The Amygdala Noradrenergic System Is Compromised With Alcohol Use Disorder

Varodayan, Florence P.; Patel, Reesha R.; Matzeu, Alessandra; Wolfe, Sarah A.; Curley, Dallece E.; Khom, Sophia; Gandhi, Pauravi J.; Rodriguez, Larry; Bajo, Michal; D’Ambrosio, Shannon; Sun, Hui; Kerr, Tony M.; Gonzales, Rueben A.; Leggio, Lorenzo; Natividad, Luis A.; Haass‐Koffler, Carolina L.; Martin‐Fardon, Rémi; Roberto, Marisa

doi:10.1016/j.biopsych.2022.02.006

Cited by 25 publications

(22 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Preparation of acute brain slices and electrophysiological recordings were performed as previously described [ 17 , 30 , 51 , 52 ]. Rats were deeply anesthetized with isoflurane (3–5%) before decapitation and brain isolation.…”

Section: Methodsmentioning

confidence: 99%

Alcohol Dependence Induces CRF Sensitivity in Female Central Amygdala GABA Synapses

Rodriguez

Kirson

Wolfe

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

Alcohol use disorder (AUD) is a chronically relapsing disease characterized by loss of control in seeking and consuming alcohol (ethanol) driven by the recruitment of brain stress systems. However, AUD differs among the sexes: men are more likely to develop AUD, but women progress from casual to binge drinking and heavy alcohol use more quickly. The central amygdala (CeA) is a hub of stress and anxiety, with corticotropin-releasing factor (CRF)-CRF1 receptor and Gamma-Aminobutyric Acid (GABA)-ergic signaling dysregulation occurring in alcohol-dependent male rodents. However, we recently showed that GABAergic synapses in female rats are less sensitive to the acute effects of ethanol. Here, we used patch-clamp electrophysiology to examine the effects of alcohol dependence on the CRF modulation of rat CeA GABAergic transmission of both sexes. We found that GABAergic synapses of naïve female rats were unresponsive to CRF application compared to males, although alcohol dependence induced a similar CRF responsivity in both sexes. In situ hybridization revealed that females had fewer CeA neurons containing mRNA for the CRF1 receptor (Crhr1) than males, but in dependence, the percentage of Crhr1-expressing neurons in females increased, unlike in males. Overall, our data provide evidence for sexually dimorphic CeA CRF system effects on GABAergic synapses in dependence.

show abstract

Section: Methodsmentioning

confidence: 99%

Alcohol Dependence Induces CRF Sensitivity in Female Central Amygdala GABA Synapses

Rodriguez

Kirson

Wolfe

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Additionally, in the same chronic alcohol treated rats, there was an increase in the probability of GABA release compared to naïve rats, suggesting that chronic alcohol enhances alcohol-induced release of GABA ( Roberto et al, 2004 ). After an acute bath application of 44 mM alcohol, there was a significant increase in action-potential dependent presynaptic GABAergic transmission in both naïve and chronic alcohol vapor treated Sprague Dawley rats and C57Bl/6J mice ( Roberto et al, 2004 ; Harris et al, 2017 ; Varodayan et al, 2017b ; Bajo et al, 2019 ). This is noteworthy, as despite the increased GABAergic transmission in basal conditions, bath application of alcohol led to an equal increase in GABAergic transmission between naïve and alcohol treated rats, suggesting a lack of tolerance to the effect of acute alcohol ( Roberto et al, 2004 ; Harris et al, 2017 ; Varodayan et al, 2017b ; Tunstall et al, 2019 ; Khom et al, 2020 ).…”

Section: Gabaergic Transmissionmentioning

confidence: 99%

“…After an acute bath application of 44 mM alcohol, there was a significant increase in action-potential dependent presynaptic GABAergic transmission in both naïve and chronic alcohol vapor treated Sprague Dawley rats and C57Bl/6J mice ( Roberto et al, 2004 ; Harris et al, 2017 ; Varodayan et al, 2017b ; Bajo et al, 2019 ). This is noteworthy, as despite the increased GABAergic transmission in basal conditions, bath application of alcohol led to an equal increase in GABAergic transmission between naïve and alcohol treated rats, suggesting a lack of tolerance to the effect of acute alcohol ( Roberto et al, 2004 ; Harris et al, 2017 ; Varodayan et al, 2017b ; Tunstall et al, 2019 ; Khom et al, 2020 ). Interestingly, when looking at action-potential independent GABAergic transmission, the effect of acute 44 mM alcohol application seems to be higher in rats and mice exposed to chronic alcohol compared to naïve rodents ( Roberto et al, 2004 ; Harris et al, 2017 ).…”

Section: Gabaergic Transmissionmentioning

confidence: 99%

“…Therefore, the use of different rat strains can uncover some of the postsynaptic effects of alcohol. Additionally, chronic alcohol has been shown to alter noradrenergic sensitivity of CeA GABAergic transmission but acute alcohol effects on CeA GABAergic transmission are not regulated by noradrenergic signaling ( Varodayan et al, 2022 ).…”

