Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use

Bock, Roland; Shin, Jung Hoon; Kaplan, Alanna R.; Dobi, Alice; Markey, Eric; Kramer, P.; Gremel, Christina M.; Christensen, Christine H.; Adrover, Martín Federico; Alvarez, Veronica A.

doi:10.1038/nn.3369

Cited by 269 publications

(264 citation statements)

References 35 publications

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“…S5, ii). These results demonstrate that cocaine-induced PRMT6 down-regulation in the NAc occurs specifically in D2-MSNs, where it counteracts the rewarding effects of cocaine, thus reinforcing the hypothesis that this MSN subtype is necessary for opposing cocaine use (26).…”

Section: Significancesupporting

confidence: 72%

Histone arginine methylation in cocaine action in the nucleus accumbens

Damez-Werno

Sun

Scobie

et al. 2016

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

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Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanismssuch as histone acetylation and methylation on Lys residues-have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motivation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction.histone arginine (R) methylation | drug addiction | medium spiny neurons | ChIP-seq | Src R epeated cocaine exposure is marked by persistent changes in gene expression within the nucleus accumbens (NAc), a central component of the brain's reward circuitry (1, 2). Important aspects of cocaine action appear to be mediated by changes in gene transcription via chromatin regulatory mechanisms such as histone acetylation or methylation on Lys (K) residues (3-11). However, in contrast to K methylation, the functional role of histone Arg (R) methylation remains underexplored in addiction models and poorly understood in the brain in general.The methylation of R residues is catalyzed by the protein R methyltransferase (PRMT) family of enzymes, which can generate different methylated R states with diverse functional consequences, including monomethylarginine (MMA) and dimethylarginine (DMA) residues, the latter of which can be either asymmetric (aDMA) or symmetric (sDMA). PRMTs that catalyze aDMA are designated type I, and those that generate sDMA are designated type II (12, 13). Histone tails are prime targets for these PRMTs, and R methylation induces alterations in chromatin architecture, either condensing or relaxing its structure, thereby creating binding sites for regulatory proteins that contain specialized binding domains (14, 15).PRMT6, a nuclear enzyme that modifies histone tails, is the primary enzyme responsible for asymmetric dimethylation of R2 on histone H3 (H3R2me2a) in mammalian cells (14,16). The H3R2me2a mark is thought to be repressive in nature because of...

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Section: Significancesupporting

confidence: 72%

Histone arginine methylation in cocaine action in the nucleus accumbens

Damez-Werno

Sun

Scobie

et al. 2016

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

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“…MSNs primarily express D1-like or D2-like dopamine receptors. Though we were not in a position to address the identity of c-Fos-positive neurons in TLR4 -/-mice in the current study, we think these neurons may be D2-MSNs as activation of these neurons mainly controls aversive behaviors [37][38][39]. It is well-known that D2-MSNs are inhibited by DA [40], and xenobiotic activation of TLR4 results in an increase in DA in the NAc [20,33].…”

Section: Discussionmentioning

confidence: 80%

Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

Yan

Cheng

et al. 2016

Neurosci. Bull.

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Abnormal approach-avoidance behavior has been linked to deficits in the mesolimbic dopamine (DA) system of the brain. Recently, increasing evidence has indicated that toll-like receptor 4 (TLR4), an important pattern-recognition receptor in the innate immune system, can be directly activated by substances of abuse, resulting in an increase of the extracellular DA level in the nucleus accumbens. We thus hypothesized that TLR4-dependent signaling might regulate approach-avoidance behavior. To test this hypothesis, we compared the novelty-seeking and social interaction behaviors of TLR4-deficient (TLR4 -/-) and wild-type (WT) mice in an approach-avoidance conflict situation in which the positive motivation to explore a novel object or interact with an unfamiliar mouse was counteracted by the negative motivation to hide in exposed, large spaces. We found that TLR4 -/-mice exhibited reduced novelty-seeking and social interaction in the large open spaces. In less stressful test apparatuses similar in size to the mouse cage, however, TLR4 -/-mice performed normally in both novelty-seeking and social interaction tests. The reduced exploratory behaviors under approachavoidance conflict were not due to a high anxiety level or an enhanced fear response in the TLR4 -/-mice, as these mice showed normal anxiety and fear responses in the open field and passive avoidance tests, respectively. Importantly, the novelty-seeking behavior in the large open field induced a higher level of c-Fos activation in the nucleus accumbens shell (NAcSh) in TLR4 -/-mice than in WT mice. Partially inactivating the NAcSh via infusion of GABA receptor agonists restored the novelty-seeking behavior of TLR4 -/-mice. These data suggested that TLR4 is crucial for positive motivational behavior under approach-avoidance conflict. TLR4-dependent activation of neurons in the NAcSh may contribute to this phenomenon.

