DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens

Maldve, Regina E.; Zhang, T. A.; Ferrani-Kile, K.; Schreiber, Sidney S.; Lippmann, Melanie J.; Snyder, Gretchen L.; Fienberg, Allen A.; Leslie, Steven W.; Gonzales, Rueben A.; Morrisett, Richard A.

doi:10.1038/nn877

Cited by 133 publications

(123 citation statements)

References 29 publications

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“…Elevation of phospho-DARPP-32 immunoreactivity is notably apparent in the cell bodies as well as in the surrounding neuropil (Figure 8a and c). Treatment with EtOH alone also increased the level of DARPP-32 phosphorylation by a small, but significant extent (Figure 8a and c) in agreement with previous reports (Maldve et al, 2002;Donohue et al, 2005). Importantly, consistent with our findings with HEK293T cells, EtOH pretreatment synergistically potentiated SKF81297-stimulated DARPP-32 phosphorylation in comparison with the agonist treatment alone (Figure 8a-c).…”

Section: Etoh Pretreatment and Darpp-32 Phosphorylation In Rat Striatumsupporting

confidence: 92%

“…DARPP-32, the downstream target of D 1 receptor signaling, has also been implicated in EtOH-mediated signaling. At the cellular level, EtOH treatment increases phosphorylation of DARPP-32 and is reported to regulate NMDA receptor activity in the NAc (Maldve et al, 2002). Moreover, in mice lacking DARPP-32, EtOH-dependent reinforcement is absent (Maldve et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…At the cellular level, EtOH treatment increases phosphorylation of DARPP-32 and is reported to regulate NMDA receptor activity in the NAc (Maldve et al, 2002). Moreover, in mice lacking DARPP-32, EtOH-dependent reinforcement is absent (Maldve et al, 2002). Despite a growing body of evidence implicating D 1 receptor function in EtOHmediated behaviors, nothing is known about the mechanisms by which EtOH regulates D 1 receptor signaling.…”

Section: Introductionmentioning

confidence: 99%

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Ethanol Regulation of D1 Dopamine Receptor Signaling is Mediated by Protein Kinase C in an Isozyme-Specific Manner

Rex

Rankin

Ariano

et al. 2008

Neuropsychopharmacol

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Ethanol consumption potentiates dopaminergic signaling that is partially mediated by the D 1 dopamine receptor; however, the mechanism(s) underlying ethanol-dependent modulation of D 1 signaling is unclear. We now show that ethanol treatment of D 1 receptor-expressing cells decreases D 1 receptor phosphorylation and concurrently potentiates dopamine-stimulated cAMP accumulation. Protein kinase C (PKC) inhibitors mimic the effects of ethanol on D 1 receptor phosphorylation and dopamine-stimulated cAMP levels in a manner that is non-additive with ethanol treatment. Ethanol was also found to modulate specific PKC activities as demonstrated using in vitro kinase assays where ethanol treatment attenuated the activities of lipid-stimulated PKCg and PKCd in membrane fractions, but did not affect the activities of PKCa, PKCb 1 , or PKCe. Importantly, ethanol treatment potentiated D 1 receptormediated DARPP-32 phosphorylation in rat striatal slices, supporting the notion that ethanol enhances D 1 receptor signaling in vivo. These findings suggest that ethanol inhibits the activities of specific PKC isozymes, resulting in decreased D 1 receptor phosphorylation and enhanced dopaminergic signaling.

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Section: Etoh Pretreatment and Darpp-32 Phosphorylation In Rat Striatumsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ethanol Regulation of D1 Dopamine Receptor Signaling is Mediated by Protein Kinase C in an Isozyme-Specific Manner

Rex

Rankin

Ariano

et al. 2008

Neuropsychopharmacol

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“…Indeed, the ability of Ro 25-6981 to enhance NMDAR function in the hippocampus can be blocked by phosphatase inhibition (Mallon et al, 2005). In support of this, evidence suggests that ethanol sensitivity of NMDARs and other channels may be regulated by posttranslational modifications (Maldve et al, 2002, but see Xu and Woodward, 2006). Finally, it is possible that the presence of NR2B specifically imparts ethanol sensitivity on synaptically activated NMDARs in the vBNST.…”

