scholarly journals Central amygdala CRF pathways in alcohol dependence

2017 ◽  
Author(s):  
Giordano de Guglielmo ◽  
Marsida Kallupi ◽  
Matthew B. Pomrenze ◽  
Elena Crawford ◽  
Sierra Simpson ◽  
...  
Keyword(s):  
Alcohol Dependence ◽  
Optical Fibers ◽  
Alcohol Drinking ◽  
Ethanol Vapor ◽  
Central Nucleus ◽  
Self Administration ◽  
Neuronal Ensemble ◽  
Excessive Alcohol ◽  
Crf Neurons

AbstractAlcohol withdrawal activates a neuronal ensemble in the central nucleus of the amygdala (CeA) that is responsible for high levels of uncontrolled alcohol drinking. However, the neuronal phenotypes and circuits controlled by these neurons are unknown. We investigated the cellular identity of this CeA neuronal ensemble and found that most neurons expressed corticotropin-releasing factor (CRF). Using Crh-Cre transgenic rats combined with in vivo optogenetics, we tested the role of CeA CRF neurons and their projections in excessive alcohol self-administration during withdrawal. Rats were injected with AAV-DIO-NpHR-eYFP or AAV-DIO-eYFP and implanted with optical fibers over the CeA. Animals were then exposed to chronic intermittent ethanol vapor to induce alcohol dependence. Inactivation of CeA CRF neurons decreased alcohol drinking in dependent rats to non-dependent levels and completely suppressed activation of the CeA neuronal ensemble (Fos+ neurons) during withdrawal. No effects were observed on water or saccharin self-administration. In a second experiment, CeA CRF neurons were infected with AAV-DIO-NpHR-eYFP and optical fibers were implanted into downstream projection regions, including the bed nucleus of the stria terminalis (BNST), lateral hypothalamus (LH), parasubthalamic nucleus (pSTN), substantia innominata (SI), and parabrachial nuclei (PBN). Optogenetic inactivation of CRF terminals in the BNST reduced alcohol drinking and withdrawal signs, whereas inactivation of all other projections had no effect. These results demonstrate that CeA CRF neurons and their projections to the BNST drive excessive alcohol drinking and withdrawal in dependent rats.

scholarly journals Recruitment of a Neuronal Ensemble in the Central Nucleus of the Amygdala Is Required for Alcohol Dependence

2016 ◽  
Vol 36 (36) ◽  
pp. 9446-9453 ◽  
Author(s):  
Giordano de Guglielmo ◽  
Elena Crawford ◽  
Sarah Kim ◽  
Leandro F. Vendruscolo ◽  
Bruce T. Hope ◽  
...  
Keyword(s):  
Alcohol Dependence ◽  
Central Nucleus ◽  
Neuronal Ensemble

scholarly journals Kappa Opioid Receptor and Dynorphin Signaling in the Central Amygdala Regulates Alcohol Intake

2019 ◽  
Author(s):  
Daniel W. Bloodgood ◽  
Dipanwita Pati ◽  
Melanie M. Pina ◽  
Sofia Neira ◽  
J. Andrew Hardaway ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Alcohol Drinking ◽  
Alcohol Intake ◽  
Gene Knockout ◽  
Kappa Opioid Receptor ◽  
Conditional Knockout ◽  
Central Nucleus ◽  
Kappa Opioid ◽  
Excessive Alcohol Consumption ◽  
Excessive Alcohol

