IL-10 normalizes aberrant amygdala GABA transmission and reverses anxiety-like behavior and dependence-induced escalation of alcohol intake

Patel, Reesha R.; Wolfe, Sarah A.; Bajo, Michal; Abeynaike, Shawn; Pahng, Amanda R.; Borgonetti, Vittoria; D’Ambrosio, Shannon; Nikzad, Rana; Edwards, Scott; Paust, Silke; Roberts, Amanda J.; Roberto, Marisa

doi:10.1016/j.pneurobio.2020.101952

Cited by 46 publications

(41 citation statements)

References 67 publications

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“…In ASD, IFN-γ is notably the most pronounced among commonly elevated pro-inflammatory cytokines (reviewed in Saghazadeh et al, 2019 ) and children with ASD have elevated nitrate plasma levels that correlate with levels of IFN-γ but not with other cytokines ( Sweeten et al, 2004 ). Alcohol dependence increases IFN-γ production in brain immune cells, as well as mIPSC frequency in the central amygdala that normalizes upon application of the anti-inflammatory cytokine interleukin 10 ( Patel et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Interferon-γ augments GABA release in the developing neocortex via nitric oxide synthase/soluble guanylate cyclase and constrains network activity

Döhne

Falck²,

Janach³

et al. 2022

Front. Cell. Neurosci.

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Interferon-γ (IFN-γ), a cytokine with neuromodulatory properties, has been shown to enhance inhibitory transmission. Because early inhibitory neurotransmission sculpts functional neuronal circuits, its developmental alteration may have grave consequences. Here, we investigated the acute effects of IFN-γ on γ-amino-butyric acid (GABA)ergic currents in layer 5 pyramidal neurons of the somatosensory cortex of rats at the end of the first postnatal week, a period of GABA-dependent cortical maturation. IFN-γ acutely increased the frequency and amplitude of spontaneous/miniature inhibitory postsynaptic currents (s/mIPSC), and this could not be reversed within 30 min. Neither the increase in amplitude nor frequency of IPSCs was due to upregulated interneuron excitability as revealed by current clamp recordings of layer 5 interneurons labeled with VGAT-Venus in transgenic rats. As we previously reported in more mature animals, IPSC amplitude increase upon IFN-γ activity was dependent on postsynaptic protein kinase C (PKC), indicating a similar activating mechanism. Unlike augmented IPSC amplitude, however, we did not consistently observe an increased IPSC frequency in our previous studies on more mature animals. Focusing on increased IPSC frequency, we have now identified a different activating mechanism—one that is independent of postsynaptic PKC but is dependent on inducible nitric oxide synthase (iNOS) and soluble guanylate cyclase (sGC). In addition, IFN-γ shifted short-term synaptic plasticity toward facilitation as revealed by a paired-pulse paradigm. The latter change in presynaptic function was not reproduced by the application of a nitric oxide donor. Functionally, IFN-γ-mediated alterations in GABAergic transmission overall constrained early neocortical activity in a partly nitric oxide–dependent manner as revealed by microelectrode array field recordings in brain slices analyzed with a spike-sorting algorithm. In summary, with IFN-γ-induced, NO-dependent augmentation of spontaneous GABA release, we have here identified a mechanism by which inflammation in the central nervous system (CNS) plausibly modulates neuronal development.

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Section: Discussionmentioning

confidence: 99%

Interferon-γ augments GABA release in the developing neocortex via nitric oxide synthase/soluble guanylate cyclase and constrains network activity

Döhne

Falck²,

Janach³

et al. 2022

Front. Cell. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Indeed, a range of anti-inflammatory agents with an ability to decrease expression of IL-1β and TNF-α, such as Ibudilast ( Ray et al, 2014 ) and Minocycline ( Garrido-Mesa et al, 2013 ) exhibit promising actions on treatments for substance use disorders. Importantly, the anti-inflammatory cytokines IL-10 effectively modulates anxiety-like behaviors after repeated exposure to substances ( Patel et al, 2021 ) and reduces alcohol intake by mediating GABA signaling ( Russell et al, 2021 ). Collectively, anti-inflammatory agents with the ability to weaken the TLR4-related neuroinflammation may be repurposed to reduce the release of extracellular neurotransmitters and thereby treat CUD.…”

