Effect of NMDA receptor antagonists on rapid tolerance to ethanol

Khanna, J. M.; Shah, G.; Weiner, Jeff L.; Wu, P.H.; Kalant, H.

doi:10.1016/0014-2999(93)90405-7

Cited by 68 publications

(22 citation statements)

References 27 publications

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“…Ethanol's effects on NMDARs have also been implicated in ethanol tolerance and dependence (6). NMDAR antagonists have been shown to block tolerance to ethanol (48) and decrease ethanol intake in operant free-choice, self-administration paradigms, as well as after periods of abstinence (49). Given STEP's ability to modulate NMDARs, LTP, and ethanol effects, this tyrosine phosphatase may serve as a key target for research and development of pharmaceutical interventions for alcoholism and addiction.…”

Section: Discussionmentioning

confidence: 99%

Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

Hicklin¹,

Radcliffe

et al. 2011

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

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Alcohol's deleterious effects on memory are well known. Acute alcohol-induced memory loss is thought to occur via inhibition of NMDA receptor (NMDAR)-dependent long-term potentiation in the hippocampus. We reported previously that ethanol inhibition of NMDAR function and long-term potentiation is correlated with a reduction in the phosphorylation of Tyr 1472 on the NR2B subunit and ethanol's inhibition of the NMDAR field excitatory postsynaptic potential was attenuated by a broad spectrum tyrosine phosphatase inhibitor. These data suggested that ethanol's inhibitory effect may involve protein tyrosine phosphatases. Here we demonstrate that the loss of striatal-enriched protein tyrosine phosphatase (STEP) renders NMDAR function, phosphorylation, and long-term potentiation, as well as fear conditioning, less sensitive to ethanol inhibition. Moreover, the ethanol inhibition was "rescued" when the active STEP protein was reintroduced into the cells. Taken together, our data suggest that STEP contributes to ethanol inhibition of NMDAR function via dephosphorylation of tyrosine sites on NR2B receptors and lend support to the hypothesis that STEP may be required for ethanol's amnesic effects.whole-cell currents | null mutant mice A lcohol-induced memory deficits have been well documented in humans, as well as animal studies (1). Long-term potentiation (LTP) is widely accepted as a cellular mechanism underlying learning and memory in the hippocampus, as well as other brain regions (2), and is dependent upon NMDA receptor (NMDAR) activation (3). Acute ethanol application in adult rodents inhibits NMDAR channel activity (4, 5). Ethanol's inhibitory effect on NMDARs is widely thought to underlie both the blockade of LTP and the acute amnesic effects of ethanol. Moreover, recent work suggests that ethanol's effect on the NMDAR may play a role in the addictive nature of ethanol (6, 7).NMDARs in the hippocampus consist of mainly NR1/NR2A, NR1/NR2B, and NR1/NR2A/NR2B receptor-subunit complexes (8). Although NR1 subunits are required to form an active ion channel, incorporation of the various NR2 subunits regulate NMDAR channel activity by altering the channel kinetics and mediating the differential effects of pharmacological agents, including alcohol (9-11). It has previously been shown that activation of members of the Src-family of kinases (SFKs) enhances NMDAR currents (12). Previous studies have demonstrated a correlation between ethanol inhibition of NMDAR function and dephosphorylation of tyrosine residues on the NR2A and NR2B subunits (13). In particular, ethanol was found to reduce the phosphorylation of a site on the NR2B subunit Tyr 1472 that has been shown to regulate endocytosis and function of NMDARs (14,15). Inhibition of protein tyrosine phosphatase activity using a nonspecific inhibitor, bpV(phen), significantly reduced ethanol inhibition of NMDAR field excitatory postsynaptic potentials (fEPSPs), suggesting that ethanol may inhibit NMDARs via activation of a tyrosine phosphatase (13). FerraniKile et al. indepe...

