Noradrenergic targets for the treatment of alcohol use disorder

Haass‐Koffler, Carolina L.; Swift, Robert M.; Leggio, Lorenzo

doi:10.1007/s00213-018-4843-6

Cited by 61 publications

(62 citation statements)

References 100 publications

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“…Although the model has not yet been translated to validated clinical applications, it informed the development of the Addictions Neuroclinical Assessment, a framework that uses neuropsychological data that correspond to the three stages of the neurobiological opponent process model to classify the individual differences in AUD to improve diagnosis and treatment 43. The model does imply specific treatment targets, such as corticotropin releasing factor44,45 and alpha 1 -noradrenergic systems 46. Simpson and colleagues found clinical benefit from prazosin, an alpha 1 antagonist, in participants with an alcohol dependence diagnosis 47.…”

Section: Neurobiological Theoriesmentioning

confidence: 99%

Co-Occurring Alcohol Use Disorder and Anxiety: Bridging the Psychiatric, Psychological, and Neurobiological Perspectives

Anker

Kushner

2019

ARCR

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A substantial number of people who have problems with alcohol also experience strong anxiety and mood problems. This article provides an overview of the evolving perspectives of this association in the context of three related disciplines-psychiatry, psychology, and neuroscience. Psychiatric and epidemiological studies show that having either an anxiety-or alcohol-related diagnosis elevates the prospective risk for developing the other disorder. From the psychological perspective, behavioral research demonstrates that drinking to cope with negative affect is a potent marker for current and future problems with alcohol. Neuroscientific research implicates overlapping neurobiological systems and psychological processes in promoting the rise of negative affect and alcohol misuse. The psychiatric perspective that alcohol misuse and co-occurring anxiety represent neurobiologically distinct diagnostic conditions has dominated the field for many decades. However, recent research provides increasing support for the neuroscientific perspective that these conditions share underlying, mutually exacerbating, neurobiological processes.

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Section: Neurobiological Theoriesmentioning

confidence: 99%

Co-Occurring Alcohol Use Disorder and Anxiety: Bridging the Psychiatric, Psychological, and Neurobiological Perspectives

Anker

Kushner

2019

ARCR

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“…Thus, we predicted that the adolescent CORT-treated rats would have a reduced sensitivity to α 2A R-mediated signaling, which could result in an increase in norepinephrine release and post-synaptic signaling in the brain, as the normal autoreceptor-mediated brake on noradrenergic-transmission would be impaired. Given the large literature on the involvement of heightened noradrenergic signaling, particularly in the amygdala, for both stress- and alcohol-related behaviors, including the potential clinical use of α 2A AR agonists as a treatment for alcohol use disorders [33,34,35], GRK2-mediated phosphorylation of α 2A AR after adolescent CORT exposure is a strong candidate as a mediator of increased motivation for alcohol. Therefore, we decided to directly test if inhibition of GRK2 in the amygdala could reduce alcohol-motivated behaviors in adolescent CORT- or H 2 O-exposed rats.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, increased phosphorylation of four serine residues in the third intracellular loop of the α2AR, which are a GRK2 substrate, was of particular interest, due to evidence pointing to the potent role of adrenergic signaling, particularly in the amygdala, in ethanol drinking and seeking. It has long been recognized that the noradrenergic system plays a critical role in the development of alcohol use disorders, but only recently has interest been revitalized in targeting this system with respect to AUD treatment [34]. Preclinical studies have shown that downregulation of noradrenergic signaling, via α 2A R agonism (clonidine; [35]), or antagonism of α1AR (prazosin; [41]) or βAR (propranolol; [42]), reduces ethanol drinking and seeking in high-consuming animals.…”

Section: Discussionmentioning

confidence: 99%

Phosphoproteomic Analysis of the Amygdala Response to Adolescent Glucocorticoid Exposure Reveals G-Protein Coupled Receptor Kinase 2 as a Target for Reducing Motivation for Alcohol

