Activity-Dependent Modulation of Limbic Dopamine D3 Receptors by CaMKII

Liu, Xianyu; Mao, Li; Zhang, Guo Chi; Papasian, Christopher J.; Fibuch, Eugene E.; Lan, Hong Xiang; Zhou, Hui; Xu, Ming; Wang, John Q.

doi:10.1016/j.neuron.2008.12.015

Cited by 114 publications

(133 citation statements)

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“…Recent work showed that the activation of CaMKII has a key role in the development and maintenance of the addiction state, and that fast and slow positive feedback loops are interlinked through CaMKII underlying drug addiction (Li et al, 2008). Recent work by Wang and colleagues showed that CaMKIIa could relieve the D3R-mediated inhibition on sensitized behavior to foster drug-seeking behavior, implicating CaMKIIa as an important negative regulator of D3R (Liu et al, 2009). In our experiments, we analyzed the effects of different isoforms of CaMKII on drug reinforcement responses.…”

Section: Discussionmentioning

confidence: 99%

Chronic Cocaine-Induced H3 Acetylation and Transcriptional Activation of CaMKIIα in the Nucleus Accumbens Is Critical for Motivation for Drug Reinforcement

Wang

et al. 2009

Neuropsychopharmacol

161

156

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The regulation of gene expression in the brain reward regions is known to contribute to the pathogenesis and persistence of drug addiction. Increasing evidence suggests that the regulation of gene transcription is mediated by epigenetic mechanisms that alter the chromatin structure at specific gene promoters. To better understand the involvement of epigenetic regulation in drug reinforcement properties, rats were subjected to cocaine self-administration paradigm. Daily histone deacetylase (HDAC) inhibitor infusions in the shell of the nucleus accumbens (NAc) caused an upward shift in the dose-response curve under fixed-ratio schedule and increased the break point under progressive-ratio schedule, indicating enhanced motivation for self-administered drug. The effect of the HDAC inhibitor is attributed to the increased elevation of histone acetylation induced by chronic, but not acute, cocaine experience. In contrast, neutralizing the chronic cocaine-induced increase in histone modification by the bilateral overexpression of HDAC4 in the NAc shell reduced drug motivation. The association between the motivation for cocaine and the transcriptional activation of addiction-related genes by H3 acetylation in the NAc shell was analyzed. Among the genes activated by chronic cocaine experiences, the expression of CaMKIIa, but not CaMKIIb, correlated positively with motivation for the drug. Lentivirus-mediated shRNA knockdown experiments showed that CaMKIIa, but not CaMKIIb, in the NAc shell is essential for the maintenance of motivation to self-administered cocaine. These findings suggest that chronic drug-use-induced transcriptional activation of genes, such as CaMKIIa, modulated by H3 acetylation in the NAc is a critical regulatory mechanism underlying motivation for drug reinforcement. Neuropsychopharmacology (2010) 35, 913-928; doi:10.1038/npp.2009; published online 9 December 2009 Keywords: histone acetylation; nucleus accumbens; motivation; cocaine self-administration; addiction; CaMKIIa INTRODUCTIONDrug addiction is a debilitating psychiatric disorder characterized by (1) a compulsion to seek and take the drug, (2) a loss of control in limiting intake, and (3) the emergence of a negative emotional state when access to the drug is prevented (Hyman et al, 2006;Kalivas et al, 2005;Koob and Kreek, 2007). The complex behavioral changes leading to drug addiction are thought to result from molecular and cellular adaptation in specific brain regions (Brami-Cherrier et al, 2005). One area of intensive research to clarify neuroadaptation addresses the regulation of gene expression induced by the drug (Nestler, 2001). The drug induces changes in gene expression in key brain reward regions, such as the nucleus accumbens (NAc), prefrontal cortex (PFC), and ventral tegmental area (VTA). For instance, the expression of the immediate early gene c-Fos and several other Fos family proteins is upregulated in the nucleus accumbens, striatum (Courtin et al, 2006) and frontal cortex (Thiriet et al, 2000) after acute cocaine treatment. T...

