A Pilot Trial of the Alpha‐1 Adrenergic Antagonist, Prazosin, for Alcohol Dependence

Simpson, Tracy L.; Saxon, Andrew J.; Meredith, Charles; Malte, Carol A.; McBride, Brittney; Ferguson, Laura; Gross, Christopher; Hart, Kim; Raskind, Murray A.

doi:10.1111/j.1530-0277.2008.00807.x

Cited by 145 publications

(153 citation statements)

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“…Prazosin treatment also facilitates abstinence in treatment-seeking alcohol-dependent men, as demonstrated in a study in which the subjects were unaware of their treatment condition (prazosin vs placebo) and there were no differences in side effects reported (Simpson et al, 2009). In addition, prazosin decreases stress-and cue-induced alcohol craving in alcohol-dependent men and women (Fox et al, 2012).…”

Section: Introductionmentioning

confidence: 77%

Prazosin Prevents Increased Anxiety Behavior That Occurs in Response to Stress During Alcohol Deprivations

Rasmussen

Kincaid

Froehlich

2016

Alcohol and Alcoholism

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Aims: Stress-induced anxiety is a risk factor for relapse to alcohol drinking. The aim of this study was to test the hypothesis that the central nervous system (CNS)-active α 1 -adrenergic receptor antagonist, prazosin, would block the stress-induced increase in anxiety that occurs during alcohol deprivations. Methods: Selectively bred male alcohol-preferring (P) rats were given three cycles of 5 days of ad libitum voluntary alcohol drinking interrupted by 2 days of alcohol deprivation, with or without 1 h of restraint stress 4 h after the start of each of the first two alcohol deprivation cycles. Prazosin (1.0 or 1.5 mg/kg, IP) or vehicle was administered before each restraint stress. Anxiety-like behavior during alcohol deprivation following the third 5-day cycle of alcohol drinking (7 days after the most recent restraint stress ± prazosin treatment) was measured by performance in an elevated plus-maze and in social approach/avoidance testing. Results: Rats that received constant alcohol access, or alcohol access and deprivations without stress or prazosin treatments in the first two alcohol deprivations did not exhibit augmented anxiety-like behavior during the third deprivation. In contrast, rats that had been stressed during the first two alcohol deprivations exhibited increased anxiety-like behavior (compared with control rats) in both anxiety tests during the third deprivation. Prazosin given before stresses in the first two cycles of alcohol withdrawal prevented increased anxiety-like behavior during the third alcohol deprivation. Conclusion: Prazosin treatment before stresses experienced during alcohol deprivations may prevent the increased anxiety during subsequent deprivation/abstinence that is a risk factor for relapse to alcohol drinking. Short summary: Administration of prazosin before stresses during repetitive alcohol deprivations in male alcohol-preferring (P) rats prevents increased anxiety during a subsequent deprivation without further prazosin treatment. Prazosin treatment during repeated alcohol deprivations may prevent the increased anxiety that is a risk factor for relapse to alcohol drinking.

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Section: Introductionmentioning

confidence: 77%

Prazosin Prevents Increased Anxiety Behavior That Occurs in Response to Stress During Alcohol Deprivations

Rasmussen

Kincaid

Froehlich

2016

Alcohol and Alcoholism

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“…The α 1 -AR antagonist prazosin has been shown to attenuate ethanol self-administration (SA) in ethanol-dependent rats (8) and reduces opiate SA (9). Furthermore, data from clinical trials have demonstrated that prazosin alleviates symptoms of posttraumatic stress disorder (PTSD) (10) and reduces alcohol drinking behavior in alcoholics (11).…”

mentioning

confidence: 99%

“…Data from human studies suggest that NE is increased in the central nervous system (CNS) of alcoholics (36), where it may play a role in the pathogenesis of alcoholism (35). Additionally, the adrenergic system remains an attractive target for intervention in alcoholism (11). Recently, α 1 -AR signaling has been linked to drinking behavior in withdrawn-dependent animals (8).…”

mentioning

confidence: 99%

Distinct forms of G _q -receptor-dependent plasticity of excitatory transmission in the BNST are differentially affected by stress