et al. 2018

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Early life stress is associated with risk for developing alcohol use disorders (AUDs) in adulthood. Though the neurobiological mechanisms underlying this vulnerability are not well understood, evidence suggests that aberrant glucocorticoid and noradrenergic system functioning play a role. The present study investigated the long-term consequences of chronic exposure to elevated glucocorticoids during adolescence on the risk of increased alcohol-motivated behavior, and on amygdalar function in adulthood. A discovery-based analysis of the amygdalar phosphoproteome using mass spectrometry was employed, to identify changes in function. Adolescent corticosterone (CORT) exposure increased alcohol, but not sucrose, self-administration, and enhanced stress-induced reinstatement with yohimbine in adulthood. Phosphoproteomic analysis indicated that the amygdala phosphoproteome was significantly altered by adolescent CORT exposure, generating a list of potential novel mechanisms involved in the risk of alcohol drinking. In particular, increased phosphorylation at serines 296–299 on the α2A adrenergic receptor (α2AAR), mediated by the G-protein coupled receptor kinase 2 (GRK2), was evident after adolescent CORT exposure. We found that intra-amygdala infusion of a peptidergic GRK2 inhibitor reduced alcohol seeking, as measured by progressive ratio and stress reinstatement tests, and induced by the α2AAR antagonist yohimbine. These results suggest that GRK2 represents a novel target for treating stress-induced motivation for alcohol which may counteract alterations in brain function induced by adolescent stress exposure.

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“…We have shown that the alpha-1 antagonists prazosin and doxazosin are effective in a preclinical model of stress-induced alcohol seeking (Lê et al, 2011; Funk et al, 2016), and there are also promising clinical data in humans with alcohol use disorders (Fox et al, 2012; Haass-Koffler et al, 2018). The brain circuitry underlying these effects of alpha-1 antagonists is unclear, however.…”

Section: Discussionmentioning

confidence: 99%

“…Prazosin also reduces yohimbine-induced brain activation in areas implicated in stress-induced reinstatement (Bing et al, 1992; Stone and Zhang, 1995; Funk et al, 2016). Consistent with this, alpha-1 adrenoceptor antagonists including prazosin have received attention as treatments for alcohol use disorders and chronic stress conditions such as post-traumatic stress disorder, which frequently co-occur with alcoholism (Walker et al, 2008; Rasmussen et al, 2009; Green, 2014; Simpson et al, 2015; Haass-Koffler et al, 2018).…”

Section: Introductionmentioning

confidence: 92%

Effects of the alpha-1 antagonist prazosin on KOR agonist-induced reinstatement of alcohol seeking

Funk

Coen

Tamadon

et al. 2019

International Journal of Neuropsychopharmacology

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Background Stress is associated with relapse to alcohol seeking during abstinence, but the processes underlying this relationship are poorly understood. Noradrenaline is a key transmitter in stress responses and in stress-induced drug seeking. The alpha-1 adrenoceptor antagonist prazosin has been investigated as a treatment for alcoholism and for chronic stress disorders that are frequently comorbid with alcoholism. In rats, we previously showed that prazosin blocks reinstatement of alcohol seeking induced by footshock and yohimbine stressors, and reduces yohimbine-induced brain activation. The role of alpha-1 adrenoceptors in reinstatement induced by other stressors is not known. Our most recent work is on the role of kappa opioid receptors (KOR) in stress-induced reinstatement of alcohol seeking and have reported that the selective KOR agonist U50,488 induces reinstatement and neuronal activation in stress- and relapse-related brain regions. Here we determine the involvement of alpha-1 receptors in reinstatement and brain activation induced by U50,488. Methods We trained male Long-Evans rats to self-administer alcohol (12% w/v), extinguished alcohol-reinforced responding and then determined the effects of prazosin (1 mg/kg) on U50,488 (2.5 mg/kg)-induced reinstatement and regional Fos expression. Results Prazosin blocked U50,488-induced reinstatement and decreased U50,488-induced Fos expression in the OFC, NAC core, ventral BNST, CeA, BLA and VTA. Conclusions These findings suggest that prazosin may reduce U50,488-induced relapse by inhibiting activity in one or more of these brain areas.

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Noradrenergic targets for the treatment of alcohol use disorder

Cited by 61 publications

References 100 publications

Co-Occurring Alcohol Use Disorder and Anxiety: Bridging the Psychiatric, Psychological, and Neurobiological Perspectives

Co-Occurring Alcohol Use Disorder and Anxiety: Bridging the Psychiatric, Psychological, and Neurobiological Perspectives

Phosphoproteomic Analysis of the Amygdala Response to Adolescent Glucocorticoid Exposure Reveals G-Protein Coupled Receptor Kinase 2 as a Target for Reducing Motivation for Alcohol

Effects of the alpha-1 antagonist prazosin on KOR agonist-induced reinstatement of alcohol seeking

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