Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal

doi:10.1016/0006-8993(93)91352-S

Brain Research

Volume 605, Issue 1, 5 March 1993, Pages 25-32

https://doi.org/10.1016/0006-8993(93)91352-S Get rights and content

Abstract

Previous studies have shown that spontaneous exploration of the Elevated Plus Maze provides a sensitive measure of ‘anxiety’ induced by pharmacological or behavioral stressors. In particular, the percent time spent exploring the open arms of the plus maze is decreased during ethanol withdrawal, and this effect is antagonized by intracerebroventricular administration of 25 μg of alpha-helical CRF, a corticotropin-releasing factor antagonist (H.A. Baldwin et al.,Psychopharmacology, 103 (1991) 227–232). The present study was designed to examine the effect of α-helical CRF infusion within the central nucleus of the amygdala during ethanol withdrawal. Rats were made dependent on ethanol by maintenance on an ethanol-containing liquid diet for 16 days, withdrawn from ethanol and tested on the elevated plus maze at 8 h post-ethanol access. In comparison with pair-fed control rats, ethanol withdrawn subjects spent significantly less percent time exploring the open arms of the plus maze. This decrease in open arm exploration was antagonized by administration of α-helical CRF (250 ng) bilaterally into the central nucleus of the amygdala, but not by intracerebroventricular administration of 250 ng of α-helical CRF. The ability of intra-amygdala α-helical CRF to antagonize decreased open arm exploration is unlikely to be due to changes in motor activity, since general activity on the maze was reduced in all EtOH withdrawal groups. These results suggest that the central nucleus of the amygdala may be an effective site for endogenous CRF systems to mediate anxious behavior associated with ethanol withdrawal.

Reference (66)

BrittonD.R. et al.
Intraventricular corticotropin-releasing factor enhances behavioral effects of novelty
Life Sci.
(1982)
BrittonK.T. et al.
Corticotropin releasing factor (CRF) receptor antagonist blocks activating and “anxiogenic” actions of CRF in the rat
Brain Res.
(1986)
DunnA.J. et al.
Physiological and behavioral responses to corticotropin-releasing factor administration: Is CRF a mediator of anxiety or stress responses?
Brain Res. Rev.
(1990)
DunnA.J. et al.
Corticotropin-releasing factor has an anxiogenic action in the social interaction test
Horm. Behav.
(1987)
EavesM. et al.
Effects of corticotropin releasing factor on locomotor activity in hypophysectomized rats
Peptides
(1985)
FileS.E. et al.
Effects of baclofen and nitrendipine on ethanol withdrawal responses in the rat
Neuropharmacology
(1991)
GonzalezL.P. et al.
Intranigral muscimol suppresses ethanol withdrawal seizures
Brain Res.
(1984)
HeinrichsS.C. et al.
Corticotropin-releasing factor antagonist reduces emotioality in socially defeated rats via direct neurotropic action
Brain Res.
(1992)
KeithL.D. et al.
Ethanol dependence and the pituitary adrenal axis in mice II. Temporal analysis of dependence and withdrawal
Life Sci.
(1983)
MerchenthalerI. et al.
Immunocytochemical localization of corticotropin-releasing factor (CRF)-like immunoreactivity in the thalamus of the rat
Brain Res.
(1984)

NolanC.J. et al.

Chronic ethanol consumption depresses hypothalamic-pituitary-adrenal function in aged rats

Life Sci.

(1991)

PohoreckyL.A. et al.

The startle response in rats: Effect of ethanol

Pharmacol. Biochem. Behav.

(1976)

RivierC. et al.

Prolonged exposure to alcohol: Effect on CRF mRNA levels, and CRF- and stress-induced ACTH secretion in the rat

Brain Res.

(1990)

SawchenkoP.E.

Evidence for differential regulation of corticotropin-releasing factor and vasopressin immunoreactivity in parvocellular neurosecretory and autonomic-related projections of the paraventricular nucleus

Brain Res.

(1987)

VolicerL. et al.

