Impulsivity Derived From the Dark Side: Neurocircuits That Contribute to Negative Urgency

Zorrilla, Eric P.; Koob, George F.

doi:10.3389/fnbeh.2019.00136

Cited by 70 publications

(49 citation statements)

References 154 publications

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“…We had hypothesized that CeA CRF neurons would not only drive negative affect but also increase alcohol drinking by mimicking negative reinforcement-driven escalation of alcohol self-administration elicited by CIE [59]. However, neither acute nor chronic chemogenetic stimulation of CeA CRF neurons altered alcohol intake in mice given limited access to alcohol.…”

Section: Discussionmentioning

confidence: 99%

Chemogenetic stimulation of mouse central amygdala corticotropin-releasing factor neurons: Effects on cellular and behavioral correlates of alcohol dependence

Kreifeldt

Herman

Sidhu

et al. 2020

Preprint

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Background. Corticotropin-releasing factor (CRF) signaling in the central nucleus of the amygdala (CeA) plays a critical role in rodent models of excessive alcohol drinking.However, the source of CRF acting in the CeA during alcohol withdrawal remains to be identified. In the present study, we hypothesized that CeA CRF interneurons may represent a behaviorally relevant source of CRF to the CeA increasing motivation for alcohol via negative reinforcement.Methods. We tested this hypothesis in male mice and used chemogenetics to stimulate CeA CRF neurons in vitro and in vivo.Results. We first observed that Crh mRNA expression in the anterior part of the mouse CeA, at the junction with the interstitial nucleus of the posterior limb of the anterior commissure, correlates positively with alcohol intake in C57BL/6J males with a history of chronic binge drinking. We then found that chemogenetic activation of CeA CRF neurons in Crh-IRES-Cre mouse brain slices increases gamma-aminobutyric acid (GABA) release in the medial CeA in part via CRF1 receptor activation, indicating local CRF release. While chemogenetic stimulation of CeA CRF neurons exacerbated novelty-induced feeding suppression, as seen in C57BL/6J males withdrawn from chronic intermittent alcohol inhalation, it had no effect on voluntary alcohol consumption, following either acute or chronic manipulation.Conclusions. Altogether, these findings indicate that hyperactivity of CeA CRF neurons may contribute to elevated CeA GABA levels and negative affect during alcohol withdrawal but is not sufficient to drive alcohol intake escalation in dependent mice. amygdala (CeA) during alcohol withdrawal [12] and blockade of CRF1 signaling in the CeA reduces the anxiogenic-like effect of alcohol withdrawal [13,14], dependenceinduced increases in alcohol self-administration [15, 16], as well as heavy binge drinking [17]. CRF1 in the CeA also mediates the elevation of gamma-aminobutyric acid (GABA) 4 dialysate induced by alcohol dependence [18] and CRF1 overexpression in the CeA potentiates stress-induced reinstatement of alcohol seeking [19].Despite this wealth of converging evidence, the specific neurons responsible for the release of CRF in the CeA during alcohol withdrawal have not been identified. In the present study, we tested the hypothesis that these neurons are intrinsic to the CeA. This hypothesis was supported by evidence that Crh is upregulated in the CeA of alcoholdependent and post-dependent rats [18,20,21], along with our own findings (reported here) that Crh expression in the anterior part of the CeA correlates with alcohol intake in mice with a history of chronic alcohol drinking followed by abstinence. Importantly, psychological stress also upregulates Crh in the CeA [22][23][24] and CRF synthesis in the CeA plays a critical role in mediating anxiety-like behavior [25, 26]. In addition, CRF1expressing neurons in the CeA receive direct input from local interneurons [27] and CeA CRF neurons provide both local inhibitory GABA and excitatory CRF1-mediated sign...

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Section: Discussionmentioning

confidence: 99%

Chemogenetic stimulation of mouse central amygdala corticotropin-releasing factor neurons: Effects on cellular and behavioral correlates of alcohol dependence

Kreifeldt

Herman

Sidhu

et al. 2020

Preprint

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“…The compulsive-like drug seeking effect associated with AUD is thought to involve, among other mechanisms, corticotropin-releasing factor (CRF) signaling in the extended amygdala (i.e., central amygdala, CeA and bed nucleus of the stria terminalis, BNST), which mediates the negative affective states typical of EtOH withdrawal and post-abstinence craving behaviors (Koob and Volkow, 2016 ; Zorrilla and Koob, 2019 ). CRF release increases within the CeA and BNST of EtOH dependent rats during withdrawal (Olive et al, 2002 ; Funk et al, 2006 ), which is thought to drive the increase in subsequent self-administration of EtOH.…”

Section: Potential Central Mechanisms Of High Fat Diet and Alcohol Bementioning

confidence: 99%

Impact of High Fat Diet and Ethanol Consumption on Neurocircuitry Regulating Emotional Processing and Metabolic Function

Coker

Keller

Arnold

et al. 2021

Front. Behav. Neurosci.