Section: Potential Mechanisms Underlying the Effects Of Glp-1ras On C...mentioning

confidence: 99%

Possible Mechanisms Underlying the Effects of Glucagon-Like Peptide-1 Receptor Agonist on Cocaine Use Disorder

Zhu

Kong

et al. 2022

Front. Pharmacol.

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Cocaine use disorder (CUD) is a major public health challenge with a high relapse rate and lack of effective pharmacotherapies; therefore, there is a substantial need to identify novel medications to treat this epidemic. Since the advent of glucagon-like peptide-1 (GLP-1) receptors (GLP-1Rs) agonists (GLP-1RAs), their potential has been extensively explored and expanded. In this review, we first summarized the biological effects of GLP-1, GLP-1Rs, and GLP-1RAs. Subsequently, the recent literature examining the behavioral effects and the possible pharmacological mechanisms of GLP-1RAs on CUD was reviewed. Increasing preclinical evidence suggests that GLP-1RAs are promising in regulating dopamine release, dopamine transporter (DAT) surface expression and function, mesolimbic reward system and GABAergic neurons, and maladaptive behaviors in animal models of self-administration and conditioned place preference. In addition, the emerging role of GLP-1RAs in inhibiting inflammatory cytokines was reported. These findings indicate that GLP-1RAs perform essential functions in the modulation of cocaine-seeking and cocaine-taking behaviors likely through multifaceted mechanisms. Although the current preclinical evidence provides convincing evidence to support GLP-1RA as a promising pharmacotherapy for CUD, other questions concerning clinical availability, impact and specific mechanisms remain to be addressed in further studies.

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“…Likewise, anti-inflammatory responses are altered in instances of substance use which leads to an unbalanced neuroimmune response. Anti-inflammatory cytokines such as IL-10 have been shown to modulate and even reverse anxiety behaviors related to substance use ( Patel et al, 2021 ). Furthermore, IL-10 could entirely diminish the escalation of alcohol intake by modulating GABA signaling in the amygdala.…”

Section: Interactions Between the Microbiota And The Immune System In Sudmentioning

confidence: 99%

The Gut Microbiome and Substance Use Disorder

et al. 2021

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Substance use disorders (SUDs) remain a significant public health challenge, affecting tens of millions of individuals worldwide each year. Often comorbid with other psychiatric disorders, SUD can be poly-drug and involve several different substances including cocaine, opiates, nicotine, and alcohol. SUD has a strong genetic component. Much of SUD research has focused on the neurologic and genetic facets of consumption behavior. There is now interest in the role of the gut microbiome in the pathogenesis of SUD. In this review, we summarize current animal and clinical evidence that the gut microbiome is involved in SUD, then address the underlying mechanisms by which the gut microbiome interacts with SUD through metabolomic, immune, neurological, and epigenetic mechanisms. Lastly, we discuss methods using various inbred and outbred mice models to gain an integrative understanding of the microbiome and host genetic controls in SUD.

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IL-10 normalizes aberrant amygdala GABA transmission and reverses anxiety-like behavior and dependence-induced escalation of alcohol intake

Cited by 46 publications

References 67 publications

Interferon-γ augments GABA release in the developing neocortex via nitric oxide synthase/soluble guanylate cyclase and constrains network activity

Interferon-γ augments GABA release in the developing neocortex via nitric oxide synthase/soluble guanylate cyclase and constrains network activity

Possible Mechanisms Underlying the Effects of Glucagon-Like Peptide-1 Receptor Agonist on Cocaine Use Disorder

The Gut Microbiome and Substance Use Disorder

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