Altered NMDA Glutamate Receptor Antagonist Response in Recovering Ethanol-Dependent Patients

Krystal, John H.; Petrakis, Ismene L.; Limoncelli, Diana; Webb, Elizabeth; Gueorgueva, Ralitza; D’Souza, Deepak Cyril; Boutros, Nashaat N.; Trevisan, Louis; Charney, Dennis S.

doi:10.1038/sj.npp.1300252

Cited by 82 publications

(73 citation statements)

References 46 publications

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“…These NMDA receptor functional changes include a shift in the reward valence of the actions of NMDA receptor antagonists, presumably including ethanol, toward the experience of a drug of predominately reduced dysphoric effects. The present results are also consistent with data from recently detoxified individuals (27) showing that when ethanol-dependent patients are subtyped, those with a family history of ethanol dependence show reduced ketamine induction of affect blunting, dysphoric mood, and impaired performance on the Wisconsin Card Sorting Test. However, other ketamine responses that discriminated healthy subjects with a family history of ethanol dependence from those without such a history did not differentiate ethanol-dependent patients with versus without a family history of ethanol dependence, including sustained or enhanced euphoria.…”

Section: Discussionsupporting

confidence: 80%

Altered NMDA Glutamate Receptor Antagonist Response in Individuals With a Family Vulnerability to Alcoholism

Petrakis

Limoncelli²,

Gueorguieva³

et al. 2004

AJP

Self Cite

118

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Objective: A family history of alcoholism is a risk factor for the development of ethanol dependence. Ethanol is an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor, and alterations in NMDA receptor function are thought to be involved in ethanol abuse and dependence. The purpose of this study was to determine in healthy individuals with no ethanol dependence whether response to the NMDA receptor antagonist ketamine would differentiate those with a family history of ethanol dependence from those without such a family history. Method:Healthy subjects between the ages of 21 and 30 received 40-minute intravenous infusions of saline, low-dose ketamine (0.1 mg/kg), and high-dose ketamine (0.5 mg/kg) on three separate test days in a randomized order under doubleblind conditions. The healthy individuals with at least one first-degree relative and another first-or second-degree relative with ethanol dependence (N=16) were compared with those who had no family history of ethanol dependence in any firstor second-degree relative (N=29). Outcome measures included the Brief Psychiatric Rating Scale, Clinician-Administered Dissociative States Scale, verbal fluency, Hopkins Verbal Learning Test, a biphasic alcohol effects scale, visual analog scales of mood states, and ketamine levels.Results: During ketamine infusion, individuals with a family history of ethanol dependence showed an attenuated response in terms of perceptual alterations and dysphoric mood relative to those without such a family history. Conclusions:These data suggest that alterations in NMDA receptor function may contribute to subjective response to ethanol and therefore also to the risk of developing alcoholism. Ther e is extensive evidence that a family history of alcoholism is a risk factor for the development of ethanol problems (1). A substantial part of the tendency for ethanol dependence to run in families is attributable to genetic factors (2). Healthy individuals with a family history of ethanol dependence exhibit a relatively lower intensity of subjective intoxication, ataxia, body sway, or flushing to moderate doses of ethanol in a laboratory setting than do healthy individuals with no family history of alcoholism. These findings have clinical importance, since follow-up studies have shown that a reduced sensitivity to the dysphoric or adverse effects of ethanol is the single strongest predictor of the subsequent development of alcoholism (3).Antagonists of the N-methyl-D-aspartate (NMDA) receptor have provided an important mechanism for evaluating the pathophysiology of neuropsychiatric disorders, such as Alzheimer's disease, anxiety, depression, and schizophrenia. For example, administration of the NMDA antagonist ketamine to healthy subjects and the subsequent cognitive deficits (4, 5) and perceptual changes (6-9) have led to further understanding of the pathophysiology of schizophrenia (6-9).NMDA glutamate receptors are among the highest affinity ethanol targets in the brain (10). NMDA receptor antagonists substitute for ethanol ...