Cyclic nucleotides and ethanol tolerance and dependence

Drug Alcohol Depend.

(1979)

WallaceD.M. et al.

The amygdalobrainstem pathway: Selective innervation of dopaminergic, noradrenergic and adrenergic cells in the rat

Neurosci. Lett.

(1989)

AllenJ.P. et al.

Role of the amygdaloid complex in the stress-induced release of ACTH in the rat

Neuroendocrinology

(1974)

BaldwinH.A. et al.

CRF antagonist reverses the ‘anxiogenic’ response to ethanol withdrawal in the rat

Psychopharmacology

(1991)

BeaulieuS. et al.

Participation of the central amygdaloid nucleus in the response of adrenocorticotropin secretion to immobilization stress: Opposing roles of the noradrenergic and dopaminergic systems

Neuroendocrinology

(1987)

BrancheyM. et al.

Modifications in the response to alcohol following the establishment of physical dependence

Psychopharmacology

(1971)

BrittonK.T. et al.

Activating the “anxiogenic” effects of CRF are not inhibited by blockade of the pituitary adrenal system with dexamethasone

Life Sci.

(1986)

BrownM.R. et al.

Corticotropin-releasing factor: Actions on the sympathetic nervous system and metabolism

Endocrinology

(1982)

CainS.T. et al.

Subcellular distribution of corticotropin-releasing factor-like immunoreactivity in rat central nervous system

Neuroendocrinology

(1991)

CooperB.R. et al.

Antagonism of the enhanced susceptibility to audiogenic seizures during alcohol withdrawal in the rat by GABA and GABA-mimetic agents

J. Pharmacol. Exp. Ther.

(1979)

DaveJ.R. et al.

Ethanol exposure decreases pituitary corticotropin-releasing factor binding, adenylate cyclase biosynthesis and plasma β-endorphin levels in the rat

Endocrinology

(1986)

EhlersC.L. et al.

Chronic ethanol exposure potentiates the locomotor activating effects of corticotropin-releasing factor (CRF) in rats

Regul. Pept.

(1987)

EisenhoferG. et al.

Plasma catecholamine responses to change of posture in alcoholics during withdrawal and after continued abstinence from alcohol

Clin. Sci.

(1985)

FileS.E. et al.

Flumazenil but not nitrendipine reverses the increased anxiety during ethanol withdrawal in the rat

Psychopharmacology

(1989)

FileS.E. et al.

Anxiolytic and anxiogenic drugs: changes in behavior and endocrine responses

Stress Medicine

(1988)

FinkR. et al.

Abnormal suppression of plasma cortisol during the intravenous infusion of dexamethasone to alcoholic patients

Clin. Endocrinol.

(1981)

FooteS.L. et al.

Distribution of corticotropin-releasing factor-like immunoreactivity in brainstem of two monkey species (Saimiru sciureus and Macaca fascicularis): An immunohistochemical study

J. Comp. Neurol.

(1988)

FreundG.

Alcohol withdrawal syndrome in mice

Arch. Neurol.

(1969)

GoldsteinD.

Alcohol withdrawal reaction in mice: Effects of drugs that modify neurotransmission

J. Pharmacol. Exp. Ther.

(1973)

Cited by (358)

