The Role of the Central Amygdala in Alcohol Dependence

Roberto, Marisa; Kirson, Dean; Khom, Sophia

doi:10.1101/cshperspect.a039339

Cited by 82 publications

(92 citation statements)

References 234 publications

(271 reference statements)

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“…The CeA serves as an integrative hub mediating key aspects of negative emotional states associated with alcohol dependence, including anxiety-like behaviors (Gilpin et al, 2015). The CeA is a mainly GABAergic nucleus, particularly sensitive to both acute and chronic ethanol (Roberto et al, 2003(Roberto et al, , 2004(Roberto et al, , 2020. Thus, elevated CeA GABA transmission is a characteristic of alcohol dependence across species, including humans (Roberto et al, 2004;Augier et al, 2018;Jimenez et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Alcohol Dependence and Withdrawal Impair Serotonergic Regulation of GABA Transmission in the Rat Central Nucleus of the Amygdala

et al. 2020

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Excessive serotonin (5-HT) signaling plays a critical role in the etiology of alcohol use disorder. The central nucleus of the amygdala (CeA) is a key player in alcohol-dependence associated behaviors. The CeA receives dense innervation from the dorsal raphe nucleus, the major source of 5-HT, and expresses 5-HT receptor subtypes (e.g., 5-HT2C and 5-HT1A) critically linked to alcohol use disorder. Notably, the role of 5-HT regulating rat CeA activity in alcohol dependence is poorly investigated. Here, we examined neuroadaptations of CeA 5-HT signaling in adult, male Sprague Dawley rats using an established model of alcohol dependence (chronic intermittent alcohol vapor exposure), ex vivo slice electrophysiology and ISH. 5-HT increased frequency of sIPSCs without affecting postsynaptic measures, suggesting increased CeA GABA release in naive rats. In dependent rats, this 5-HT-induced increase of GABA release was attenuated, suggesting blunted CeA 5-HT sensitivity, which partially recovered in protracted withdrawal (2 weeks). 5-HT increased vesicular GABA release in naive and dependent rats but had split effects (increase and decrease) after protracted withdrawal indicative of neuroadaptations of presynaptic 5-HT receptors. Accordingly, 5-HT abolished spontaneous neuronal firing in naive and dependent rats but had bidirectional effects in withdrawn. Alcohol dependence and protracted withdrawal did not alter either 5-HT1A-mediated decrease of CeA GABA release or Htr1a expression but disrupted 5-HT2C-signaling without affecting Htr2c expression. Collectively, our study provides detailed insights into modulation of CeA activity by the 5-HT system and unravels the vulnerability of the CeA 5-HT system to chronic alcohol and protracted withdrawal.

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Section: Introductionmentioning

confidence: 99%

Alcohol Dependence and Withdrawal Impair Serotonergic Regulation of GABA Transmission in the Rat Central Nucleus of the Amygdala

et al. 2020

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“…This is of interest because cSNC effects have shared neurochemical and neurobiological underpinnings with addiction (for a review, see Ortega et al, 2017); for example, recent research has shown that inactivation of the central amygdala (CeA) prevents a cSNC effect following a sucrose downshift task (Guarino et al, 2020). These findings suggest that the CeA, a brain region also implicated in the development of AUD (for a review, see Roberto et al, 2020), is crucial for cSNC. Recent work has also found that rats exposed to binge levels of EtOH during adolescence show greater cSNC (lower sucrose consumption) following a downshift protocol than control (Lerma-Cabrera et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

High Alcohol–Preferring Mice Show Reaction to Loss of Ethanol Reward Following Repeated Binge Drinking

Ardinger

Grahame

Lapish

et al. 2020

Alcoholism Clin & Exp Res

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Background Beyond yielding high blood ethanol (EtOH) concentrations (BECs), binge‐drinking models allow examination of drinking patterns which may be associated with EtOH’s rewarding effects, including front‐loading and consummatory successive negative contrast (cSNC), a decrease in intake when only water is available to subjects expecting EtOH. The goals of the current study were to broaden our understanding of these reward‐related behaviors during binge EtOH access in high alcohol–preferring (HAP) replicate lines (HAP2 and HAP3) of mice selectively bred to prefer alcohol. We hypothesized that both lines would show evidence of front‐loading during binge EtOH access and that we would find a cSNC effect in groups where EtOH was replaced with water, as these results have been shown previously in HAP1 mice. Methods HAP replicate 2 and replicate 3 female and male mice were given 2 hours of EtOH or water access in the home cage for 15 consecutive days using "drinking in the dark" (DID) procedures. Mice received the same fluid (either 20% unsweetened EtOH or water) for the first 14 days. However, on the 15th day, half of the mice from these 2 groups were provided with the opposite assigned fluid (EtOH groups received water and vice versa). Intake was measured in 1‐minute bins using specialized sipper tubes, which allowed within‐session analyses of binge‐drinking patterns. Results EtOH front‐loading was observed in both replicates. HAP3 mice displayed front‐loading on the first day of EtOH access, whereas front‐loading developed following alcohol experience in HAP2 mice, which may suggest differences in initial sensitivity to EtOH reward. Consummatory SNC, which manifests as lower water intake in mice expecting EtOH as compared to mice expecting water, was observed in both replicates. Conclusions These findings increase confidence that defined changes in home cage consummatory behavior are driven by the incentive value of EtOH. The presence of cSNC across HAP replicates indicates that this reaction to loss of reward is genetically mediated, which suggests that there is a biological mechanism that might be targeted.