Section: Nmdar Subtype Selectivity Of Ethanol Inhibitionmentioning

confidence: 95%

Alcohol Inhibits NR2B-Containing NMDA Receptors in the Ventral Bed Nucleus of the Stria Terminalis

Kash

Matthews

Winder

2007

Neuropsychopharmacol

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Components of the mesolimbic dopamine system, in particular dopaminergic cells in the ventral tegmental area (VTA), have been implicated in the acute reinforcing actions of ethanol. The ventral bed nucleus of the stria terminalis (vBNST) potently regulates dopaminergic cell firing in the VTA, and has been implicated in the behavioral actions of ethanol. The N-methyl-D-asparate receptor (NMDAR) is a major molecular target of ethanol, however, current evidence suggests that ethanol regulation of NMDAR function is widely variable and likely depends on a number of factors. Thus, it is critical to investigate ethanol regulation of NMDAR function at synapses relevant to ethanol-regulated behaviors, such as in the vBNST. Here we show, using multiple techniques, that ethanol inhibits NMDAR function in vBNST neurons in a postsynaptic fashion. Further, we demonstrate the functional presence of both NR2A and NR2B-containing NMDARs in the vBNST. While genetic removal of NR2A did not alter the magnitude of ethanol inhibition, pharmacological blockade of NR2B rendered synaptically activated NMDARs insensitive to ethanol inhibition. Finally, we demonstrate that ethanol inhibits NMDARs in cells in the vBNST that project to the VTA, providing a direct means by which ethanol in the vBNST can modulate the dopaminergic system.

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“…In the adult hippocampus, LTP is associated with increased tyrosine phosphorylation of the NR2B subunit and increased NMDA receptor surface expression (Rostas, et al, 1996). It has also been reported in the nucleus accumbens that acute tolerance to ethanol involves alterations in serine phosphorylation of the NR1 subunit (Maldve, et al, 2002). We suggest that while rapid adaptive responses to acute ethanol involve phosphorylation-dependent changes in channel conductance and/or surface expression, long lasting changes that occur in response to chronic ethanol involve alterations in their synaptic localization.…”

Section: Activity-dependent Targeting Of Nmda Receptors To the Synapsmentioning

confidence: 99%

Adaptive plasticity of NMDA receptors and dendritic spines: Implications for enhanced vulnerability of the adolescent brain to alcohol addiction

Carpenter-Hyland

Chandler

2007

Pharmacology Biochemistry and Behavior

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It is now known that brain development continues into adolescence and early adulthood and is highly influenced by experience-dependent adaptive plasticity during this time. Behaviorally, this period is also characterized by increased novelty-seeking and risk-taking. This heightened plasticity appears to be important in shaping behaviors and cognitive processes that contribute to proper development of an adult phenotype. However, increasing evidence has linked these same experience-dependent learning mechanisms with processes that underlie drug addiction. As such, the adolescent brain appears be particularly susceptible to experience-dependent learning processes associated with consumption of alcohol and addictive drugs. At the level of the synapse, homeostatic changes during ethanol consumption are invoked to counter the destabilizing effects of ethanol on neural networks. This homeostatic response may be especially pronounced in the adolescent and young adult brain due to its heightened capacity to undergo experience-dependent changes, and appears to involve increased synaptic targeting of NMDA receptors. Interestingly, recent work from our lab also indicates that the enhanced synaptic localization of NMDA receptors promotes increases in the size of dendritic spines. This increase may represent a structural-based mechanism that supports the formation and stabilization of maladapted synaptic connections that, in a sense, "fix" the addictive behavior in the adolescent and young adult brain.

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DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens

Cited by 133 publications

References 29 publications

Ethanol Regulation of D1 Dopamine Receptor Signaling is Mediated by Protein Kinase C in an Isozyme-Specific Manner

Ethanol Regulation of D1 Dopamine Receptor Signaling is Mediated by Protein Kinase C in an Isozyme-Specific Manner

Alcohol Inhibits NR2B-Containing NMDA Receptors in the Ventral Bed Nucleus of the Stria Terminalis

Adaptive plasticity of NMDA receptors and dendritic spines: Implications for enhanced vulnerability of the adolescent brain to alcohol addiction

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