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Section: Discussionmentioning

confidence: 99%

Chronic Cocaine-Induced H3 Acetylation and Transcriptional Activation of CaMKIIα in the Nucleus Accumbens Is Critical for Motivation for Drug Reinforcement

Wang

et al. 2009

Neuropsychopharmacol

161

156

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“…It has been reported recently that CaMKII phosphorylation causes desensitization of D 3 receptors (Liu et al, 2009) and also D 2 receptors (JQ Wang, personal communication), both (Beckstead et al, 2004;Davila et al, 2003). Furthermore, activation of D 2 receptors, as well as D 4 receptors, has been shown to activate CaMKII via G i/o and intracellular Ca 2 + release (Gu and Yan, 2004;Takeuchi et al, 2002).…”

Section: Ca 2 + -Dependent Desensitization Of D 2 Receptor-mediated Imentioning

confidence: 95%

In Vivo Ethanol Experience Increases D2 Autoinhibition in the Ventral Tegmental Area

Perra

Clements

Bernier

et al. 2011

Neuropsychopharmacol

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Alcoholism is characterized by compulsive alcohol intake after a history of chronic consumption. A reduction in mesolimbic dopaminergic transmission observed during abstinence may contribute to the negative affective state that drives compulsive intake. Although previous in vivo recording studies in rodents have demonstrated profound decreases in the firing activity of ventral tegmental area (VTA) dopamine neurons after withdrawal from long-term ethanol exposure, the cellular mechanisms underlying this reduced activity are not well understood. Somatodendritic dopamine release within the VTA exerts powerful feedback inhibition of dopamine neuron activity via stimulation of D 2 autoreceptors and subsequent activation of G protein-gated inwardly rectifying K + (GIRK) channels. Here, by performing patch-clamp recordings from putative dopamine neurons in the VTA of mouse brain slices, we show that D 2 receptor/ GIRK-mediated inhibition becomes more potent and exhibits less desensitization after withdrawal from repeated in vivo ethanol exposure (2 g/kg, i.p., three times daily for 7 days). In contrast, GABA B receptor/GIRK-mediated inhibition and its desensitization are not affected. Chelating cytosolic Ca 2 + with BAPTA augments D 2 inhibition and suppresses its desensitization in control mice, while these effects of BAPTA are occluded in ethanol-treated mice. Furthermore, inositol 1,4,5-trisphosphate (IP 3 )-induced intracellular Ca 2 + release and Ca 2 + /calmodulin-dependent protein kinase II are selectively involved in the desensitization of D 2 , but not GABA B , receptor signaling. Consistent with this, activation of metabotropic glutamate receptors that are coupled to IP 3 generation leads to cross-desensitization of D 2 /GIRK-mediated responses. We propose that enhancement of D 2 receptor-mediated autoinhibition via attenuation of a Ca 2 + -dependent desensitization mechanism may contribute to the hypodopaminergic state during ethanol withdrawal.

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“…CaMKII interacts with many types of Ca 2þ channels and transmitter receptors including L-type voltage-sensitive calcium channels (VSCCs) (Hudmon et al 2005;Wheeler et al 2008), T-type VSCCs (Welsby et al 2003), P/Q-type VSCCs (Jiang et al 2008), dopamine receptors (Liu et al 2009), muscarinic receptors (Guo et al 2010), and the NR2B subunit of NMDAR (Bayer et al 2001;Merrill et al 2005). This naturally leads to the hypothesis that opening of specific channels activates bound pools of CaM-KII via nanodomain Ca 2þ .…”

Section: Camkiimentioning

confidence: 99%

Studying Signal Transduction in Single Dendritic Spines

Yasuda

2012

Cold Spring Harbor Perspectives in Biology

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Activity-Dependent Modulation of Limbic Dopamine D3 Receptors by CaMKII

Cited by 114 publications

References 56 publications

Chronic Cocaine-Induced H3 Acetylation and Transcriptional Activation of CaMKIIα in the Nucleus Accumbens Is Critical for Motivation for Drug Reinforcement

Chronic Cocaine-Induced H3 Acetylation and Transcriptional Activation of CaMKIIα in the Nucleus Accumbens Is Critical for Motivation for Drug Reinforcement

In Vivo Ethanol Experience Increases D2 Autoinhibition in the Ventral Tegmental Area

Studying Signal Transduction in Single Dendritic Spines

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