Anxiety during alcohol withdrawal involves 5-HT2C receptors and M-channels in the lateral habenula

Fu, Rao; Mei, Qinghua; Shiwalkar, Nimisha; Zuo, Wanhong; Zhang, Haifeng; Gregor, Danielle; Patel, Shivani; Ye, Jiang-Hong

doi:10.1016/j.neuropharm.2019.107863

Cited by 39 publications

(35 citation statements)

References 95 publications

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“…The IA2BC paradigm provides a platform to address multiple aspects of alcohol abuse in a rat model, including transition from social-like drinking to excessive alcohol consumption, binge drinking, alcohol seeking, relapse, and neuroadaptations related to excessive alcohol intake (Carnicella et al, 2014). Although some labs, including ours, report minimal alcohol deprivation effects (Simms et al, 2008;Meyer et al, 2013), others report marked withdrawal behaviors, such as anxiety-like symptoms and hyperalgesia after withdrawal from > 8 weeks of IA2BC (Kang et al, 2019;Li et al, 2019;Fu et al, 2020). Peak plasma EtOH concentrations obtained following 30 min of IA2BC 20% EtOH range between 4 and 93 mg/dL in Wistar rats (Simms et al, 2008); with a blood EtOH concentration of > 80 mg/dL meeting the criteria of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) for binge drinking in humans.…”

Section: Intermittent Access 2-bottle Choice Drinking Paradigmmentioning

confidence: 86%

Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats

et al. 2020

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Alcohol use disorder (AUD) is a chronic relapsing condition characterized by compulsive alcohol-seeking behaviors, with serious detrimental health consequences. Despite high prevalence and societal burden, available approved medications to treat AUD are limited in number and efficacy, highlighting a critical need for more and novel pharmacotherapies. Glucagon-like peptide-1 (GLP-1) is a gut hormone and neuropeptide involved in the regulation of food intake and glucose metabolism via GLP-1 receptors (GLP-1Rs). GLP-1 analogs are approved for clinical use for diabetes and obesity. Recently, the GLP-1 system has been shown to play a role in the neurobiology of addictive behaviors, including alcohol seeking and consumption. Here we investigated the effects of different pharmacological manipulations of the GLP-1 system on escalated alcohol intake and preference in male Wistar rats exposed to intermittent access 2-bottle choice of 10% ethanol or water. Administration of AR231453 and APD668, two different agonists of G-protein receptor 119, whose activation increases GLP-1 release from intestinal L-cells, did not affect voluntary ethanol intake. By contrast, injections of either liraglutide or semaglutide, two long-acting GLP-1 analogs, potently decreased ethanol intake. These effects, however, were transient, lasting no longer than 48 h. Semaglutide, but not liraglutide, also reduced ethanol preference on the day of injection. As expected, both analogs induced a reduction in body weight. Co-administration of exendin 9-39, a GLP-1R antagonist, did not prevent liraglutide- or semaglutide-induced effects in this study. Injection of exendin 9-39 alone, or blockade of dipeptidyl peptidase-4, an enzyme responsible for GLP-1 degradation, via injection of sitagliptin, did not affect ethanol intake or preference. Our findings suggest that among medications targeting the GLP-1 system, GLP-1 analogs may represent novel and promising pharmacological tools for AUD treatment.

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Section: Intermittent Access 2-bottle Choice Drinking Paradigmmentioning

confidence: 86%

Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats

et al. 2020

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“…Whatever the study, the data suggest that acute and chronic nicotine induce specific, regional changes of 5-HT 2C R function restricted to some brain areas. The behavioral effects inherent to acute and chronic nicotine involve an extended network in which the LHb is crucial in the control of the motivational system [ 51 ] and its 5-HT 2C R alteration has being involved in the pathogenesis of depressive disorders [ 40 ] and drugs of addiction [ 44 , 52 ] including nicotine [ 42 , 43 ]. The 5-HT 2C R anti-addictive effects are believed to be based on the inhibition of dopaminergic neurotransmission [ 2 , 53 ] acknowledging that this inhibitory action could be sustained by other brain regions.…”

Section: Discussionmentioning

confidence: 99%

Lateral Habenula 5-HT2C Receptor Function Is Altered by Acute and Chronic Nicotine Exposures

Bombardi

Delicata

Tagliavia

et al. 2021

IJMS

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Serotonin (5-HT) is important in some nicotine actions in the CNS. Among all the 5-HT receptors (5-HTRs), the 5-HT2CR has emerged as a promising drug target for smoking cessation. The 5-HT2CRs within the lateral habenula (LHb) may be crucial for nicotine addiction. Here we showed that after acute nicotine tartrate (2 mg/kg, i.p.) exposure, the 5-HT2CR agonist Ro 60-0175 (5–640 µg/kg, i.v.) increased the electrical activity of 42% of the LHb recorded neurons in vivo in rats. Conversely, after chronic nicotine treatment (6 mg/kg/day, i.p., for 14 days), Ro 60-0175 was incapable of affecting the LHb neuronal discharge. Moreover, acute nicotine exposure increased the 5-HT2CR-immunoreactive (IR) area while decreasing the number of 5-HT2CR-IR neurons in the LHb. On the other hand, chronic nicotine increased both the 5-HT2CR-IR area and 5-HT2CR-IR LHb neurons in the LHb. Western blot analysis confirmed these findings and further revealed an increase of 5-HT2CR expression in the medial prefrontal cortex after chronic nicotine exposure not detected by the immunohistochemistry. Altogether, these data show that acute and chronic nicotine exposure differentially affect the central 5-HT2CR function mainly in the LHb and this may be relevant in nicotine addiction and its treatment.

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“…The inhibition of serotonergic pathways can also treat alcohol withdrawal–associated anxiety. Inhibiting serotonergic pathway increases K v 7.2/7.3 channel expression, which reduces firing in lateral habenula neurons and helps treat alcohol addiction ( Fu et al, 2020 ). In addition to the use of SK activators, which can restore regular firing activity in VTA, NAc, and hippocampal neurons and assist in alcohol abstinence, SK blocker treatment in the infralimbic prefrontal cortex causes alcohol extinction memory ( Cannady et al, 2017 ).…”

Section: Therapeutic Potentials Of Mahp Modulatorsmentioning

confidence: 99%

Physiology and Therapeutic Potential of SK, H, and M Medium AfterHyperPolarization Ion Channels

Dwivedi

Bhalla

2021

Front. Mol. Neurosci.

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SK, HCN, and M channels are medium afterhyperpolarization (mAHP)-mediating ion channels. The three channels co-express in various brain regions, and their collective action strongly influences cellular excitability. However, significant diversity exists in the expression of channel isoforms in distinct brain regions and various subcellular compartments, which contributes to an equally diverse set of specific neuronal functions. The current review emphasizes the collective behavior of the three classes of mAHP channels and discusses how these channels function together although they play specialized roles. We discuss the biophysical properties of these channels, signaling pathways that influence the activity of the three mAHP channels, various chemical modulators that alter channel activity and their therapeutic potential in treating various neurological anomalies. Additionally, we discuss the role of mAHP channels in the pathophysiology of various neurological diseases and how their modulation can alleviate some of the symptoms.

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Anxiety during alcohol withdrawal involves 5-HT2C receptors and M-channels in the lateral habenula

Cited by 39 publications

References 95 publications

Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats

Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats

Lateral Habenula 5-HT2C Receptor Function Is Altered by Acute and Chronic Nicotine Exposures

Physiology and Therapeutic Potential of SK, H, and M Medium AfterHyperPolarization Ion Channels

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