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“…Strengthening of excitatory synapses in MSNs in the NAc involves the initial formation of silent synapses lacking AMPA receptors during chronic exposure to cocaine, followed by insertion of AMPA receptors into spines during withdrawal (9)(10)(11). Accumulating evidence indicates that adaptive cocaine action involves potentiation of glutamatergic afferents arising from mPFC, amygdala, and ventral hippocampus preferentially onto D1-MSNs (41-44), although D2-MSNs still contribute to certain behavioral features of cocaine action (45,46). Previous studies showed that WAVE1 is highly localized to dendritic spines (47).…”

Section: Discussionmentioning

confidence: 99%

WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine

Ceglia

Lee

Cahill

et al. 2017

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

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Wiskott-Aldrich syndrome protein (WASP) family verprolin homologous protein 1 (WAVE1) regulates actin-related protein 2/3 (Arp2/3) complex-mediated actin polymerization. Our previous studies have found WAVE1 to be inhibited by Cdk5-mediated phosphorylation in brain and to play a role in the regulation of dendritic spine morphology. Here we report that mice in which WAVE1 was knocked out (KO) in neurons expressing the D1 dopamine receptor (D1-KO), but not mice where WAVE1 was knocked out in neurons expressing the D2 dopamine receptor (D2-KO), exhibited a significant decrease in place preference associated with cocaine. In contrast to wild-type (WT) and WAVE1 D2-KO mice, cocaine-induced sensitized locomotor behavior was not maintained in WAVE1 D1-KO mice. After chronic cocaine administration and following withdrawal, an acute cocaine challenge induced WAVE1 activation in striatum, which was assessed by dephosphorylation. The cocaine-induced WAVE1 dephosphorylation was attenuated by coadministration of either a D1 dopamine receptor or NMDA glutamate receptor antagonist. Upon an acute challenge of cocaine following chronic cocaine exposure and withdrawal, we also observed in WT, but not in WAVE1 D1-KO mice, a decrease in dendritic spine density and a decrease in the frequency of excitatory postsynaptic AMPA receptor currents in medium spiny projection neurons expressing the D1 dopamine receptor (D1-MSNs) in the nucleus accumbens. These results suggest that WAVE1 is involved selectively in D1-MSNs in cocaine-evoked neuronal activitymediated feedback regulation of glutamatergic synapses.W iskott-Aldrich syndrome protein (WASP) family verprolin homologous protein (WAVE) initiates de novo actin polymerization through its ability to activate the actin-related protein 2/3 (Arp2/3) complex (1). Three members of the family (WAVE1-3) exist, with WAVE1 being highly expressed in brain (2). WAVE1 was purified from bovine or rat brain as part of a heteropentameric protein complex together with PIR121 [also called cytoplasmic FMR1-interacting protein 2, (Cyfip2)], Nck-associated protein 1 (Nckap1), Abl-interactor 2 (Abi2), and HSPC300 (3, 4). Whereas WAVE1 plays a key role in Arp2/3 complex binding and actin polymerization, other protein components in the complex are important for its subcellular localization and interaction with upstream ligands or activators (5, 6).In our initial study in striatum, the WAVE1 complex was found to interact with p35, the regulatory subunit of cyclin-dependent kinase 5 (Cdk5) (4). Phosphorylation of WAVE1 at Ser310, Ser397, and Ser441 by Cdk5/p35, in the complex purified from rat brain, or with recombinant WAVE1, resulted in inhibition of actin polymerization in vitro (4). We also observed that the stoichiometry of WAVE1 phosphorylation by Cdk5 is high in brain, suggestive of the protein being largely inactive under basal conditions (4). However, studies using mouse striatal slices indicated that WAVE1 can be dephosphorylated at all three Cdk5 sites and thereby activated upon stimulation of D1 dopa...

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Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use

Cited by 269 publications

References 35 publications

Histone arginine methylation in cocaine action in the nucleus accumbens

Histone arginine methylation in cocaine action in the nucleus accumbens

Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine

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