Chronic alcohol disrupts hypothalamic responses to stress by modifying CRF and NMDA receptor function

Marty, Vincent; Mulpuri, Yatendra; Munier, Joseph J.; Spigelman, Igor

doi:10.1016/j.neuropharm.2020.107991

Cited by 17 publications

(24 citation statements)

References 144 publications

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“…Preclinical studies are still needed to further characterize the cellular mechanisms and neuronal circuitry which mediate the suppressant effects of GLP-1 analogs on alcohol intake. It is also important to note that chronic exposure to alcohol and alcohol dependence lead to dysregulation of several neural circuits, such as the mesolimbic dopamine and the corticotropin releasing factor systems ( Diana et al, 1993 ; Weiss et al, 1996 ; Volkow et al, 2007 ; Roberto et al, 2010 ; Marty and Spigelman, 2012 ; Liang et al, 2014a , b ; Herman et al, 2016 ; Marty et al, 2020 ), which could alter the beneficial effects of GLP-1 analogs observed in non-dependent subjects – an important question that should be explored in future studies. Overall, the present study adds to the growing literature suggesting that the GLP-1 receptor could be a novel and promising pharmacotherapeutic target for AUD.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Stimulus was adjusted to elicit a sustained amplitude reaching ~1/2 maximal response for the first current. Paired‐pulse ratio (PPR) was obtained by applying a pair of equipotent stimuli at an interval of 25 ms and a rate of 0.2 Hz, as described previously (Marty et al, 2020). High‐frequency stimulation (HFS) of afferents at 100 Hz for 1 s, repeated four times with a 5‐s interval (Marty et al, 2020), was performed following the washout of all drugs.…”

Section: Methodsmentioning

confidence: 99%

“…PNCs exhibit a unique stress‐ and CRF receptor 1 (CRF1R)‐dependent short‐term glutamatergic plasticity (STP) following high‐frequency afferent stimulation (Kuzmiski et al, 2010). CRF1R activation suppresses postsynaptic N‐methyl D‐aspartate receptors (NMDARs) to prevent the release of a retrograde messenger to consequently gate STP formation (Kuzmiski et al, 2010; Marty et al, 2020). Freezing in response to a threatening stimulus is related to STP formation in PVN PNCs (Daviu et al, 2020), which highlights the importance of this glutamatergic plasticity in coordinating adaptive behavior.…”

Section: Introductionmentioning

confidence: 99%

“…Freezing in response to a threatening stimulus is related to STP formation in PVN PNCs (Daviu et al, 2020), which highlights the importance of this glutamatergic plasticity in coordinating adaptive behavior. We have recently shown that both stress‐mediated STP formation and stress‐induced increases in grooming behavior are lost in male rats following CIE exposure (Marty et al, 2020). To our knowledge, no one has demonstrated the efficacy of acute drug exposure to remedy this loss of hypothalamic synaptic plasticity following CIE.…”

Section: Introductionmentioning

confidence: 99%

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Sex differences in α‐adrenergic receptor function contribute to impaired hypothalamic metaplasticity following chronic intermittent ethanol exposure

