Enhancement of NMDA-induced functional responses without concomitant NMDA receptor changes following chronic ethanol exposure in cerebellar granule cells

Cebere, Aleta; Cebers, Gvido; Liljequist, Sture

doi:10.1007/s002109900133

Cited by 32 publications

(31 citation statements)

References 45 publications

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“…On one hand, some authors reported no changes in subunit expression at all [30], and others found changes solely in the expression of the NR1 [60] or NR2A [46] subunit in consequence of long-term ethanol exposure. On the other hand, there are papers concluding that besides several other types of subunits and certain NR1 splice variants, the expression of the NR2B subunit is increased.…”

Section: Effect Of Long-term Ethanol Exposure On the Structure Of Nmdarsmentioning

confidence: 99%

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Nagy

Kolok²,

Boros³

et al. 2005

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Long-term alcohol exposure gives rise to development of physical dependence on alcohol in consequence of changes in certain neurotransmitter functions. Accumulating evidence suggests that the glutamatergic neurotransmitter system, especially the N-methyl-D-aspartate (NMDA) type of glutamate receptors is a particularly important site of ethanol's action, since ethanol is a potent inhibitor of the NMDA receptors (NMDARs) and prolonged ethanol exposition leads to a compensatory "upregulation" of NMDAR mediated functions supposedly contributing to the occurrence of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal.Recently, expression of different types of NMDAR subunits was found altered after long-term ethanol exposure. Especially, the expression of the NR2B and certain splice variant forms of the NR1 subunits were increased in primary neuronal cultures treated intermittently with ethanol. Since NMDA ion channels with such an altered subunit composition have increased permeability for calcium ions, increased agonist sensitivity, and relatively slow closing kinetics, the abovementioned alterations may underlie the enhanced NMDAR activation observed after long-term ethanol exposure. In accordance with these changes, the inhibitory potential of NR2B subunit-selective NMDAR antagonists is also increased, demonstrating excellent potency against alcohol withdrawal-induced in vitro cytotoxicity. Although in vivo data are few with these compounds, according to the effectiveness of the classic NMDAR antagonists in attenuation, not only the physical symptoms,but also some affective and motivational components of alcohol withdrawal, novel NR2B subunit selective NMDAR antagonists may offer a preferable alternative in the pharmacotherapy of alcohol dependence.

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Section: Effect Of Long-term Ethanol Exposure On the Structure Of Nmdarsmentioning

confidence: 99%

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Nagy

Kolok²,

Boros³

et al. 2005

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“…Although ethanol-induced enhancement of NMDA receptor function has been widely reported, there is controversy concerning the cellular basis for this increase in function. Some studies have reported increases in NMDA receptor subunit protein and/or mRNA expression (Trevisan et al, 1994;Follesa and Ticku, 1996;Hu et al, 1996;Snell et al, 1996;Chen et al, 1997;Kumari, 2001), whereas others have observed increases in NMDA receptor function without changes in NMDA receptor levels (Chandler et al, 1997;Rudolph et al, 1997;Cebere et al, 1999;Winkler et al, 1999;Ferreira et al, 2001). These results suggest that although bulk increases in NMDA receptors can occur in response to prolonged ethanol exposure, additional processes that regulate NMDA receptor function are likely engaged (Chandler et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Chronic Ethanol Induces Synaptic But Not Extrasynaptic Targeting of NMDA Receptors

Carpenter-Hyland¹,

Woodward²,

Chandler³

2004

J. Neurosci.

143

168

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“…Hoffman et al ( , 1996 reported a 47% increase in [^H]MK-801 binding and a 20% increase in NRl and a 30% decrease in NR2A subunit levels in cultured cerebellar granule neurons exposed to 100 mM ethanol for 2 to 4 days. In contrast, Cebere et al (1999) reported that exposure of cultured cerebellar granule neurons to 50 to 100 mM ethanol for 3 days did not change [^H]MK-801 binding or expression of NRl splice variants and NR2A, NR2B, and NR2C subunits. More recently, Kumari (2001) found that exposure of cultured cortical neurons to 50 mM ethanol for 5 days induced a decrease in the mRNA and protein levels of splice variants containing the Nl cassette (NRl-3b and NRl-4b) and an increase in the protein expression levels of splice variants lacking this cassette (NRl-3a and NRl-4a).…”

Section: Discussionmentioning

confidence: 92%

Effects of Chronic Alcohol Exposure on Kainate Receptor-Mediated Neurotransmission in the Hippocampus

Valenzuela¹,

Savage²,

Weiner³

2002

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SUPPLEMENTARY NOTES 12a. DISTRIBUTION /AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited 12b. DISTRIBUTION CODE Abstract (Maximum 200 Words) labstract should contain no proprietary or confidential information)We have been testing the hypothesis that chronic alcohol exposure alters expression and/or function of kainate receptors (KA-Rs) in the hippocampus. KA-Rs control hippocampal excitability and an ethanol-induced upregulation of KA-Rs could contribute to the hyperexcitability associated with alcohol withdrawal. Unexpectedly, Western immunoblotting and immunohistochemical studies have demonstrated that chronic ethanol exposure does not upregulate KA-R subunit expression. However, studies with cultured neurons suggest that alcohol withdrawal itself, but not chronic ethanol exposure, upregulates KA-R function. Therefore, we are now focusing our efforts at testing if this is also true for animals exposed to ethanol. We have switched to a different method of alcohol exposure; we are using the inhalation route, which reproducibly produces high ethanol levels. We are currently processing brain sections from control rats and rats withdrawn from a 14-day inhalational ethanol exposure paradigm. These sections will be immunostained with anti-GluR6/7 antibodies and will be used for radioligand binding experiments. We have also characterized the acute effects of ethanol on the function of interneuronal KA-Rs. Moreover, a preliminary experiment with hippocampal slices from rats withdrawn from a 6-day inhalational exposure paradigm suggests that the function of these receptors is upregulated. During the last year of support, we will concentrate on characterizing the function of KA-Rs in the CA1 and CAS regions in alcohol withdrawn rats. Alcohol-related medical disorders affect many organs and systems of the body, including the central nervous system (CNS). As with other drugs of abuse, long-term alcohol ingestion results in the development of tolerance, addiction, and dependence. Alcohol produces these effects by altering the actions of neurotransmitters and their receptors in the brain. Chronic ethanol exposure has complex and long-lasting effects on the function and/or expression of a myriad of neurotransmitter receptors and their modulators. A group of proteins affected by chronic ethanol exposure are hgand-gated ion channels such as the glutamatergic ionotropic receptors. Glutamate activates three major classes of ionotropic receptors. These three major types of channels are the NMD A, AMPA and kainate receptors (KA-Rs). The purpose of this proposal is to test whether or not chronic ethanol exposure results in alterations in subunit expression and/or function of KA-Rs in the hippocampus. Maladaptive changes in hippocampal KA-R expression could contribute to the pathophysiology of alcohol withdrawal syndrome. The alcohol withdrawal syndrome is associated with neuronal hyperexcitabiUty and seizures. Since kainate receptors are important regulators of excitability in the hippocampus, upregulation o...

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Enhancement of NMDA-induced functional responses without concomitant NMDA receptor changes following chronic ethanol exposure in cerebellar granule cells

Cited by 32 publications

References 45 publications

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Chronic Ethanol Induces Synaptic But Not Extrasynaptic Targeting of NMDA Receptors

Effects of Chronic Alcohol Exposure on Kainate Receptor-Mediated Neurotransmission in the Hippocampus

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