The Hidden Side of Addiction: Allostatic Load, Health Disparities, and Opioids in the Time of COVID
2023, Biological Psychiatry
Corticotropin releasing factor and drug seeking in substance use disorders: Preclinical evidence and translational limitations
2022, Addiction Neuroscience
The neuropeptide, corticotropin releasing factor (CRF), has been an enigmatic target for the development of medications aimed at treating stress-related disorders. Despite a large body of evidence from preclinical studies in rodents demonstrating that CRF receptor antagonists prevent stressor-induced drug seeking, medications targeting the CRF-R1 have failed in clinical trials. Here, we provide an overview of the abundant findings from preclinical rodent studies suggesting that CRF signaling is involved in stressor-induced relapse. The scientific literature that has defined the receptors, mechanisms and neurocircuits through which CRF contributes to stressor-induced reinstatement of drug seeking following self-administration and conditioned place preference in rodents is reviewed. Evidence that CRF signaling is recruited with repeated drug use in a manner that heightens susceptibility to stressor-induced drug seeking in rodents is presented. Factors that may determine the influence of CRF signaling in substance use disorders, including developmental windows, biological sex, and genetics are examined. Finally, we discuss the translational failure of medications targeting CRF signaling as interventions for substance use disorders and other stress-related conditions. We conclude that new perspectives and research directions are needed to unravel the mysterious role of CRF in substance use disorders.
Knockdown of the astrocytic glucocorticoid receptor in the central nucleus of the amygdala diminishes conditioned fear expression and anxiety
2021, Behavioural Brain Research
The amygdala is a key structure involved in both physiological and behavioural effects of fearful and stressful stimuli. The central stress response is controlled by the activity of the hypothalamic-pituitary-adrenal (HPA) axis via glucocorticoid hormones, acting mainly through glucocorticoid receptors (GR), widely expressed among different brain regions, including the central nucleus of the amygdala (CeA). Although to date, neuronal GR was postulated to be involved in the mediating stress effects, increasing evidence points to the vital role of glial GR. Here, we aimed to evaluate the role of astrocytic GR in CeA in various aspects of the stress response. We used a lentiviral vector to disrupt an astrocytic GR in the CeA of Aldh1l1-Cre transgenic mice. Astrocytic GR knockdown mice (GR KD) exhibited an attenuated expression of fear-related memory in the fear conditioning paradigm. Interestingly, the consolidation of non-stressful memory in the novel object recognition test remained unchanged. Moreover, GR KD group presented reduced anxiety, measured in the open field test. However, knockdown of astrocytic GR in the CeA did not affect an acute response to stress in the tail suspension test. Taken together, obtained results suggest that astrocytic GR in the CeA promotes aversive memory consolidation and some aspects of anxiety behaviour.
Alcohol: Neurobiology of Addiction
2021, Alcohol: Neurobiology of Addiction
Drug addiction co-morbidity with alcohol: Neurobiological insights
2021, International Review of Neurobiology
Addiction is a chronic disorder that consists of a three-stage cycle of binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These stages involve, respectively, neuroadaptations in brain circuits involved in incentive salience and habit formation, stress surfeit and reward deficit, and executive function. Much research on addiction focuses on the neurobiology underlying single drug use. However, alcohol use disorder (AUD) can be co-morbid with substance use disorder (SUD), called dual dependence. The limited epidemiological data on dual dependence indicates that there is a large population of individuals suffering from addiction who are dependent on more than one drug and/or alcohol, yet dual dependence remains understudied in addiction research. Here, we review neurobiological data on neurotransmitter and neuropeptide systems that are known to contribute to addiction pathology and how the involvement of these systems is consistent or divergent across drug classes. In particular, we highlight the dopamine, opioid, corticotropin-releasing factor, norepinephrine, hypocretin/orexin, glucocorticoid, neuroimmune signaling, endocannabinoid, glutamate, and GABA systems. We also discuss the limited research on these systems in dual dependence. Collectively, these studies demonstrate that the use of multiple drugs can produce neuroadaptations that are distinct from single drug use. Further investigation into the neurobiology of dual dependence is necessary to develop effective treatments for addiction to multiple drugs.
Corticotropin releasing factor, but not alcohol, modulates norepinephrine release in the rat central nucleus of the amygdala
2020, Neuropharmacology
Citation Excerpt :
CRF release (measured using microdialysis) in the CeA is increased during withdrawal in alcohol-dependent animals (Merlo Pich et al., 1995), and appears to contribute to withdrawal-related anxiety. This withdrawal-related anxiety can be reduced by injection of CRF receptor antagonists into the CeA (Rassnick et al., 1993). Additionally, acute restraint stress induced rapid elevation in extracellular NE content in rat CeA (Galvez et al., 1996; Inglis and Moghaddam, 1999; Khoshbouei et al., 2002; Reznikov et al., 2007, 2009).
Alcohol misuse and dependence is a widespread health problem. The central nucleus of the amygdala (CeA) plays important roles in both the anxiety associated with alcohol (ethanol) dependence and the increased alcohol intake that is observed during withdrawal in dependent animals. We and others have shown the essential involvement of the corticotropin releasing factor (CRF) system in alcohol's synaptic effects on the CeA and in the development of ethanol dependence. Another system that has been shown to be critically involved in the molecular underpinnings of alcohol dependence is the norepinephrine (NE) system originating in the locus coeruleus. Both the CRF and NE systems act in concert to facilitate a stress response: central amygdalar afferents release CRF in the locus coeruleus promoting widespread release of NE. In this study, we are the first to use fast-scan cyclic voltammetry to classify local electrically-evoked NE release in the CeA and to determine if acute alcohol and CRF modulate it. Evoked NE release is action potential dependent, is abolished after depletion of monoaminergic vesicles, differs pharmacologically from dopamine release, is insensitive to acute alcohol, and decreases in response to locally applied CRF. Taken together, these results indicate that NE release in the CeA is released canonically in a vesicular-dependent manner, and that while acute alcohol does not directly alter NE release, CRF decreases it. Our results suggest that CRF acts locally on NE terminals as negative feedback and potentially prevents hyperactivation of the CRF-norepinephrine stress pathway.