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“…Furthermore, alterations in the expression of genes encoding some GABA A and GABA B receptor subunits, as well as GABA transporters, have been shown to influence the predisposition to high alcohol consumption and vulnerability to AUD in humans, as well as AUD-like behaviour in rodents 11,12 . The central nucleus of the amygdala (CeA) is a key neural locus in which the GABAergic system mediates neuroadaptations involved in alcohol drinking behaviours 13,14 . Both acute and chronic alcohol exposure increase GABAergic transmission in CeA and alcoholdependent rats show increased baseline GABA levels in the CeA compared to alcohol-naïve rats 13,14 .…”

Section: Introductionmentioning

confidence: 99%

“…The central nucleus of the amygdala (CeA) is a key neural locus in which the GABAergic system mediates neuroadaptations involved in alcohol drinking behaviours 13,14 . Both acute and chronic alcohol exposure increase GABAergic transmission in CeA and alcoholdependent rats show increased baseline GABA levels in the CeA compared to alcohol-naïve rats 13,14 . Infusion of a GABA A receptor antagonist into the CeA reduces alcohol selfadministration in non-dependent rats 15 , whereas microinjection of a GABA A receptor agonist reduces self-administration in alcohol-dependent but not in non-dependent rats 14,16 , indicating that the development of alcohol dependence is associated with adaptations in the GABAergic system within the CeA.…”

Section: Introductionmentioning

confidence: 99%

Baclofen decreases compulsive alcohol drinking in rats characterised by reduced levels of GAT-3 in the central amygdala

Martí‐Prats

Belin

Fouyssac

et al. 2020

Preprint

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AbstractWhile most individuals with access to alcohol drink it recreationally, about 5 % lose control over their intake and progressively develop an alcohol use disorder (AUD), characterised by compulsive alcohol drinking accompanied by decreased interest in alternative sources of reinforcement. The neural and molecular mechanisms underlying the vulnerability to switch from controlled to compulsive alcohol intake have not been fully characterized, so limiting the development of new treatments for AUD. It has recently been shown that rats having reduced levels of expression of the gamma-aminobutyric acid (GABA) transporter, GAT-3, in the amygdala tend to persist in seeking and drinking alcohol even when adulterated with quinine, suggesting that pharmacological interventions aimed at restoring GABA homeostasis in these individuals may provide a targeted treatment to limit compulsive alcohol drinking. Here, we tested the hypothesis that the GABAB receptor agonist baclofen, which decreases GABA release, specifically decreases compulsive alcohol drinking in vulnerable individuals. In a large cohort of Sprague-Dawley rats allowed to drink alcohol under an intermittent two-bottle choice procedure, a cluster of individuals was identified that persisted in drinking alcohol despite adulteration or the availability of an alternative ingestive reinforcer, saccharin. In these rats, that were characterised by decreased GAT-3 mRNA levels in the central amygdala, acute baclofen administration (1.5 mg/kg, intraperitoneal) resulted in a decrease in compulsive drinking. These results indicate that low GAT-3 mRNA levels in the central amygdala represent an endophenotype of AUD and that the associated compulsive alcohol drinking characteristic is sensitive to baclofen.

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The Role of the Central Amygdala in Alcohol Dependence

Cited by 82 publications

References 234 publications

Alcohol Dependence and Withdrawal Impair Serotonergic Regulation of GABA Transmission in the Rat Central Nucleus of the Amygdala

Alcohol Dependence and Withdrawal Impair Serotonergic Regulation of GABA Transmission in the Rat Central Nucleus of the Amygdala

High Alcohol–Preferring Mice Show Reaction to Loss of Ethanol Reward Following Repeated Binge Drinking

Baclofen decreases compulsive alcohol drinking in rats characterised by reduced levels of GAT-3 in the central amygdala

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