Role of the GABAa and GABAb receptors of the central nucleus of the amygdala in compulsive cocaine-seeking behavior in male rats

Sun, Wenlin; Yuill, Matt B

doi:10.1007/s00213-020-05653-2

Cited by 11 publications

(4 citation statements)

References 52 publications

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“…Our results rule out the role of Cg1-aIC circuit in compulsive cocaine use. However, the current data could not fully exclude a small number of aIC-OFC projections and the other aIC-related pathways, such as amygdala to aIC projections ( 49 ), which might also contribute to compulsive cocaine use.…”

Section: Discussionmentioning

confidence: 73%

An orbitofrontal cortex–anterior insular cortex circuit gates compulsive cocaine use

et al. 2022

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Compulsive drug use, a cardinal symptom of drug addiction, is characterized by persistent substance use despite adverse consequences. However, little is known about the neural circuit mechanisms behind this behavior. Using a footshock-punished cocaine self-administration procedure, we found individual variability of rats in the process of drug addiction, and rats with compulsive cocaine use presented increased neural activity of the anterior insular cortex (aIC) compared with noncompulsive rats. Chemogenetic manipulating activity of aIC neurons, especially aIC glutamatergic neurons, bidirectionally regulated compulsive cocaine intake. Furthermore, the aIC received inputs from the orbitofrontal cortex (OFC), and the OFC-aIC circuit was enhanced in rats with compulsive cocaine use. Suppression of the OFC-aIC circuit switched rats from punishment resistance to sensitivity, while potentiation of this circuit increased compulsive cocaine use. In conclusion, our results found that aIC glutamatergic neurons and the OFC-aIC circuit gated the shift from controlled to compulsive cocaine use, which could serve as potential therapeutic targets for drug addiction.

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Section: Discussionmentioning

confidence: 73%

An orbitofrontal cortex–anterior insular cortex circuit gates compulsive cocaine use

et al. 2022

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“…Moreover, short hairpin RNA knockdown of GAT-3 in the high incentive preferring group increased choice behaviour for alcohol, demonstrating a causal role of GABA-ergic mechanisms in the CeA in the development of alcohol-choice behaviour. Activation of GABA receptors in the CeA has also been shown to influence cocaine seeking under punishment (Sun & Yuill, 2020). Thus, reversibly inactivating doses of GABA agonists in the CeA increased the number of punished seeking responses.…”

Section: Gabamentioning

confidence: 99%

Neurochemical substrates linked to impulsive and compulsive phenotypes in addiction: A preclinical perspective

Jones

Zühlsdorff

Dalley

2021

Journal of Neurochemistry

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Drug compulsion manifests in some but not all individuals and implicates multifaceted processes including failures in top‐down cognitive control as drivers for the hazardous pursuit of drug use in some individuals. As a closely related construct, impulsivity encompasses rash or risky behaviour without foresight and underlies most forms of drug taking behaviour, including drug use during adverse emotional states (i.e., negative urgency). While impulsive behavioural dimensions emerge from drug‐induced brain plasticity, burgeoning evidence suggests that impulsivity also predates the emergence of compulsive drug use. Although the neural substrates underlying the apparently causal relationship between trait impulsivity and drug compulsion are poorly understood, significant advances have come from the interrogation of defined limbic cortico‐striatal circuits involved in motivated behaviour and response inhibition, together with chemical neuromodulatory influences from the ascending neurotransmitter systems. We review what is presently known about the neurochemical mediation of impulsivity, in its various forms, and ask whether commonalities exist in the neurochemistry of compulsive drug‐motivated behaviours that might explain individual risk for addiction. image

