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

Abstract

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 ...

Acute and chronic effects of ketamine upon human memory: a review

“…There also appear to be individual differences in the effects of ketamine which may reflect genetic differences (Petrakis et al 2004), and a recent analysis suggests that there are subtle gender differences in ketamine's effects on verbal recall (Morgan et al 2006a). There are clearly individual differences in recreational drug user's response to ketamine, with many anecdotal reports of people trying it once and never taking it again compared with others who use it frequently.…”

“…Studies using a 'dose-response' methodology, by testing frequent and infrequent ketamine users, may circumvent this problem to some degree (Curran and Monaghan 2001), although one cannot exclude the possibility that preexisting differences predispose some people to use ketamine more than others. It may be that a synthesis of research that examines the factors that account for individual differences in response to ketamine in the laboratory my be able to inform research into factors that predispose people to ketamine use, especially in light of research suggesting a reduced dysphoric response to ketamine in unaffected relatives of alcoholics (Petrakis et al 2004).…”

Greater vulnerability to the amnestic effects of ketamine in males

“…Many factors may play a role in determining the response to ketamine, some of which have only recently begun to be investigated, including family history of alcohol abuse (Petrakis et al 2004), previous exposure to ketamine (Cho et al 2005), and genetic variation in the apolipoprotein E epsilon 4 allele . Other important factors have not been investigated adequately so far due to small sample sizes.…”

Neurobiology's little alphabet of alcohol use disorders

“…Bei der Einnahme der Substanz beschrieben kürzlich entgiftete, alkoholabhängige Patienten eine dosisabhängige Wirkung, die vergleichbar mit dem sedierenden Effekt einer Ethanolwirkung war (Krystal et al 1998). Bei Probanden mit einer positiven Familienanamnese bezüg-lich einer Alkoholabhängigkeit bestand eine erhöhte Ansprechbarkeit auf Ketamin (Petrakis et al 2004). Ehemals alkoholabhängige Patienten zeigten hingegen eine verminderte Ansprechbarkeit auf diesen NMDA-Antagonisten (Krystal et al 2003).…”

“…Ehemals alkoholabhängige Patienten zeigten hingegen eine verminderte Ansprechbarkeit auf diesen NMDA-Antagonisten (Krystal et al 2003). Teil der Alkoholwirkung bei diesen Patienten ist also möglicherweise die Dämpfung einer genetisch determinierten Glutamat-Übererregbarkeit (Petrakis et al 2004). …”