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Section: Discussionsupporting

confidence: 80%

Altered NMDA Glutamate Receptor Antagonist Response in Individuals With a Family Vulnerability to Alcoholism

Petrakis

Limoncelli²,

Gueorguieva³

et al. 2004

AJP

Self Cite

118

View full text Add to dashboard Cite

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“…Acutely, alcohol has been shown to decrease MMN amplitude (He et al, 2013;Jaaskelainen et al, 1995a;Jaaskelainen et al, 1995b;Jaaskelainen et al, 1996;Kenemans et al, 2010), supporting the notion that alcohol elicits a blockade of the NMDA receptor (Lovinger et al, 1989). Additionally, increased MMN amplitudes have been found in alcohol dependent patients (Ahveninen et al, 2000b) supporting the upregulation of NMDA receptor functioning as a result of continued alcohol use (Krystal et al, 2003b).…”

Section: Mismatch Negativity Bipolar Disorder and Alcoholsupporting

confidence: 50%

Alcohol use in bipolar disorder: A neurobiological model to help predict susceptibility, select treatments and attenuate cortical insult

Chitty

Lagopoulos

Hickie

et al. 2015

Neuroscience & Biobehavioral Reviews

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In a series of neurophysiological and neuroimaging studies we investigated the neurobiology related to alcohol use in young people with bipolar disorder. Impairments were identified across frontal and temporal representations of event-related potential and proton magnetic resonance spectroscopy markers; mismatch negativity and in vivo glutathione, respectively. We propose these findings reflect impairments in the Nmethyl-D-aspartate receptor and antioxidant capacity. This review seeks to place these findings within the broader literature in the context of two propositions:

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“…They appeared for testing at approximately 0830 hours on test days. This study employed cognitive and clinical assessments that we have used previously to study ketamine effects in healthy subjects and alcohol dependent patients (Krystal et al, 1994(Krystal et al, , 1998(Krystal et al, , 2003a. The Positive and Negative Syndrome Scale (PANSS (Kay et al, 1989)) was employed to assess several dimensions of behavior.…”

Section: Methodsmentioning

confidence: 99%

Potentiation of Low Dose Ketamine Effects by Naltrexone: Potential Implications for the Pharmacotherapy of Alcoholism

Krystal

Madonick

Perry

et al. 2006

Neuropsychopharmacol

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The interplay of opiate and NMDA glutamate receptors may contribute to psychosis, cognitive function, alcoholism, and substance dependence. Ketamine and ethanol block the NMDA glutamate receptor. The purpose of this randomized double-blind, placebocontrolled human laboratory study was to evaluate whether the interactive effects of drugs acting at opiate and NMDA glutamate receptors might partially explain the efficacy of naltrexone for the treatment of alcoholism, that is, whether naltrexone 25 mg pretreatment would modulate ketamine effects in healthy human subjects. Two groups of healthy subjects were studied. An initial group (n ¼ 31) received a perception-altering subanesthetic dose of ketamine (bolus of 0.23 mg/kg over 1 min followed by a 60-min infusion of 0.58 mg/kg or saline bolus and infusion). A second group (n ¼ 24) completed the same testing procedures, but received a subperceptual ketamine dose (bolus 0.081 mg/kg over 10 min followed by an infusion of 0.4 mg/kg/h). Ketamine produced positive symptoms, negative symptoms, emotional discomfort, and cognitive effects as measured by the Positive and Negative Syndrome Scale (PANSS) in a doserelated fashion. The lower ketamine dose produced subjective effects similar to two standard ethanol drinks, whereas the higher ketamine dose produced effects similar to five standard drinks. Although naltrexone produced no significant behavioral effects, it significantly magnified the increase in the total PANSS score produced by the lower subperceptual dose of ketamine, but not the higher perception-altering dose of ketamine. These data suggest that the interplay of opiate receptor antagonism and NMDA receptor antagonism may be relevant to the protective effects of naltrexone on alcohol consumption via potentiation of dysphoric effects associated with the NMDA receptor antagonist effects of ethanol. However, these data suggest that at levels of NMDA receptor antagonism associated with heavy drinking, this protective effect of naltrexone on drinking is no longer present.

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Altered NMDA Glutamate Receptor Antagonist Response in Recovering Ethanol-Dependent Patients

Cited by 82 publications

References 46 publications

Altered NMDA Glutamate Receptor Antagonist Response in Individuals With a Family Vulnerability to Alcoholism

Altered NMDA Glutamate Receptor Antagonist Response in Individuals With a Family Vulnerability to Alcoholism

Alcohol use in bipolar disorder: A neurobiological model to help predict susceptibility, select treatments and attenuate cortical insult

Potentiation of Low Dose Ketamine Effects by Naltrexone: Potential Implications for the Pharmacotherapy of Alcoholism

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