Munier

Marty

Spigelman

2022

Alcoholism Clin & Exp Res

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Background: Individuals with alcohol use disorder (AUD) exhibit maladaptive responses of the hypothalamic-pituitary-adrenal (HPA) axis to stress, which has been linked to high rates of relapse to drinking among abstinent individuals. Corticotropinreleasing factor (CRF) parvocellular neuroendocrine cells (PNCs) within the paraventricular nucleus of the hypothalamus (PVN) are critical to stress-induced HPA axis activation. Here, we investigate sex differences in synaptic transmission and plasticity in PNCs following the application of the stress-associated neurotransmitter norepinephrine (NE) in a rat model of AUD.Methods: Adult Sprague-Dawley rats were exposed to 40 days of chronic intermittent ethanol (CIE) vapor and 30 to 108 days of protracted withdrawal. We measured changes in holding current, evoked synaptic currents, and short-term glutamatergic plasticity (STP) in putative PNCs following the application of NE (10 μM) with and without the selective α1 adrenergic receptor (AR) antagonist prazosin (10 μM) or the α2AR antagonist atipamezole (10 μM). The experiments were performed using wholecell patch clamp recordings in slices from CIE rats and air-exposed controls.Results: NE application caused two distinct effects: a depolarizing, inward, postsynaptic current and a reduction in amplitude of an evoked glutamatergic excitatory postsynaptic current (eEPSC). Both effects were sex-and CIE-specific. Prazosin blocked the postsynaptic inward current, while atipamezole blocked the NE-mediated suppression of eEPSCs. Additionally, STP formation was facilitated following NE application only in stress-naïve males and this response was lost in stressed animals exposed to a 30-min restraint stress following CIE exposure. Furthermore, NE + prazosin restored STP formation in stressed CIE males.Conclusions: NE exerts excitatory and inhibitory effects on CRF PVN PNCs, and both effects are influenced by sex and CIE. Behavioral and hormonal responses to stress are influenced by STP formation within the PVN, which is lost following CIE and restored with the preapplication of prazosin. The selective blockade of α1AR may, therefore, ameliorate CIE-induced deficits in HPA responses to stress in a sex-specific manner.

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“…Oxidative stress impairs glucocorticoid receptor function (Tian et al 2019, Schiavone et al 2013). Increased hydroxyl radical production is responsible for impaired nuclear translocation of the glucocorticoid receptor and its dysfunction (Marty et al 2020, Tanaka et al1999. A disturbance in the HPG axis can result in an imbalance in plasma circulating hormone levels.…”

Section: Discussionmentioning

confidence: 99%

Alcohol-Induced Mitochondrial and NADPH Oxidase Mediated ROS Generation Alter Neuroendocrine Status: Role of Pterocarpus Santalinus

Bulle

Pulakuntla

Padmavathi

et al. 2021

Preprint

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The association between oxidative stress and endocrine status with respect to the role of Pterocarpus santalinus (PSE) against alcohol-induced neurotoxicity in rats was investigated. Male albino rats were divided into, control, alcohol treated, alcohol + PSE treated, and PSE treated group. Twenty percent of ethanol (5g/kg body weight/day) was given with and without PSE (250 mg/kg body weight/day) for 60 days. Decreased plasma testosterone, estradiol, thyroid hormones (T3 and T4), and increased cortisol concentrations in alcohol treated rats were observed. Besides, elevated lipid peroxidation, protein carbonyls, NADPH oxidase (NOX), and cytochrome P-450 (CYP-450) activities, with mitochondrial dysfunction were noticed. Moreover, increased protein expression of the phosphorylated protein kinase C (p-PKC), phospholipase C (p-PLC), and NOX2 with decreased antioxidant status was also noticed in alcohol ingested rats. Administration of PSE to alcohol treated rats reduced oxidative stress by increasing antioxidant status, also modulated mitochondrial dysfunction and protein expression of p-PKC, p-PLC and NOX2. In conclusion, ROS generated via mitochondrial dysfunction causes activation of NOX activity through PLC and PKC dependent pathways leading to more ROS generation, which in turn alters the circulating hormonal levels. The phytocompounds present in PSE confer therapeutic efficacy by scavenging ROS and thereby offer protection.

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Chronic alcohol disrupts hypothalamic responses to stress by modifying CRF and NMDA receptor function

Cited by 17 publications

References 144 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

Sex differences in α‐adrenergic receptor function contribute to impaired hypothalamic metaplasticity following chronic intermittent ethanol exposure

Alcohol-Induced Mitochondrial and NADPH Oxidase Mediated ROS Generation Alter Neuroendocrine Status: Role of Pterocarpus Santalinus

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