View all citing articles on Scopus

View full text

Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal

Abstract

Life Sci.

Brain Res.

Brain Res. Rev.

Horm. Behav.

Peptides

Neuropharmacology

Brain Res.

Brain Res.

Life Sci.

Brain Res.

Life Sci.

Pharmacol. Biochem. Behav.

Brain Res.

Brain Res.

Drug Alcohol Depend.

Neurosci. Lett.

Role of the amygdaloid complex in the stress-induced release of ACTH in the rat

Neuroendocrinology

CRF antagonist reverses the ‘anxiogenic’ response to ethanol withdrawal in the rat

Psychopharmacology

Participation of the central amygdaloid nucleus in the response of adrenocorticotropin secretion to immobilization stress: Opposing roles of the noradrenergic and dopaminergic systems

Neuroendocrinology

Modifications in the response to alcohol following the establishment of physical dependence

Psychopharmacology

Activating the “anxiogenic” effects of CRF are not inhibited by blockade of the pituitary adrenal system with dexamethasone

Life Sci.

Corticotropin-releasing factor: Actions on the sympathetic nervous system and metabolism

Endocrinology

Subcellular distribution of corticotropin-releasing factor-like immunoreactivity in rat central nervous system

Neuroendocrinology

Antagonism of the enhanced susceptibility to audiogenic seizures during alcohol withdrawal in the rat by GABA and GABA-mimetic agents

J. Pharmacol. Exp. Ther.

Ethanol exposure decreases pituitary corticotropin-releasing factor binding, adenylate cyclase biosynthesis and plasma β-endorphin levels in the rat

Endocrinology

Chronic ethanol exposure potentiates the locomotor activating effects of corticotropin-releasing factor (CRF) in rats

Regul. Pept.

Plasma catecholamine responses to change of posture in alcoholics during withdrawal and after continued abstinence from alcohol

Clin. Sci.

Flumazenil but not nitrendipine reverses the increased anxiety during ethanol withdrawal in the rat

Psychopharmacology

Anxiolytic and anxiogenic drugs: changes in behavior and endocrine responses

Stress Medicine

Abnormal suppression of plasma cortisol during the intravenous infusion of dexamethasone to alcoholic patients

Clin. Endocrinol.

Distribution of corticotropin-releasing factor-like immunoreactivity in brainstem of two monkey species (Saimiru sciureus and Macaca fascicularis): An immunohistochemical study

J. Comp. Neurol.

Alcohol withdrawal syndrome in mice

Arch. Neurol.

Alcohol withdrawal reaction in mice: Effects of drugs that modify neurotransmission

J. Pharmacol. Exp. Ther.