOS or treatment with NOS inhibitors (7-nitroindazole (7-NI) or 1-(2-trifluoro-methyl-phenyl) imidazole (TRIM)) prevents chronic mild stressor (CMS)-induced depression-related behavioural and cellular changes in mice, further confirming the antidepressant potential of NOS inhibition Zhou et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Despite the additional selectivity of these two drugs for nNOS (Alderton et al, 2001;Moore and Handy, 1997), selectivity is not exclusive. NOS inhibitors that are more selective for the neuronal isoform are not devoid of adverse effects and may decrease locomotion and/or motor coordination (Dzoljic et al, 1997;Harkin et al, 2003;Mutlu et al, 2011;Ulak et al, 2010;Volke et al, 2003). Moreover 7-NI seems to have a less favourable side-effect profile than TRIM in several paradigms that investigated learning and memory (Holscher et al, 1996;Mutlu et al, 2011;Yildiz Akar et al, 2009;Yildiz Akar et al, 2007;Zou et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule Inhibitors at the PSD-95/nNOS Interface have Antidepressant-Like Properties in Mice

Doucet

Levine

Dev

et al. 2013

Neuropsychopharmacol

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Previous studies have demonstrated that nitric oxide (NO) synthase inhibitors are as efficacious as tricyclic antidepressants in preclinical antidepressant screening procedures and in attenuating behavioural deficits associated with animal models of depression. The N-methyl-D-aspartate receptor (NMDA-R) complex gates Ca 2 þ , which interacts with calmodulin to subsequently activate NO synthase. We hypothesised that uncoupling neuronal nitric oxide synthase (nNOS) from the NMDA-R through the scaffolding protein postsynaptic density protein 95 (PSD-95) would produce behavioural antidepressant effects similar to NO synthase inhibitors. Small-molecule inhibitors of the PSD-95/nNOS interaction, IC87201 (0.01-2 mg/kg) and ZL006 (10 mg/kg) were tested for antidepressant properties in tests of antidepressant activity namely the tail suspension and forced swim tests in mice. We now report that IC87201 and ZL006 produce antidepressant-like responses in the forced swimming test (FST) and tail suspension test (TST) following a single administration in mice. By contrast to the tricyclic antidepressant imipramine (25 mg/kg), the effects are not observed 1 h following drug administration but are apparent 24 and 72 h later. Furthermore prior exposure to the TST or FST is required in order to observe the antidepressantrelated activity. Similar delayed and sustained antidepressant-like effects were observed following TRIM (50 mg/kg) and ketamine (30 mg/kg) in the TST. The antidepressant-like effects of ZL006 also generalise to IC87201 in the TST. IC87201 was devoid of effects on locomotor activity and step-through latency in the passive avoidance cognition test. These data support the hypothesis that targeting the PSD-95/nNOS interaction downstream of NMDA-R produces antidepressant effects and may represent a novel class of therapeutics for major depressive disorders.

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“…A crucial involvement of the NMDA-NO signaling pathway in the pathophysiology of MD and in the mechanism of action of antidepressant drugs has been suggested. For example, NMDA receptor antagonists or NOS inhibitors exhibit antidepressant-like properties in animal screening procedures (13)(14)(15). In addition, chronic treatment with an NOS inhibitor also down-regulates ß-adrenergic receptors in the frontal cortex of mice with a magnitude comparable to imipramine (16).…”

Section: Introductionmentioning

confidence: 99%

Expression of neuronal nitric oxide synthase in the hippocampal formation in affective disorders

Oliveira

Guimarães

Deakin

2008

Braz J Med Biol Res

112

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Hippocampal output is increased in affective disorders and is mediated by increased glutamatergic input via N-methyl-Daspartate (NMDA) receptor and moderated by antidepressant treatment. Activation of NMDA receptors by glutamate evokes the release of nitric oxide (NO) by the activation of neuronal nitric oxide synthase (nNOS). The human hippocampus contains a high density of NMDA receptors and nNOS-expressing neurons suggesting the existence of an NMDA-NO transduction pathway which can be involved in the pathogenesis of affective disorders. We tested the hypothesis that nNOS expression is increased in the human hippocampus from affectively ill patients. Immunocytochemistry was used to demonstrate nNOS-expressing neurons in sections obtained from the Stanley Consortium postmortem brain collection from patients with major depression (MD, N = 15), bipolar disorder (BD, N = 15), and schizophrenia (N = 15) and from controls (N = 15). nNOS-immunoreactive (nNOS-IR) and Nissl-stained neurons were counted in entorhinal cortex, hippocampal CA1, CA2, CA3, and CA4 subfields, and subiculum. The numbers of Nissl-stained neurons were very similar in different diagnostic groups and correlated significantly with the number of nNOS-IR neurons. Both the MD and the BD groups had greater number of nNOS-IR neurons/400 µm 2 in CA1 (mean ± SEM: MD = 9.2 ± 0.6 and BD = 8.4 ± 0.6) and subiculum (BD = 6.7 ± 0.4) when compared to control group (6.6 ± 0.5) and this was significantly more marked in samples from the right hemisphere. These changes were specific to affective disorders since no changes were seen in the schizophrenic group (6.7 ± 0.8). The results support the current view of the NMDA-NO pathway as a target for the pathophysiology of affective disorders and antidepressant drug development.

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Serotonergic mediation of the antidepressant-like effects of nitric oxide synthase inhibitors

Cited by 139 publications

References 28 publications

A role for serotonin in the antidepressant activity of NG-Nitro-L-arginine, in the rat forced swimming test

A role for serotonin in the antidepressant activity of NG-Nitro-L-arginine, in the rat forced swimming test

Small-Molecule Inhibitors at the PSD-95/nNOS Interface have Antidepressant-Like Properties in Mice

Expression of neuronal nitric oxide synthase in the hippocampal formation in affective disorders

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