Adolescent Alcohol Drinking Renders Adult Drinking BLA-Dependent: BLA Hyper-Activity as Contributor to Comorbid Alcohol Use Disorder and Anxiety Disorders

Moaddab, Mahsa; Mangone, Elizabeth; Ray, Madelyn H.; McDannald, Michael A.

doi:10.3390/brainsci7110151

Cited by 14 publications

(8 citation statements)

References 110 publications

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“…However, differences in observed drinking patterns are not uncommon and can be due to a variety of methodological differences such as age, bottle type, housing conditions, and the nature of previous alcohol experience [ 25 , 44 ]. The pattern we observed is highly consistent with previous reports from our laboratory irrespective of [ 27 , 45 , 46 ] and following fear discrimination [ 47 ]. OF course, we cannot rule out that prior fear conditioning influenced alcohol consumption.…”

Section: Discussionsupporting

confidence: 93%

“…The partitioning hypothesis, and our data, suggest that a primary result of lOFC damage is to alter information processing pertaining to fear and alcohol in a larger neural network. LOFC projects to a variety of brain regions critical to processes of fear and alcohol, including prelimibic cortex [ 54 – 56 ], basolateral amygdala [ 45 , 57 , 58 ], central amygdala [ 58 – 60 ], and nucleus accumbens [ 61 – 63 ]. Just as the lOFC organizes and separates information within a single reward task, the lOFC may organize and separate information across distinct motivational mechanisms (fear versus alcohol) in single neurons, or neural ensembles, in a wider neural network.…”

Section: Discussionmentioning

confidence: 99%

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Lateral orbitofrontal cortex partitions mechanisms for fear regulation and alcohol consumption

2018

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Anxiety disorders and alcohol use disorder are highly comorbid, yet identifying neural dysfunction driving comorbidity has been challenging. Lateral orbitofrontal cortex (lOFC) dysfunction has been independently observed in each disorder. Here we tested the hypothesis that the lOFC is essential to partition mechanisms for fear regulation and alcohol consumption. Specifically, the capacity to regulate fear and the propensity to consume alcohol are unrelated when lOFC is intact, but become linked through lOFC dysfunction. Male Long Evans rats received bilateral, neurotoxic lOFC lesions or sham surgery. Fear regulation was determined by establishing discrimination to danger, uncertainty, and safety cues then shifting the shock probability of the uncertainty cue. Alcohol consumption was assessed through voluntary, intermittent access to 20% ethanol. The neurotoxic lesion approach ensured lOFC dysfunction spanned testing in fear regulation and alcohol consumption. LOFC-lesioned rats demonstrated maladaptive fear generalization during probability shifts, inverting normal prediction error assignment, and subsequently consumed more alcohol. Most novel, fear regulation and alcohol consumption were inextricably linked only in lOFC-lesioned rats: extreme fear regulation predicted excessive alcohol consumption. The results reveal the lOFC is essential to partition mechanisms for fear regulation and alcohol consumption and uncover a plausible source of neural dysfunction contributing to comorbid anxiety disorders and alcohol use disorder.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Lateral orbitofrontal cortex partitions mechanisms for fear regulation and alcohol consumption

2018

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“…Alcohol consumption in rodents is known to vary by species, strain, method, and environment (Crabbe et al., ; Fritz and Boehm, ). Nevertheless, the majority of rodent studies, including those from the NADIA Consortium, report that AIE often, although not always (Moaddab et al., ; Nentwig et al., ; Toalston et al., ; Varlinskaya et al., ), promotes adult alcohol drinking in multiple rat strains (Alaux‐Cantin et al., ; Broadwater et al., ; Gass et al., ; Lee et al., ; Pandey et al., ; Pascual et al., ; Rodd‐Henricks et al., ; Toalston et al., ; Wille‐Bille et al., ). These studies use a variety of AIE exposures as well as alcohol consumption paradigms.…”

Section: Persistent Aie‐induced Effects On Behaviormentioning

confidence: 99%

Mechanisms of Persistent Neurobiological Changes Following Adolescent Alcohol Exposure: NADIA Consortium Findings

