Involvement of nitric oxide (NO) signaling pathway in the antidepressant action of bupropion, a dopamine reuptake inhibitor
Abstract
The present study was undertaken to elucidate the alterations in various behavioral and neurochemical basis of antidepressant action of bupropion [(+/-)-alpha-t-butylamino-3-chloropropiophenone], a dopamine reuptake inhibitor and to elucidate the possible mechanism of its action. The involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of bupropion was investigated besides its actions on various brain transmitters like norepinephrine, dopamine and homovanillic acid. Bupropion (10, 15, 20 and 40 mg/kg., i.p.) dose dependently inhibited the immobility period in mice in both forced swim test and tail suspension test. ED(50) values of bupropion in reducing the immobility period was found to be 18.5 and 18 mg/kg i.p., in forced swim test and tail suspension test, respectively. Bupropion (10, 20 and 40 mg/kg., i.p.) reversed the reserpine-induced behavioral despair also. When different doses (10, 15, 20 and 40 mg/kg., i.p.) of bupropion were tested for locomotor activity, it (15, 20 and 40 mg/kg., i.p.) increased locomotor activity. At 20 and 40 mg/kg doses the drug showed hypothermia. The neurochemical analysis of brain samples revealed that bupropion dose dependently (10-40 mg/kg., i.p.) increased the brain contents of dopamine and homovanillic acid in the mouse whole brain. The levels of norepinephrine were also increased at 20 mg/kg dose. The antidepressant-like effect of bupropion (20 mg/kg., i.p.) was prevented by pretreatment with L-arginine (750 mg/kg., i.p.) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (25 mg/kg., i.p.) [a specific neuronal nitric oxide synthase (nNOS) inhibitor] produced potentiation of the action of subeffective dose of bupropion (10 mg/kg i.p.). In addition, treatment of mice with methylene blue (10 mg/kg., i.p.) [direct inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] potentiated the effect of bupropion (10 mg/kg., i.p.) in the forced swim test. Furthermore, the reduction in the immobility period elicited by bupropion (20 mg/kg., i.p.) was also inhibited by pretreatment with sildenafil (5 mg/kg., i.p.) [phosphodiesterase 5 inhibitor]. The study indicated that bupropion possesses antidepressant activities in different animal models of depression through its dopaminergic and/or by modulating the L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway.
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Bupropion possesses antidepressant-like activities in different animal models possibly through dopaminergic and L-arginine-NO-cGMP signaling pathways.
“This study suggests that bupropion possesses antidepressant-like activities in different animal models possibly through dopaminergic and L-arginine-NO-cyclic guanosine monophosphate (cGMP) signaling pathways.”
From Preclinical and Clinical Evidence of Antioxidant Effects of Antidepressant Agents: Implications for the Pathophysiology of Major Depressive Disorder (2012) · cites this paper as [13]
Pretreatment with 7-nitroindazole potentiates bupropion's effects.
“Pretreatment with 7-nitroindazole (a specific neuronal NO synthase, nNOS inhibitor) potentiated bupropion's effects.”
From Preclinical and Clinical Evidence of Antioxidant Effects of Antidepressant Agents: Implications for the Pathophysiology of Major Depressive Disorder (2012) · cites this paper as [13]
Treatment with methylene blue potentiates the effect of bupropion in the forced swim test.
“In addition, treatment with methylene blue (a direct inhibitor of NOS and soluble guanylate cyclase, sGC) potentiated the effect of the drug in the forced swim test [13].”
From Preclinical and Clinical Evidence of Antioxidant Effects of Antidepressant Agents: Implications for the Pathophysiology of Major Depressive Disorder (2012) · cites this paper as [13]
The antidepressant-like effect of bupropion is prevented by pretreatment with L-arginine in male rats.
“The antidepressant-like effect of bupropion was prevented by pretreatment with L-arginine (a substrate of nitric oxide synthase, NOS).”
From Preclinical and Clinical Evidence of Antioxidant Effects of Antidepressant Agents: Implications for the Pathophysiology of Major Depressive Disorder (2012) · cites this paper as [13]
Antidepressants reduce NO levels in patients' serum.
“and antidepressants have been shown to reduce NO levels in the patient’s serum [7–9].”
From Possible involvement of l-arginine-nitric oxide pathway in the antidepressant activity of Auraptene in mice (2022) · cites this paper as [7]
nNOS plays a role in the pathophysiology of depression.
“Several studies have shown the role of nNOS in the pathophysiology of depression”
From Possible involvement of l-arginine-nitric oxide pathway in the antidepressant activity of Auraptene in mice (2022) · cites this paper as [7]
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- Authors
- Dhir, A., & Kulkarni, S. K.
- Affiliations
- Panjab University (IN)
- Corresponding author
- Kulkarni, S.K.
- Venue
- European Journal of Pharmacology
- Publisher
- Elsevier BV
- Published
- 2007-07
- Volume
- 568
- Issue
- 1-3
- Pages
- 177-185
- ISSN
- 0014-2999 (ISSN-L)
- OpenAlex
- W2142786903
- Cited by
- 133
- References
- 67
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 7 · 2020: 4 · 2019: 8 · 2018: 12 · 2017: 4 · 2016: 8 · 2015: 5 · 2014: 8 · 2013: 5 · 2012: 15
- FWCI
- 6.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- bupropion, antidepressant mechanism, nitric oxide signaling, neuronal nitric oxide synthase, dopamine reuptake inhibitors, norepinephrine, homovanillic acid, forced swim test, tail suspension test, locomotor activity, hypothermia, 7-nitroindazole
- MeSH terms
- Animals, Arginine, Behavior, Animal, Body Temperature, Brain, Depression, Dopamine, Cyclic GMP, Homovanillic Acid, Male, Motor Activity, Nitric Oxide, Norepinephrine, Reserpine, Swimming, Signal Transduction, Bupropion, Rats, Wistar, Antidepressive Agents, Second-Generation, Dopamine Uptake Inhibitors, Mice, Rats
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