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

Wang, Jun; Carnicella, Sébastien; Phamluong, Khanhky; Jeanblanc, Jérôme; Ronesi, Jennifer A.; Chaudhri, Nadia; Janak, Patricia H.; Lovinger, David M.; Ron, Dorit

doi:10.1523/jneurosci.4749-06.2007

Cited by 161 publications

(257 citation statements)

References 66 publications

(79 reference statements)

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“…This finding is consistent with other reports showing that EtOH decreases the amplitude of NMDA EPSCs in various brain regions including the mPFC (Weitlauf and Woodward, 2008), hippocampus (Lovinger et al, 1990), amygdala (Roberto et al, 2004), BNST (Kash et al, 2008), and striatum (Wang et al, 2007). In the present study, 66 mM EtOH significantly inhibited NMDA EPSCs while lower EtOH concentrations (11, 33 mM) had little effect suggesting that NMDA receptors in the adult OFC, unlike some areas, are not particularly sensitive to EtOH.…”

Section: Etoh Inhibits Synaptic Nmda Receptor Functionsupporting

confidence: 93%

Ethanol Reduces Neuronal Excitability of Lateral Orbitofrontal Cortex Neurons Via a Glycine Receptor Dependent Mechanism

Badanich

Mulholland

Beckley

et al. 2013

Neuropsychopharmacol

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Trauma-induced damage to the orbitofrontal cortex (OFC) often results in behavioral inflexibility and impaired judgment. Human alcoholics exhibit similar cognitive deficits suggesting that OFC neurons are susceptible to alcohol-induced dysfunction. A previous study from this laboratory examined OFC mediated cognitive behaviors in mice and showed that behavioral flexibility during a reversal learning discrimination task was reduced in alcohol-dependent mice. Despite these intriguing findings, the actions of alcohol on OFC neuron function are unknown. To address this issue, slices containing the lateral OFC (lOFC) were prepared from adult C57BL/6J mice and whole-cell patch clamp electrophysiology was used to characterize the effects of ethanol (EtOH) on neuronal function. EtOH (66 mM) had no effect on AMPA-mediated EPSCs but decreased those mediated by NMDA receptors. EtOH (11-66 mM) also decreased current-evoked spike firing and this was accompanied by a decrease in input resistance and a modest hyperpolarization. EtOH inhibition of spike firing was prevented by the GABA A antagonist picrotoxin, but EtOH had no effect on evoked or spontaneous GABA IPSCs. EtOH increased the holding current of voltage-clamped neurons and this action was blocked by picrotoxin but not the more selective GABA A antagonist biccuculine. The glycine receptor antagonist strychnine also prevented EtOH's effect on holding current and spike firing, and western blotting revealed the presence of glycine receptors in lOFC. Overall, these results suggest that acutely, EtOH may reduce lOFC function via a glycine receptor dependent process and this may trigger neuroadaptive mechanisms that contribute to the impairment of OFC-dependent behaviors in alcohol-dependent subjects.

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Section: Etoh Inhibits Synaptic Nmda Receptor Functionsupporting

confidence: 93%

Ethanol Reduces Neuronal Excitability of Lateral Orbitofrontal Cortex Neurons Via a Glycine Receptor Dependent Mechanism

Badanich

Mulholland

Beckley

et al. 2013

Neuropsychopharmacol

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“…A similar increase of NMDAR currents after ethanol treatment had been previously observed in the hippocampus (33) and in dorsal striatum (34). It has been reported that STEP inactivates Fyn (35), a SFK that phosphorylates tyrosine residues on the NMDAR and enhances its function (12).…”

Section: Discussionsupporting

confidence: 80%

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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“…In vivo studies demonstrate that Fyn activation is necessary for a number of aversive conditioned behaviors as well as alcohol-conditioned place preference, alcohol self-administration, and drug-primed reinstatement of alcohol-seeking behavior, in a brain region-specific manner (Isosaka et al, 2008;Kojima et al, 2005;Schafe et al, 1996;Wang et al, 2007;Wang et al, 2010; but see Yaka et al, 2003). Within the DH, Fyn activation is required for contextual fear conditioning (Isosaka et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking

Xie

Arguello

Wells

et al. 2013

Neuropsychopharmacol

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Glutamatergic neurotransmission in the dorsal hippocampus (DH) is necessary for drug context-induced reinstatement of cocaineseeking behavior in an animal model of drug relapse. Furthermore, in vitro studies suggest that the Src family of tyrosine kinases critically regulates glutamatergic cellular functions within the DH. Thus, Src-family kinases in the DH may similarly control contextual cocaineseeking behavior. To test this hypothesis, rats were trained to lever press for un-signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine-seeking behavior (non-reinforced active lever pressing) was then assessed in the previously cocaine-paired and extinction contexts after AP5 (N-methyl-D-aspartate glutamate (NMDA) receptor (NMDAR) antagonist; 0.25 or 2.5 mg/0.5 ml/hemisphere), PP2 (Src-family kinase inhibitor; 6.25 or 62.5 ng/0.5 ml/hemisphere), Ro25-6981 (NR2B subunitcontaining NMDAR antagonist; 0.2 or 2 mg/0.5 ml/hemisphere), or vehicle administration into the DH. Administration of AP5, PP2, or Ro25-6981 into the DH dose-dependently impaired drug context-induced reinstatement of cocaine-seeking behavior relative to vehicle, without altering instrumental behavior in the extinction context or food-reinforced instrumental responding and general motor activity in control experiments. Cocaine-seeking behavior during the first 20 min of the test session in the cocaine-paired context was associated with an increase in NR2B subunit activation, and intra-DH PP2 pretreatment disrupted this relationship. Together, these findings suggest that Src-family kinase activation, NMDAR stimulation, and likely Src-family kinase-mediated NR2B subunit-containing NMDAR activation in the DH are necessary for incentive motivational and/or memory processes that promote contextual cocaine-seeking behavior.

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

Cited by 161 publications

References 66 publications

Ethanol Reduces Neuronal Excitability of Lateral Orbitofrontal Cortex Neurons Via a Glycine Receptor Dependent Mechanism

Ethanol Reduces Neuronal Excitability of Lateral Orbitofrontal Cortex Neurons Via a Glycine Receptor Dependent Mechanism

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

Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking

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