Crews

Robinson

Chandler³

et al. 2019

Alcoholism Clin & Exp Res

134

153

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The Neurobiology of Adolescent Drinking in Adulthood (NADIA) Consortium has focused on the impact of adolescent binge drinking on brain development, particularly on effects that persist into adulthood. Adolescent binge drinking is common, and while many factors contribute to human brain development and alcohol use during adolescence, animal models are critical for understanding the specific consequences of alcohol exposure during this developmental period and the underlying mechanisms. Using adolescent intermittent ethanol (AIE) exposure models, NADIA investigators identified long‐lasting AIE‐induced changes in adult behavior that are consistent with observations in humans, such as increased alcohol drinking, increased anxiety (particularly social anxiety), increased impulsivity, reduced behavioral flexibility, impaired memory, disrupted sleep, and altered responses to alcohol. These behavioral changes are associated with multiple molecular, cellular, and physiological alterations in the brain that persist long after AIE exposure. At the molecular level, AIE results in long‐lasting changes in neuroimmune/trophic factor balance and epigenetic–microRNA (miRNA) signaling across glia and neurons. At the cellular level, AIE history is associated in adulthood with reduced expression of cholinergic, serotonergic, and dopaminergic neuron markers, attenuated cortical thickness, decreased neurogenesis, and altered dendritic spine and glial morphology. This constellation of molecular and cellular adaptations to AIE likely contributes to observed alterations in neurophysiology, measured by synaptic physiology, EEG patterns, and functional connectivity. Many of these AIE‐induced brain changes replicate findings seen in postmortem brains of humans with alcohol use disorder (AUD). NADIA researchers are now elucidating mechanisms of these adaptations. Emerging data demonstrate that exercise, antiinflammatory drugs, anticholinesterases, histone deacetylase inhibitors, and other pharmacological compounds are able to prevent (administered during AIE) and/or reverse (given after AIE) AIE‐induced pathology in adulthood. These studies support hypotheses that adolescent binge drinking increases risk of adult hazardous drinking and influences brain development, and may provide insight into novel therapeutic targets for AIE‐induced neuropathology and AUDs.

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“…Interestingly, adolescent ethanol exposure produces alterations to histone modification and DNA methylation mechanisms in the central amygdala, but not the BLA, which have been linked to increased anxiety-like behaviors (Pandey et al, 2015;Sakharkar et al, 2019). However, functional changes in the BLA caused by adolescent ethanol exposure have been implicated in affective and reward-related dysfunction in adulthood (Moaddab, Mangone, Ray, & McDannald, 2017). This suggests that mechanisms in the BLA independent of epigenetic processes, such as synaptic transmission, may be disrupted long term.…”

Section: Introductionmentioning

confidence: 99%

Moderate adolescent chronic intermittent ethanol exposure sex-dependently disrupts synaptic transmission and kappa opioid receptor function in the basolateral amygdala of adult rats

Przybysz

Gamble

Diaz

2020

Preprint

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Adolescent alcohol exposure is associated with many negative outcomes that persist into adulthood, including altered affective and reward-related behaviors. However, the long-term neurological disruptions underlying these behavioral states are not fully understood. The basolateral amygdala (BLA) plays a critical role in many of these behaviors, and shifts in the excitatory/inhibitory balance in this area are capable of directly modulating their expression.While changes to BLA physiology have been demonstrated during the acute withdrawal phase following adolescent ethanol exposure, no studies to date have examined whether these persist long-term. The kappa opioid receptor (KOR) system is a neuromodulatory system that acts as a prominent mediator of negative affective behaviors, and alterations of this system have been implicated in the behavioral profile caused by chronic alcohol exposure in adulthood. Notably, in the BLA, the KOR system undergoes functional changes between adolescence and adulthood, but whether BLA KORs are functionally disrupted by adolescent ethanol exposure has not been examined. In this study, we exposed male and female Sprague-Dawley rats to a vapor inhalation model of moderate adolescent chronic intermittent ethanol (aCIE) and examined the long-term effects on GABAergic and glutamatergic neurotransmission within the adult BLA using whole-cell patch-clamp electrophysiology. We also assessed how KOR activation modulated these neurotransmitter systems in aCIE versus control rats using the selective KOR agonist, U69593. This investigation revealed that aCIE exposure disrupted basal glutamate transmission in females by increasing spontaneous excitatory postsynaptic current (sEPSC) frequency, while having no effects on glutamate transmission in males or GABA transmission in either sex.Interestingly, we also found that aCIE exposure unmasked a KOR-mediated suppression of spontaneous inhibitory postsynaptic current (sIPSC) frequency and sEPSC amplitude only in males, with no effects of aCIE exposure on KOR function in females. Together, these data suggest that moderate-level adolescent ethanol exposure produces long-term changes to BLA physiology and BLA KOR function, and that these changes are sex-dependent. This is the first study to examine persistent adaptations to both BLA physiology and KOR function following adolescent alcohol exposure, and opens a broad avenue for future investigation into other neurobiological and behavioral consequences of adolescent ethanol exposure-induced disruptions of these systems.

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Adolescent Alcohol Drinking Renders Adult Drinking BLA-Dependent: BLA Hyper-Activity as Contributor to Comorbid Alcohol Use Disorder and Anxiety Disorders

Cited by 14 publications

References 110 publications

Lateral orbitofrontal cortex partitions mechanisms for fear regulation and alcohol consumption

Lateral orbitofrontal cortex partitions mechanisms for fear regulation and alcohol consumption

Mechanisms of Persistent Neurobiological Changes Following Adolescent Alcohol Exposure: NADIA Consortium Findings

Moderate adolescent chronic intermittent ethanol exposure sex-dependently disrupts synaptic transmission and kappa opioid receptor function in the basolateral amygdala of adult rats

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