Ethanol and the NMDA Receptor: Implications for Intoxication, Tolerance, Dependence, and Alcoholic Brain Damage

Lovinger, David M.

doi:10.1007/978-3-642-80193-8_1

Cited by 12 publications

(4 citation statements)

References 153 publications

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“…Consistent with this antagonist action on NMDA receptors is the fact that acamprosate reduces several symptoms of acute ethanol withdrawal which are accompanied by neuronal hyperexcitability (Spanagel and Zieglgänsberger 1997). Ethanol blocks NMDA receptors and chronic ethanol treatment upregulates these glutamate receptors (for reviews see Hoffman and Tabakoff 1996;Lovinger 1996;Fadda and Rossetti 1998). The NMDA receptor mediated enhancement of EAA neurotransmission can be considered the cause of the excitatory syndrome that results upon withdrawal of chronic ethanol.…”

Section: Discussionmentioning

confidence: 96%

Local acamprosate modulates dopamine release in the rat nucleus accumbens through NMDA receptors: an in vivo microdialysis study

Cano-Cebrián

Zornoza-Sabina

Guerri³

et al. 2003

Naunyn-Schmiedeberg's Arch Pharmacol

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The effects of acamprosate on the in vivo dopamine extracellular levels in the nucleus accumbens and the involvement of N-methyl-D-aspartate (NMDA) receptors in these effects were investigated. Microdialysis in freely moving rats was used to assess dopamine levels before and during simultaneous perfusion of acamprosate and/or different agonists or antagonists of NMDA receptors. Perfusion with acamprosate at concentrations of 0.5 and 5 mM provoked a concentration-dependent increase in extracellular dopamine in nucleus accumbens. The lowest concentration of acamprosate assayed (0.05 mM) had no effect on dopamine levels. Infusion of NMDA (25 and 500 microM) and the glutamate uptake blocker, L-trans-pyrrolidine-2,4-dicarboxilic acid (PDC) (0.5 mM) into the NAc caused a significant increase in DA, whereas acamprosate (0.05 mM) co-infusion with these compounds blocked or attenuated the NMDA and PDC-induced increases in DA levels. Co-infusion of the selective antagonist of NMDA receptors, DL-2-amino-5-phosphonopentanoic acid (AP5) (400 microM) with acamprosate (0.5 mM), did not reduce the increase of DA levels induced by acamprosate. These results demonstrate that acamprosate is able to modulate DA extracellular levels in NAc via NMDA receptors and suggest that acamprosate acts as an antagonist of NMDA receptors.

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Section: Discussionmentioning

confidence: 96%

Local acamprosate modulates dopamine release in the rat nucleus accumbens through NMDA receptors: an in vivo microdialysis study

Cano-Cebrián

Zornoza-Sabina

Guerri³

et al. 2003

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Earlier, we observed (Oretti et al 1996) that prevention of this induction by the translational inhibitor cycloheximide prevented the development of the AWS. The hyperexcitability and other behavioural features of the AWS are thought to involve activation of the excitatory NMDA-type of glutamate receptors as a response to cessation of long-term alcohol consumption (Gonzales, 1990;Lovinger, 1995), and it is known that, apart from glutamate itself, the Trp metabolite quinolinic acid is perhaps the most powerful indirect-acting (via glutamate) endogenous agonist of NMDA receptors (Stone, 1993). The possible involvement of quinolinic acid in the AWS has already been hypothesized (Morgan, 1991) and induction of liver TP activity during alcohol withdrawal may provide the link, since, as stated earlier, at least 50 % of brain quinolinate is of peripheral origin (Heyes & Morrison, 1997) and elevation of brain levels of this excitotoxin could therefore occur following liver TP enhancement.…”

Section: Withdrawal Effectsmentioning

confidence: 99%

Tryptophan metabolism in alcoholism

Badawy

2002

NRR

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Acute and chronic alcohol (ethanol) intake and subsequent withdrawal exert major effects on tryptophan (Trp) metabolism and disposition in human subjects and experimental animals. In rats, activity of the ratelimiting enzyme of Trp degradation, liver Trp pyrrolase (TP), is enhanced by acute, but inhibited after chronic, ethanol administration, then enhanced during withdrawal. These changes lead to alterations in brain serotonin synthesis and turnover mediated by corresponding changes in circulating Trp availability to the brain. A low brain-serotonin concentration characterizes the alcohol-preferring C57BL/6J mouse strain and many alcoholpreferring rat lines. In this mouse strain, liver TP enhancement causes the serotonin decrease. In man, acute ethanol intake inhibits brain serotonin synthesis by activating liver TP. This may explain alcohol-induced depression, aggression and loss of control in susceptible individuals. Chronic alcohol intake in dependent subjects may be associated with liver TP inhibition and a consequent enhancement of brain serotonin synthesis, whereas subsequent withdrawal may induce the opposite effects. The excitotoxic Trp metabolite quinolinate may play a role in the behavioural disturbances of the alcohol-withdrawal syndrome. Some abstinent alcoholics may have a central serotonin deficiency, which they correct by liver TP inhibition through drinking. Further studies of the Trp and serotonin metabolic status in long-term abstinence in general and in relation to personality characteristics, alcoholism typology and genetic factors in particular may yield important information which should facilitate the development of more effective screening, and preventative and therapeutic strategies in this area of mental health.

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“…An increased release of the excitatory amino acids aspartate and glutamate could be one of the biochemical mechanisms responsible for the environment-dependent tolerance to ethanol. Indeed, such an increased release would compensate the ethanol depressant effect on brain cells, and more precisely the inhibitory effect of acute ethanol on excitatory amino acid receptors, such as NMDA receptors (Lovinger 1996). Anatomical and electrophysiological evidence suggests that the basolateral nucleus of the amygdala projects excitatory efferents into both the core and shell regions of the nucleus accumbens neurons.…”

Section: Introductionmentioning

confidence: 99%

Changes in the amygdala amino acid microdialysate after conditioning with a cue associated with ethanol

Quertemont¹,

Neuville²,

Witte³

1998

Psychopharmacology

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The excitatory amino acid neurotransmission within the amygdala has been implicated in learning associations between external stimuli and intrinsic reward values such that it may play a key role in conditioned drug effects. In the present studies, the responses of the excitatory amino acids, aspartate and glutamate together with the neuromodulatory sulphonated amino acid taurine, within the basolateral amygdala, to an odor cue repeatedly associated with acute ethanol injections (2g/kg, IP) have been investigated by a microdialysis technique combined with HPLC-EC analysis. After presentation of the ethanol-conditioned stimulus, a single IP saline injection induced an immediate and significant increase in the taurine microdialysate content which could be related to the neuromodulatory action of taurine. Furthermore, when the conditioned stimulus was combined with the ethanol injection (2g/kg, IP), significant increases in both taurine and glutamate microdialysate content were observed and indicated a learned compensatory response to counteract the acute effects of ethanol. These results demonstrate that changes in amygdala extracellular glutamate and taurine concentrations can be conditioned to ethanol-associated stimuli and are therefore probably implicated in the phenomenon of environmental-dependent tolerance to ethanol.

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Ethanol and the NMDA Receptor: Implications for Intoxication, Tolerance, Dependence, and Alcoholic Brain Damage

Cited by 12 publications

References 153 publications

Local acamprosate modulates dopamine release in the rat nucleus accumbens through NMDA receptors: an in vivo microdialysis study

Local acamprosate modulates dopamine release in the rat nucleus accumbens through NMDA receptors: an in vivo microdialysis study

Tryptophan metabolism in alcoholism

Changes in the amygdala amino acid microdialysate after conditioning with a cue associated with ethanol

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