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Section: Discussionmentioning

confidence: 99%

Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

Hicklin¹,

Radcliffe

et al. 2011

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

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“…This blockade of tolerance was not due to any change in the pharmacokinetics of EtOH, because the NMDA antagonists had no effect at all on the blood or brain levels of EtOH (Khanna et al 1993). Trujillo and Akil (1991) have shown similar prevention of tolerance to the analgesic effect of morphine by NMDA antagonists.…”

Section: Introductionmentioning

confidence: 92%

Dizocilpine prevents the development of tolerance to ethanol-induced error on a circular maze test

et al. 1996

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Dizocilpine [(+)MK-801] and ketamine, in doses that disrupt learning and memory, also prevent the development of tolerance to the motor impairing effects of ethanol (EtOH). However, dizocilpine itself affects motor behavior. In order to separate the possible influence of these two effects on the development of tolerance to EtOH, food-reinforced performance on a circular maze test was used in two different experiments. EtOH alone (1.2 g/kg) tended to increase the error score and reduce number of runs per trial, running speed, and total distance run, but on chronic administration of EtOH, tolerance developed progressively to all these effects. Dizocilpine also increased the error score, but had a biphasic effect on measures of running: low and intermediate doses (0.009 and 0.075 mg/kg, IP) increased running distance, whereas a high dose (0.15 mg/kg) decreased running speed and distance. When combined with EtOH, dizocilpine tended to overcome the effect of EtOH on running activity, but not on error score. Chronically, dizocilpine (0.075 and 0.15 mg/kg) prevented the development of tolerance to the effect of EtOH on error score, even though the lower dose of dizocilpine permitted tolerance to the effects of EtOH on running. These results suggest that NMDA receptor antagonists selectively inhibit tolerance to cognitive effects of ethanol even when the antagonists do not affect motor performance.

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“…For example, NMDAR antagonists block the development of rapid tolerance to ethanol (Khanna et al, 1993), decrease ethanol intake (Holter et al, 2000), and reduce the intensity of ethanol withdrawal symptoms (Bisaga et al, 2000). In addition, administration of a NMDAR antagonist decreases ethanol intake in a rodent relapse model (Holter et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Ethanol Induces Long-Term Facilitation of NR2B-NMDA Receptor Activity in the Dorsal Striatum: Implications for Alcohol Drinking Behavior

Wang

Carnicella²,

Phamluong³

et al. 2007

J. Neurosci.

165

242

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Addiction is characterized by compulsive alcohol or drug taking and seeking, and the dorsal striatum has been implicated in such maladaptive persistent habits. The NMDA receptor (NMDAR), which is a major target of alcohol, is implicated in striatal-based habit learning. We found that, in the dorsal striatum, alcohol (ethanol) exposure produced an increase in the phosphorylation of the NR2B subunit of the NMDAR, and a corresponding increase in the activity of Fyn kinase, which phosphorylates NR2B. We further observed an ethanol-mediated long-term facilitation (LTF) of the activity of NR2B-containing NMDARs (NR2B-NMDARs) in the dorsal striatum. This LTF is Fyn kinase dependent, because it was observed in Fyn wild-type but not in Fyn knock-out mice. Importantly, none of these biochemical and physiological changes was observed in the ventral striatum. Finally, dorsal but not ventral striatum infusion of a Fyn or NR2B-NMDAR inhibitor reduced rat operant self-administration of ethanol. Our results suggest that the Fyn-mediated phosphorylation and LTF of NR2B-NMDAR activity in the dorsal striatum after exposure to ethanol may underlie aberrant plasticity that contributes to mechanisms underlying alcohol drinking behavior.

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Effect of NMDA receptor antagonists on rapid tolerance to ethanol

Cited by 68 publications

References 27 publications

Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

Dizocilpine prevents the development of tolerance to ethanol-induced error on a circular maze test

Ethanol Induces Long-Term Facilitation of NR2B-NMDA Receptor Activity in the Dorsal Striatum: Implications for Alcohol Drinking Behavior

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