Effects of nitric oxide synthase inhibition in the dorsolateral periaqueductal gray matter on ethanol withdrawal-induced anxiety-like behavior in rats

Bonassoli, Vivian Taciany; Contardi, Ewandro Braz; Milani, Humberto; Oliveira, Rúbia Maria Weffort de

doi:10.1007/s00213-013-3049-1

Cited by 23 publications

(15 citation statements)

References 94 publications

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“…Nitric oxide (NO) in the PAG is involved in anxiety‐like behaviors. NO scavengers and antagonists of neuronal nitric oxide synthase ( Nos1 ) injected into the PAG have been shown to reduce anxiogenic effects of alcohol withdrawal in rats (Bonassoli et al., ). Nos1 increased 1.75‐fold in the PAG.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Changes in Glutamate and GABA-A Receptors, Neuropeptides, Ion Channels, and Cholesterol Synthesis in the Periaqueductal Gray Following Binge-Like Alcohol Drinking by Adolescent Alcohol-Preferring (P) Rats

McClintick

McBride

Bell

et al. 2016

Alcohol Clin Exp Res

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Background Binge-drinking of alcohol during adolescence is a serious public health concern with long-term consequences, including increased pain, fear and anxiety. The periaqueductal gray (PAG) is involved in processing pain, fear and anxiety. The effects of adolescent binge drinking on gene expression in this region have yet to be studied. Methods Male adolescent P (alcohol preferring) rats were exposed to repeated binge-drinking (three 1-h sessions/day during the dark-cycle, 5 days/week for 3 weeks starting at 28 days of age; ethanol intakes of 2.5 – 3 g/kg/session). We used RNA sequencing to assess the effects of ethanol intake on gene expression. Results Ethanol significantly altered expression of 1670 of the 12,123 detected genes: 877 (53%) decreased. In the glutamate system, 23 genes were altered, including reduction in 7 of 10 genes for metabotropic and NMDA receptors. Subunit changes in the NMDA receptor may make it less sensitive to ethanol. Changes in GABAA genes would most likely increase the ability of the PAG to produce tonic inhibition. Five serotonin receptor genes, 6 acetylcholine receptor genes and 4 glycine receptor genes showed decreased expression in the alcohol drinking rats. Opioid genes (e.g., Oprk1, Oprm1) and genes for neuropeptides linked to anxiety and panic behaviors (e.g., Npy1r) had mostly decreased expression. Genes for 27 potassium, 10 sodium and 5 calcium ion channels were differentially expressed. Nine genes in the cholesterol synthesis pathway had decreased expression, including Hmgcr, encoding the rate limiting enzyme. Genes involved in the production of myelin also had decreased expression. Conclusion The results demonstrate that binge-alcohol drinking during adolescence produces developmental changes in the expression of key genes within the PAG; many of these changes point to increased susceptibility to pain, fear and anxiety, which could contribute to excessive drinking to relieve these negative effects.

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Section: Discussionmentioning

confidence: 99%

Gene Expression Changes in Glutamate and GABA-A Receptors, Neuropeptides, Ion Channels, and Cholesterol Synthesis in the Periaqueductal Gray Following Binge-Like Alcohol Drinking by Adolescent Alcohol-Preferring (P) Rats

McClintick

McBride

Bell

et al. 2016

Alcohol Clin Exp Res

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“…Synaptic targeting of GluN1- and GluN2B-containing NMDA receptors by chronic alcohol and their subsequent overstimulation during withdrawal produces excessive Ca 2+ influx and promotes pathological NO signaling and cellular injury. The production of NO and the increased activity of NOS contributes to the alcohol withdrawal-induced anxiety-like behaviors [97,98], and inhibitors of NOS attenuate the severity of alcohol withdrawal and reduce alcohol consumption in rodents [97-99]. Endogenous NO-induced S -nitrosylation of GluN1 and GluN2A subunits of NMDA receptors at extracellular cysteine residues leads to an inhibition of NMDA-evoked currents [96].…”