AbstractExcessive alcohol drinking has been shown to modify brain circuitry to predispose individuals for future alcohol abuse. Previous studies have implicated the central nucleus of the amygdala (CeA) as an important site for mediating the somatic symptoms of withdrawal and for regulating alcohol intake. In addition, recent work has established a role for both the Kappa Opioid Receptor (KOR) and its endogenous ligand dynorphin in mediating these processes. However, it is unclear whether these effects are due to dynorphin or KOR arising from within the CeA itself or other input brain regions. To directly examine the role of preprodynorphin (PDYN) and KOR expression in CeA neurons, we performed region-specific conditional knockout of these genes and assessed the effects on the Drinking in the Dark (DID) and Intermittent Access (IA) paradigms. We then examined the effects of DID on PDYN and KOR modulation of CeA circuit physiology. Conditional gene knockout resulted in sex-specific responses wherein PDYN knockout decreased alcohol drinking in both male and female mice, whereas KOR knockout decreased drinking in males only. We also found that neither PDYN nor KOR knockout protected against anxiety caused by alcohol drinking. Lastly, a history of alcohol drinking did not alter synaptic transmission in PDYN neurons in the CeA of either sex, but excitability of PDYN neurons was increased in male mice only. Taken together, our findings indicate that PDYN and KOR signaling in the CeA plays an important role in regulating excessive alcohol consumption and highlight the need for future studies to examine how this is mediated through downstream effector regions.

scholarly journals Glutamate plasticity woven through the progression to alcohol use disorder: a multi-circuit perspective

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 298 ◽  
Author(s):  
Lara Hwa ◽  
Joyce Besheer ◽  
Thomas Kash
Keyword(s):  
Alcohol Use ◽  
Alcohol Drinking ◽  
Metabotropic Glutamate Receptor ◽  
Heavy Drinking ◽  
Ethanol Vapor ◽  
Research Field ◽  
Self Administration ◽  
Excitatory Neurotransmitter ◽  
Heavy Alcohol ◽  
Heavy Alcohol Use

Glutamate signaling in the brain is one of the most studied targets in the alcohol research field. Here, we report the current understanding of how the excitatory neurotransmitter glutamate, its receptors, and its transporters are involved in low, episodic, and heavy alcohol use. Specific animal behavior protocols can be used to assess these different drinking levels, including two-bottle choice, operant self-administration, drinking in the dark, the alcohol deprivation effect, intermittent access to alcohol, and chronic intermittent ethanol vapor inhalation. Importantly, these methods are not limited to a specific category, since they can be interchanged to assess different states in the development from low to heavy drinking. We encourage a circuit-based perspective beyond the classic mesolimbic-centric view, as multiple structures are dynamically engaged during the transition from positive- to negative-related reinforcement to drive alcohol drinking. During this shift from lower-level alcohol drinking to heavy alcohol use, there appears to be a shift from metabotropic glutamate receptor-dependent behaviors to N-methyl-D-aspartate receptor-related processes. Despite high efficacy of the glutamate-related pharmaceutical acamprosate in animal models of drinking, it is ineffective as treatment in the clinic. Therefore, research needs to focus on other promising glutamatergic compounds to reduce heavy drinking or mediate withdrawal symptoms or both.

scholarly journals Bioinformatics identification and pharmacological validation of Kcnn3/KCa2 channels as a mediator of negative affective behaviors and excessive alcohol drinking in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Audrey E. Padula ◽  
Jennifer A. Rinker ◽  
Marcelo F. Lopez ◽  
Megan K. Mulligan ◽  
Robert W. Williams ◽  
...  
Keyword(s):  
Alcohol Dependence ◽  
Mood Disorders ◽  
Alcohol Drinking ◽  
Heavy Drinking ◽  
Alcohol Exposure ◽  
Sk Channel ◽  
Affective Behaviors ◽  
Positive Modulator ◽  
Excessive Alcohol ◽  
Alcohol Dependent