McElligott

Klug

Nobis

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Long-term depression (LTD) is an important synaptic mechanism for limiting excitatory influence over circuits subserving cognitive and emotional behavior. A major means of LTD induction is through the recruitment of signaling via G q -linked receptors activated by norepinephrine (NE), acetylcholine, and glutamate. Receptors from these transmitter families have been proposed to converge on a common postsynaptic LTD maintenance mechanism, such that hetero-and homosynaptic induction produce similar alterations in glutamate synapse efficacy. We report that in the dorsolateral and ventrolateral bed nucleus of the stria terminalis (BNST), recruitment of G q -linked receptors by glutamate or NE initiates mechanistically distinct forms of postsynaptically maintained LTD and these LTDs are differentially regulated by stress exposure. In particular, we show that although both mGluR5-and α 1 -adrenergic receptor (AR)-dependent LTDs involve postsynaptic endocytosis, the α 1 -AR-initiated LTD exclusively involves modulation of signaling through calcium-permeable AMPA receptors. Further, α 1 -AR-but not mGluR5-dependent LTD is disrupted by restraint stress. α 1 -AR LTD is also impaired in mice chronically exposed to ethanol. These data thus suggest that in the BNST, NE-and glutamate-activated G q -linked signaling pathways differentially tune glutamate synapse efficacy in response to stress.addiction | norepinephrine | metabotropic glutamate receptor | calcium-permeable AMPA receptor | ethanol A lterations in key amygdalar and reward circuitries have been proposed as potential mechanisms underlying interrelated anxiety disorders and addiction. The bed nucleus of the stria terminalis (BNST) is a nucleus within a series of structures known as the "extended amygdala," which receives a mix of glutamatergic inputs from cognitive and systemic brain centers and projects to key nuclei in both the reward and stress circuitries (1, 2). Consistent with this anatomy, a large literature indicates key roles of this region in anxiety-related behaviors, addiction, and other affective disorders (3).The BNST receives intense noradrenergic innervation through the ventral noradrenergic bundle (VNAB) (4). Disruption of the VNAB or noradrenergic signaling in the BNST alters responses to stressors, preference for opiates, and stress-induced reinstatement to drug seeking (5, 6). α 1 -Adrenergic receptors (ARs) are G qlinked G-protein-coupled receptors (GPCRs) that participate in shaping responses to stressors. Signaling through BNST α 1 -ARs within the BNST potently regulates the hypothalamic-pituitaryadrenal (HPA) stress axis and anxiety responses after stressors (7). The α 1 -AR antagonist prazosin has been shown to attenuate ethanol self-administration (SA) in ethanol-dependent rats (8) and reduces opiate SA (9). Furthermore, data from clinical trials have demonstrated that prazosin alleviates symptoms of posttraumatic stress disorder (PTSD) (10) and reduces alcohol drinking behavior in alcoholics (11).Like α 1 -ARs, group I metabotropic glutamat...

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“…Prazosin is generally well tolerated with gradual dose titration, and benefit usually continues for years once an effective dose is achieved. Prazosin may also prove beneficial for alcohol use disorder [48,49] and persistent postconcussive headaches [50]. Clinical effectiveness of prazosin is supported by increased utilization every year among veterans with a PTSD diagnosis receiving care in the Veterans Health Care System since publication of the first case report series in 2000 [43,51].…”

Section: Resultsmentioning

confidence: 99%

Prazosin for the Treatment of PTSD

Raskind

2015

Curr Treat Options Psych

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Opinion statementPrazosin is a generically available central nervous system (CNS) active alpha-1 adrenoreceptor antagonist that has been demonstrated effective in randomized controlled trials (RCTs) for posttraumatic stress disorder (PTSD) trauma nightmares, distressed awakenings, daytime hyperarousal symptoms, and global clinical function. The contribution of increased CNS noradrenergic activity to PTSD pathophysiology and the involvement of the postsynaptic alpha-1 adrenoreceptor in brain systems relevant to PTSD symptomatology provide neurobiologic rationale for prazosin as a PTSD pharmacotherapeutic. This article reviews the clinical observations that led to the development of prazosin therapy for PTSD in combat veterans and the subsequent RCTs that demonstrated prazosin efficacy. IntroductionPosttraumatic stress disorder (PTSD) encompasses clusters of symptoms that follow exposure to one or more major traumatic events. The four PTSD symptom clusters include intrusion (or reexperiencing), avoidance, negative alterations in c o g n i t i o n a n d m o o d a s s o c i a t e d w i t h t h e trauma(s), and hyperarousal. The phenomenologic features of several major PTSD hyperarousal symptoms including sleep disturbance (particularly distressed awakenings), hypervigilance, irritability/low anger threshold, and trauma nightmares, particularly when associated with sweating, tachycardia, and other manifestations of autonomic arousal, suggest that increased noradrenergic outflow and/ or postsynaptic adrenoreceptor (AR) responsiveness to norepinephrine (NE) contribute to their pathophysiology [1]. Increased central nervous system (CNS) noradrenergic activity in PTSD is supported by multiple clinical studies [2][3][4][5][6]. Therefore, reducing CNS noradrenergic activity is a rational therapeutic strategy when distressing trauma nightmares and hyperarousal symptoms are major components of the patient's clinical presentation. This article focuses on the pharmacotherapeutic strategy of reducing CNS postsynaptic responsiveness in PTSD using the alpha-1 AR antagonist prazosin. Among the clinically available alpha-1 ARs, prazosin is the most lipid soluble and therefore crosses the periphery into the CNS most easily [7].

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A Pilot Trial of the Alpha‐1 Adrenergic Antagonist, Prazosin, for Alcohol Dependence

Abstract: Prazosin holds promise as a pharmacologic treatment for AD and deserves further evaluation in a larger controlled trial.

Cited by 145 publications

References 60 publications

Prazosin Prevents Increased Anxiety Behavior That Occurs in Response to Stress During Alcohol Deprivations

Prazosin Prevents Increased Anxiety Behavior That Occurs in Response to Stress During Alcohol Deprivations

Distinct forms of G _q -receptor-dependent plasticity of excitatory transmission in the BNST are differentially affected by stress

Prazosin for the Treatment of PTSD

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A Pilot Trial of the Alpha‐1 Adrenergic Antagonist, Prazosin, for Alcohol Dependence

Abstract: Prazosin holds promise as a pharmacologic treatment for AD and deserves further evaluation in a larger controlled trial.

Cited by 145 publications

References 60 publications

Prazosin Prevents Increased Anxiety Behavior That Occurs in Response to Stress During Alcohol Deprivations

Prazosin Prevents Increased Anxiety Behavior That Occurs in Response to Stress During Alcohol Deprivations

Distinct forms of G q -receptor-dependent plasticity of excitatory transmission in the BNST are differentially affected by stress

Prazosin for the Treatment of PTSD

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Product

Resources

About

Distinct forms of G _q -receptor-dependent plasticity of excitatory transmission in the BNST are differentially affected by stress