Section: Drugs Of Abuse and Oxidative/nitrosative Stressmentioning

confidence: 99%

Glutathione and redox signaling in substance abuse

Uys

Mulholland

Townsend

2014

Biomedicine & Pharmacotherapy

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Throughout the last couple decades, the cause and consequences of substance abuse has expanded to identify the underlying neurobiological signaling mechanisms associated with addictive behavior. Chronic use of drugs, such as cocaine, methamphetamine and alcohol leads to the formation of oxidative or nitrosative stress (ROS/RNS) and changes in glutathione and redox homeostasis. Of importance, redox-sensitive post-translational modifications on cysteine residues, such as S-glutathionylation and S-nitrosylation could impact on the structure and function of addiction related signaling proteins. In this commentary, we evaluate the role of glutathione and redox signaling in cocaine-, methamphetamine- and alcohol addiction and conclude by discussing the possibility of targeting redox pathways for the therapeutic intervention of these substance abuse disorders.

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“…Contradictory results were already observed in previous studies using L‐arginine or other NO increasing drugs (e.g., NO donor) in different animal models of anxiety, and both anxiolytic‐like (e.g., Kalouda & Pitsikas, ; Spiacci, Kanamaru, Guimarães, & Oliveira, ) and anxiogenic‐like effects were found (e.g., Umathe et al, ). However, despite these contradictory results of L‐arginine in animal models of anxiety, L‐arginine challenge had been successfully used to detect a nitrergic mediation of anxiolytic‐like effect of treatments in different conditions (e.g., Bonassoli, Contardi, Milani, & De Oliveira, ; Siba et al, ), including marble‐burying behavior (Gawali et al, ; Krass et al, ; Umathe et al, ). Thus, for the first time, the present results indicated an important role of NO transmission on anxiolytic‐like effect of C. sinensis essential oil.…”

Section: Discussionmentioning

confidence: 99%

The nitrergic neurotransmission contributes to the anxiolytic‐like effect of Citrus sinensis essential oil in animal models

Hocayen

Wendler

Vecchia

et al. 2019

Phytotherapy Research

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Citrus fragrances have been used in aromatherapy for the treatment of anxiety, and the essential oil of Citrus sinensis (sweet orange) has shown promising results, although its mechanism of action was not known. The objective of this study was to evaluate the involvement of nitric oxide (NO) neurotransmission in the anxiolytic-like effect of C. sinensis essential oil. Swiss male mice were submitted to 15 min of C. sinensis essential oil inhalation (1%, 2.5%, 5%, and 10%) and tested in the marble-burying test, neophobia-induced hypophagia, and light/dark test. Locomotor activity was evaluated in an automated locomotor activity box. The coadministration of C. sinensis essential oil with L-arginine (200 mg/kg, i.p.), an NO precursor, was used for the behavioral evaluation of nitrergic system mediation. Additionally, the NO synthase activity was measured by nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) analysis in the cerebral cortex. C. sinensis essential oil exerted anxiolytic-like effect at dose that did not change locomotor activity. Moreover, L-arginine pretreatment prevented this anxiolytic-like effect on marble-burying test. Finally, C. sinensis essential oil reduced the NADPH-d positive cells. Thus, the nitrergic neurotransmission plays a relevant role in the anxiolytic-like effect C. sinensis essential oil.

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Effects of nitric oxide synthase inhibition in the dorsolateral periaqueductal gray matter on ethanol withdrawal-induced anxiety-like behavior in rats

Abstract: NO production in the dlPAG may play a role in the modulation of ethanol withdrawal-induced anxiety-like behavior in rats. Furthermore, iNOS-mediated NO synthesis in the dlPAG is predominantly involved in the behavioral expression of anxiety-like behavior during ethanol withdrawal.

Cited by 23 publications

References 94 publications

Gene Expression Changes in Glutamate and GABA-A Receptors, Neuropeptides, Ion Channels, and Cholesterol Synthesis in the Periaqueductal Gray Following Binge-Like Alcohol Drinking by Adolescent Alcohol-Preferring (P) Rats

Gene Expression Changes in Glutamate and GABA-A Receptors, Neuropeptides, Ion Channels, and Cholesterol Synthesis in the Periaqueductal Gray Following Binge-Like Alcohol Drinking by Adolescent Alcohol-Preferring (P) Rats

Glutathione and redox signaling in substance abuse

The nitrergic neurotransmission contributes to the anxiolytic‐like effect of Citrus sinensis essential oil in animal models

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