Section: Gabaergic Transmissionmentioning

confidence: 99%

See 1 more Smart Citation

Subregional Differences in Alcohol Modulation of Central Amygdala Neurocircuitry

Melkumyan

Silberman

2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Alcohol use disorder is a highly significant medical condition characterized by an impaired ability to stop or control alcohol use, compulsive alcohol seeking behavior, and withdrawal symptoms in the absence of alcohol. Understanding how alcohol modulates neurocircuitry critical for long term and binge-like alcohol use, such as the central amygdala (CeA), may lead to the development of novel therapeutic strategies to treat alcohol use disorder. In clinical studies, reduction in the volume of the amygdala has been linked with susceptibility to relapse to alcohol use. Preclinical studies have shown the involvement of the CeA in the effects of alcohol use, with lesions of the amygdala showing a reduction in alcohol drinking, and manipulations of cells in the CeA altering alcohol drinking. A great deal of work has shown that acute alcohol, as well as chronic alcohol exposure via intake or dependence models, alters glutamatergic and GABAergic transmission in the CeA. The CeA, however, contains heterogeneous cell populations and distinct subregional differences in neurocircuit architecture which may influence the mechanism by which alcohol modulates CeA function overall. The current review aimed to parse out the differences in alcohol effects on the medial and lateral subregions of the CeA, and what role neuroinflammatory cells and markers, the endocannabinoid system, and the most commonly studied neuropeptide systems play in mediating these effects. A better understanding of alcohol effects on CeA subregional cell type and neurocircuit function may lead to development of more selective pharmacological interventions for alcohol use disorder.

show abstract

“…In addition, currently approved medications for AUD show modest therapeutic efficacy, and there is a critical need for novel therapies, especially drugs that are already FDA approved and could be quickly repurposed (Spanagel, 2009; Kranzler et al, 2018; Downs et al, 2022). However, even with robust evidence for an important relation between AUD and stress activation, there are no approved medication targeting the brain stress system to modulate excessive alcohol drinking (Haass-Koffler et al, 2018; Downs et al, 2022; Varodayan et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

The Role of Alpha- And Beta-Adrenergic Receptors on Compulsion-Like Alcohol Drinking

Sergio

Wean

Katner

et al. 2022

Preprint

View full text Add to dashboard Cite

Alcohol Use Disorders (AUD) is characterized by compulsion-like alcohol drinking (CLAD), and this intake despite negative consequences can be a major clinical obstacle. With the quite limited treatment options available for AUD, there is a significant and critical unmet need for novel therapies. The noradrenergic system is an important hub for the stress response as well as maladaptive drives for alcohol, and pre-clinical (including our own) and clinical studies have shown that drugs targeting the α1 adrenenergic receptors (ARs) may represent a pharmacological treatment for pathological drinking. However, the involvement of β ARs for treating human drinking AUD has received somewhat scant investigation, and we sought to provide pre-clinical validation for possible AR utility for CLAD. Thus, we first examined whether β AR antagonist propranolol, betaxolol (β1), and ICI, 118 551 (β2) impacted compulsion-like intake and alcohol-only drinking (AOD) in male Wistar rats through systemic injections. The systemic highest dose of propranolol (10mg/kg) reduced both AOD and CLAD. 5mg/kg propranolol affected CLAD more than AOD, with no effects of 2.5mg/kg. Similar to propranolol, betaxolol also only decreased CLAD at the lower dose (2.5mg/kg). ICI 118.551 had no effects, suggesting propranolol regulates alcohol intake through β1. Also, while AR compounds might have utility for AUD, these compounds can also lead to undesirable cardiovascular system side effects; thus, any strategy incorporating lower doses of these compounds to reduce drinking could have broad utility. Importantly, here we found that a combination of ineffective doses of 2 propranolol and prazosin administrated together did reduce both CLAD and AOD. Finally, we investigated the effect of propranolol and betaxolol into two brain areas related to pathological drinking, the anterior insula (aINS) and medial prefrontal cortex (mPFC). Surprisingly, propranolol (1-10μg) in aINS or mPFC did not affect CLAD or AOD (although with a trend for aINS betaxolol to impact CLAD), suggesting propranolol regulation of alcohol drinking through a target other than aINS and mPFC. Together, our findings provide new pharmacological insights into noradrenergic regulation of alcohol consumption, which may inform AUD therapy.

show abstract

The Amygdala Noradrenergic System Is Compromised With Alcohol Use Disorder

Cited by 25 publications

References 64 publications

Alcohol Dependence Induces CRF Sensitivity in Female Central Amygdala GABA Synapses

Alcohol Dependence Induces CRF Sensitivity in Female Central Amygdala GABA Synapses

Subregional Differences in Alcohol Modulation of Central Amygdala Neurocircuitry

The Role of Alpha- And Beta-Adrenergic Receptors on Compulsion-Like Alcohol Drinking

Contact Info

Product

Resources

About