AbstractMood disorders are often comorbid with alcohol use disorder (AUD) and play a considerable role in the development and maintenance of alcohol dependence and relapse. Because of this high comorbidity, it is necessary to determine shared and unique genetic factors driving heavy drinking and negative affective behaviors. In order to identify novel pharmacogenetic targets, a bioinformatics analysis was used to quantify the expression of amygdala K+ channel genes that covary with anxiety-related phenotypes in the well-phenotyped and fully sequenced family of BXD strains. We used a model of stress-induced escalation of drinking in alcohol-dependent mice to measure negative affective behaviors during abstinence. A pharmacological approach was used to validate the key bioinformatics findings in alcohol-dependent, stressed mice. Amygdalar expression of Kcnn3 correlated significantly with 40 anxiety-associated phenotypes. Further examination of Kcnn3 expression revealed a strong eigentrait for anxiety-like behaviors and negative correlations with binge-like and voluntary alcohol drinking. Mice treated with chronic intermittent alcohol exposure and repeated swim stress consumed more alcohol in their home cages and showed hypophagia on the novelty-suppressed feeding test during abstinence. Pharmacologically targeting Kcnn gene products with the KCa2 (SK) channel-positive modulator 1-EBIO decreased drinking and reduced feeding latency in alcohol-dependent, stressed mice. Collectively, these validation studies provide central nervous system links into the covariance of stress, negative affective behaviors, and AUD in the BXD strains. Further, the bioinformatics discovery tool is effective in identifying promising targets (i.e., KCa2 channels) for treating alcohol dependence exacerbated by comorbid mood disorders.

scholarly journals Viral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats

2021 ◽  
Vol 15 ◽  
Author(s):  
Margaret A. Minnig ◽  
Tayun Park ◽  
Maria Echeveste Sanchez ◽  
Pietro Cottone ◽  
Valentina Sabino
Keyword(s):  
Nucleus Accumbens ◽  
Alcohol Drinking ◽  
Fixed Ratio ◽  
Loss Of Function ◽  
Nucleus Accumbens Shell ◽  
Self Administration ◽  
Pac1 Receptor ◽  
Excessive Alcohol Consumption ◽  
Excessive Alcohol ◽  
Shrna Knockdown

Alcohol use disorder (AUD) is a chronic, relapsing disorder whose genetic and environmental susceptibility components are not fully understood. Neuropeptidergic signaling has been repeatedly implicated in modulating excessive alcohol drinking, especially within sub-regions of the striatum. Here, we investigated the potential involvement of the selective receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), PAC1R, in the nucleus accumbens shell (NAcc Shell) in excessive alcohol drinking in alcohol-preferring rats, an established animal model of the genetic propensity for alcoholism. Scr:sP alcohol-preferring rats were trained to operantly self-administer alcohol and then either an AAV virus short-hairpin RNA (shRNA) targeted to knockdown PAC1R, or an AAV control virus were microinfused into the NAcc Shell. NAcc Shell PAC1R shRNA knockdown virus was confirmed to significantly decrease PAC1R levels in the NAcc Shell. The effects of NAcc Shell PAC1R shRNA knockdown on ethanol self-administration were investigated using a Fixed Ratio (FR) 1 and a Progressive Ratio (PR) schedule of reinforcement. The effect of PAC1R knockdown on self-administration of an alternative reinforcer, saccharin, was also assessed. The results showed that the reduction in PAC1R in the NAcc Shell led to excessive ethanol drinking, increased preference for ethanol, and higher motivation to drink. NAcc Shell PAC1R shRNA knockdown did not comparably increase saccharin self-administration, suggesting selectivity of action. These data suggest that NAcc Shell PAC1R may serves as a “brake” on alcohol drinking, and thereby the loss of function of PAC1R leads to excessive alcohol consumption. Therefore, the PACAP/PAC1R system may represent a novel target for the treatment of AUD.

scholarly journals Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence

2013 ◽  
Vol 20 (1) ◽  
pp. 38-42 ◽  
Author(s):  
Richard L. Bell ◽  
Marcelo F. Lopez ◽  
Changhai Cui ◽  
Mark Egli ◽  
Kirk W. Johnson ◽  
...  
Keyword(s):  
Animal Models ◽  
Alcohol Dependence ◽  
Alcohol Drinking
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