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The prevalence of psychiatry disorders such as anxiety and depression has steadily increased in recent years in the United States. This increased risk for anxiety and depression is associated with excess weight gain, which is often due to over-consumption of western diets that are typically high in fat, as well as with binge eating disorders, which often overlap with overweight and obesity outcomes. This finding suggests that diet, particularly diets high in fat, may have important consequences on the neurocircuitry regulating emotional processing as well as metabolic functions. Depression and anxiety disorders are also often comorbid with alcohol and substance use disorders. It is well-characterized that many of the neurocircuits that become dysregulated by overconsumption of high fat foods are also involved in drug and alcohol use disorders, suggesting overlapping central dysfunction may be involved. Emerging preclinical data suggest that high fat diets may be an important contributor to increased susceptibility of binge drug and ethanol intake in animal models, suggesting diet could be an important aspect in the etiology of substance use disorders. Neuroinflammation in pivotal brain regions modulating metabolic function, food intake, and binge-like behaviors, such as the hypothalamus, mesolimbic dopamine circuits, and amygdala, may be a critical link between diet, ethanol, metabolic dysfunction, and neuropsychiatric conditions. This brief review will provide an overview of behavioral and physiological changes elicited by both diets high in fat and ethanol consumption, as well as some of their potential effects on neurocircuitry regulating emotional processing and metabolic function.

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“…Taken together these data suggest that several weeks of drug seeking under conditioned reinforcement results in an urge for action ( 55 ) that emerges when animals are deprived of the opportunity to express this well-consolidated, or ingrained, cocaine seeking habit. This urge to act ( 55 ) following instrumental deprivation may resemble the motor urges characteristic of impulsive/compulsive disorders such as Tourette syndrome ( 56 ) or compulsive eating ( 57 ), that have been suggested to be a manifestation of the negative urgency ( 58–60 ) that can precede and mediate relapse ( 59, 61 ).…”

Section: Main Textmentioning

confidence: 99%

“…We hypothesized that the post-instrumental deprivation rebound of responding at relapse reflects a behavioural response driven by an urge to act that is goal-directed, but the goal is not the drug, but to respond and hence alleviate the negative state associated with the urge ( 59 ). We further hypothesized that rather than being mediated by the aDLS-dependent habit system on which well-established cue-controlled cocaine seeking has been consistently shown to rely ( 14, 41, 42, 44, 62 ), the rebound would instead depend on re-engagement of the pDMS goal-directed system ( 63, 64 ).…”

Section: Main Textmentioning

confidence: 99%

Maladaptive cue-controlled cocaine-seeking habits promote increased relapse severity in rats

Fouyssac

Peña-Oliver

Puaud

et al. 2021

Preprint

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The inflexible pursuit of drug-seeking and great tendency to relapse that characterize addiction has been associated with the recruitment of the dorsolateral striatum-dependent habit system. However, the mechanisms by which maladaptive drug-seeking habits influence subsequent relapse are obscure. Here, we show that rats with a long history of cocaine-seeking, controlled by drug-paired cues and mediated by the habit system, show highly exacerbated drug-seeking at relapse that is not mediated by cocaine withdrawal. This heightened tendency to relapse is underpinned by transient engagement of the dorsomedial striatum goal-directed system and reflects emergent negative urgency resulting from the prevention of enacting the seeking habit during abstinence. These results reveal a novel mechanism underlying the pressure to relapse and indicate a target for preventing it.One Sentence SummaryInstrumental deprivation triggers flexibility in the well-established cue-controlled cocaine-seeking behaviour.

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Impulsivity Derived From the Dark Side: Neurocircuits That Contribute to Negative Urgency

Cited by 70 publications

References 154 publications

Chemogenetic stimulation of mouse central amygdala corticotropin-releasing factor neurons: Effects on cellular and behavioral correlates of alcohol dependence

Chemogenetic stimulation of mouse central amygdala corticotropin-releasing factor neurons: Effects on cellular and behavioral correlates of alcohol dependence

Impact of High Fat Diet and Ethanol Consumption on Neurocircuitry Regulating Emotional Processing and Metabolic Function

Maladaptive cue-controlled cocaine-seeking habits promote increased relapse severity in rats

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