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“…The CeA is composed primarily of GABAergic neurons and represents the major output area of the larger amygdaloid complex ( Gilpin et al, 2015 ; Roberto et al, 2020 ). Chronic administration of drugs of abuse including ethanol ( Roberto et al, 2010 , 2004 ; Gilpin et al, 2015 ; Kirson et al, 2021 ), cocaine ( Kallupi et al, 2013 ; Schmeichel et al, 2017 ; Sun and Yuill, 2020 ), methamphetamine ( Li et al, 2015 ), or opioids ( Bajo et al, 2014 , 2011 ; Nguyen et al, 2017b ; Kallupi et al, 2020 ) enhance CeA GABA transmission representing a key molecular mechanism underlying maladaptive behaviors associated with addiction. Importantly, the CeA expresses several pro- and anti-stress promoting systems regulating its neuronal activity including the dynorphin/kappa opioid receptor (KOR) system, and chronic administration of drugs of abuse recruits these CeA stress systems ( Koob and Schulkin, 2019 ; Koob, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Self-Administration of Entactogen Psychostimulants Dysregulates Gamma-Aminobutyric Acid (GABA) and Kappa Opioid Receptor Signaling in the Central Nucleus of the Amygdala of Female Wistar Rats

Khom

Nguyen

Vandewater

et al. 2021

Front. Behav. Neurosci.

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Male rats escalate intravenous self-administration of entactogen psychostimulants, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxymethamphetamine (MDMA) under extended access conditions, as with typical psychostimulants. Here, we investigated whether female rats escalate self-administration of methylone, 3,4-methylenedioxypentedrone (pentylone), and MDMA and then studied consequences of MDMA and pentylone self-administration on GABAA receptor and kappa opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA), a brain area critically dysregulated by extended access self-administration of alcohol or cocaine. Adult female Wistar rats were trained to self-administer methylone, pentylone, MDMA (0.5 mg/kg/infusion), or saline-vehicle using a fixed-ratio 1 response contingency in 6-h sessions (long-access: LgA) followed by progressive ratio (PR) dose-response testing. The effects of pentylone-LgA, MDMA-LgA and saline on basal GABAergic transmission (miniature post-synaptic inhibitory currents, mIPSCs) and the modulatory role of KOR at CeA GABAergic synapses were determined in acute brain slices using whole-cell patch-clamp. Methylone-LgA and pentylone-LgA rats similarly escalated their drug intake (both obtained more infusions compared to MDMA-LgA rats), however, pentylone-LgA rats reached higher breakpoints in PR tests. At the cellular level, baseline CeA GABA transmission was markedly elevated in pentylone-LgA and MDMA-LgA rats compared to saline-vehicle. Specifically, pentylone-LgA was associated with increased CeA mIPSC frequency (GABA release) and amplitude (post-synaptic GABAA receptor function), while mIPSC amplitudes (but not frequency) was larger in MDMA-LgA rats compared to saline rats. In addition, pentylone-LgA and MDMA-LgA profoundly disrupted CeA KOR signaling such as both KOR agonism (1 mM U50488) and KOR antagonism (200 nM nor-binaltorphimine) decreased mIPSC frequency suggesting recruitment of non-canonical KOR signaling pathways. This study confirms escalated self-administration of entactogen psychostimulants under LgA conditions in female rats which is accompanied by increased CeA GABAergic inhibition and altered KOR signaling. Collectively, our study suggests that CeA GABA and KOR mechanisms play a critical role in entactogen self-administration like those observed with escalation of alcohol or cocaine self-administration.

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Role of the GABAa and GABAb receptors of the central nucleus of the amygdala in compulsive cocaine-seeking behavior in male rats

Cited by 11 publications

References 52 publications

An orbitofrontal cortex–anterior insular cortex circuit gates compulsive cocaine use

An orbitofrontal cortex–anterior insular cortex circuit gates compulsive cocaine use

Neurochemical substrates linked to impulsive and compulsive phenotypes in addiction: A preclinical perspective

Self-Administration of Entactogen Psychostimulants Dysregulates Gamma-Aminobutyric Acid (GABA) and Kappa Opioid Receptor Signaling in the Central Nucleus of the Amygdala of Female Wistar Rats

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