The NMDA receptor antagonist MK-801 produces ethanol-like discrimination in the rat

Schechter, Martin; Meehan, Susanne M.; Gordon, Timothy L.; McBurney, Denise L.

doi:10.1016/0741-8329(93)90035-m

Cited by 39 publications

(17 citation statements)

References 28 publications

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“…In this paradigm, PCP and MK-801 substitute for ethanol completely in rodent [16]. Pigeons trained to discriminate ethanol from saline respond to NMDA receptor antagonists in a similar fashion to ethanol [114]. Behavioral stimulation that has been reinforced by ethanol is completely replaced by competitive (CGP 39551) and noncompetitive NMDA antagonists (MK-801) [64].…”

Section: Behavioral Studiesmentioning

confidence: 99%

Glutamatergic Neurotransmission in Alcoholism

Tsai¹

1998

J Biomed Sci

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Substance abuse and dependence is the most common psychiatric problem. Alcohol is the most commonly abused substance and most people who abuse other substance(s) abuse alcohol at the same time. Accumulating evidence suggests that neurophysiological and pathological effects of ethanol are mediated to a considerable extent via the glutamatergic system. Ethanol disrupts glutamatergic neurotransmission by inhibiting the response of the N-methyl-D-aspartate (NMDA) receptor and by promoting neuronal toxicity through upregulation of the NMDA receptor density. Therefore, short-term/acute ethanol treatment results in a blockade of NMDA receptor-mediated neurotransmission and apoptotic cell death by inhibiting the trophic effect mediated by the NMDA receptor whereas chronic ethanol treatment and withdrawal results in an enhanced toxic response toward glutamate. The neurobiology of human alcoholism such as ethanol intoxication, dependence, withdrawal seizures, delirium tremens, Wernicke-Korsakoff syndrome, and fetal alcohol syndrome can be better understood as a spectrum of consequences of ethanol’s effect on the NMDA glutamatergic system.

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Section: Behavioral Studiesmentioning

confidence: 99%

Glutamatergic Neurotransmission in Alcoholism

Tsai¹

1998

J Biomed Sci

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“…As such, activation of mGlu2/3 receptors decreases the synaptic availability of glutamate, allowing for 'refinement' of glutamatergic neurotransmission (Schoepp, 2001;Pinheiro and Mulle, 2008). Given the functional role of mGlu2/3 receptors in modulating glutamate release and that the discriminative stimulus effects of alcohol are generally characterized by processes that reduce/inhibit glutamatergic neurotransmission (Kostowski and Bienkowski, 1999), such that N-methyl-Daspartic acid (NMDA) antagonists and g-aminobutyric acid type A (GABA A )-positive modulators produce alcohol-like discriminative stimulus effects (Jarbe and McMillan, 1983;Schechter et al, 1993;Ator et al, 1993;Bienkowski et al, 1997;Hundt et al, 1998;Grant et al, 2000;Shelton and Grant, 2002;Vivian et al, 2002;Helms et al, 2009), we hypothesized that mGlu2/3 receptors may have a modulatory role in the expression of the discriminative stimulus effects of alcohol. Further support for this hypothesis comes from studies showing that mGlu2/3 receptors are highly expressed in limbic brain regions (Petralia et al, 1996;Ohishi et al, 1998;Ferraguti and Shigemoto, 2006) known to modulate the discriminative stimulus effects of alcohol, such as the nucleus accumbens and the amygdala (Hodge and Aiken, 1996;Hodge and Cox, 1998;Hodge et al, 2001;Besheer et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Activation of Group II Metabotropic Glutamate Receptors Inhibits the Discriminative Stimulus Effects of Alcohol via Selective Activity Within the Amygdala

Cannady

Grondin

Fisher

et al. 2011

Neuropsychopharmacol

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Metabotropic glutamate receptor subtypes (mGlu2/3) regulate a variety of alcohol-associated behaviors, including alcohol reinforcement, and relapse-like behavior. To date, the role of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol has not been examined. Given that the discriminative stimulus effects of drugs are determinants of abuse liability and can influence drug seeking, we examined the contributions of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol. In male Long-Evans rats trained to discriminate between alcohol (1 g/kg, IG) and water, the mGlu2/3 agonist LY379268 (0.3-10 mg/kg) did not produce alcohollike stimulus effects. However, pretreatment with LY379268 (1 and 3 mg/kg; in combination with alcohol) inhibited the stimulus effects of alcohol (1 g/kg). Systemic LY379268 (3 mg/kg, i.p.) was associated with increases in neuronal activity within the amygdala, but not the nucleus accumbens, as assessed by c-Fos immunoreactivity. Intra-amygdala activation of mGlu2/3 receptors by LY379268 (6 mg) inhibited the discriminative stimulus effects of alcohol, without altering response rate. In contrast, intra-accumbens LY379268 (3 mg) profoundly reduced response rate; however, at lower LY379268 doses (0.3, 1 mg), the discriminative stimulus effects of alcohol and response rate were not altered. These data suggest that amygdala mGlu2/3 receptors have a functional role in modulating the discriminative stimulus properties of alcohol and demonstrate differential motor sensitivity to activation of mGlu2/3 receptors in the amygdala and the accumbens. Understanding the neuronal mechanisms that underlie the discriminative stimulus effects of alcohol may prove to be important for future development of pharmacotherapies for treating alcoholism.

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“…NMDA receptor antagonists substitute for ethanol in drug discrimination studies conducted in animals, particularly for higher ethanol doses (11)(12)(13). Postmortem studies of brain tissue suggest that certain subunits of NMDA receptors are increased in cortical structures of ethanol-dependent individuals (14), and in vivo ethanol withdrawal increases cerebrospinal fluid glutamate levels.…”

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confidence: 99%

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

Petrakis

Limoncelli²,

Gueorguieva³

et al. 2004

AJP

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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The NMDA receptor antagonist MK-801 produces ethanol-like discrimination in the rat

Cited by 39 publications

References 28 publications

Glutamatergic Neurotransmission in Alcoholism

Glutamatergic Neurotransmission in Alcoholism

Activation of Group II Metabotropic Glutamate Receptors Inhibits the Discriminative Stimulus Effects of Alcohol via Selective Activity Within the Amygdala

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

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