Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections

Kupchik, Yonatan M.; Brown, Robyn M.; Heinsbroek, Jasper A.; Lobo, Mary Kay; Schwartz, Danielle; Kalivas, Peter W.

doi:10.1038/nn.4068

Cited by 399 publications

(382 citation statements)

References 25 publications

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“…In a recent study (Kupchik et al, 2015), we provided the first definitive evidence that the direct and indirect pathways of the NAc are not coded by MSN cell types (Figure 1). Using optogenetics in transgenic mice combined with neural tracing tools we showed that D1-MSNs comprise a significant portion of the classical indirect pathway by synapsing on VP neurons that project to the VM.…”

Section: Funding and Disclosurementioning

confidence: 69%

The Direct and Indirect Pathways of the Nucleus Accumbens are not What You Think

Kupchik

Kalivas

2016

Neuropsychopharmacol

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Section: Funding and Disclosurementioning

confidence: 69%

The Direct and Indirect Pathways of the Nucleus Accumbens are not What You Think

Kupchik

Kalivas

2016

Neuropsychopharmacol

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“…S1 B and C). Anatomically, D1-MSNs and D2-MSNs in dorsal striatum project to distinct brain areas (22) but projections of D1-MSNs and D2-MSNs from the NAc are more overlapping and remain to be further defined (11,23). Importantly, stimulation of MSNs by dopamine results in opposite regulation of cAMP and PKA via stimulatory G protein (G s /G olf )-mediated signaling in D1-MSNs compared with inhibitory G protein (G i /G o )-mediated signaling in D2-MSNs (24).…”

Section: Resultsmentioning

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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“…Although the literature has been consistent in this regard, an important caveat that is discussed in more detail in this section is that although behaviors coded by D1 and D2 MSNs are traditionally interpreted as mediated by the direct and indirect pathways, respectively, D1 and D2 accumbens MSNs send a mixed projection to the VP, making the classic interpretation of direct and indirect pathways at least partly incorrect (Kupchik et al, 2015).…”

Section: A Medium Spiny Neuronsmentioning

confidence: 99%

“…Nucleus Accumbens Core Efferents. The NAcore sends projections primarily to GABAergic basal ganglia nuclei, but it also contains neurons that send inputs directly to glutamatergic neurons in the subthalamus and dopaminergic neurons in the paranigral part of the VTA (Groenewegen et al, 1999;Tripathi et al, 2010;Watabe-Uchida et al, 2012;Bocklisch et al, 2013;Matsui et al, 2014;Kupchik et al, 2015). The NAcore also projects to the substantia nigra pars reticulata and sends a striatopallidal projection to the dorsolateral VP and lateral globus pallidus (Heimer et al, 1991;Tripathi et al, 2010).…”

Section: A Nucleus Accumbens Corementioning

confidence: 99%

“…However, this assumption does not hold true for the accumbens efferents in which substantial involvement of D1 MSNs in the indirect projections and D2 MSNs in the direct projections can be demonstrated. Projections from these cells to the VP are a mixture of D1 and D2 MSN axons (Lu et al, 1998;Zhou et al, 2003;Smith et al, 2013;Kupchik et al, 2015). Selective optogenetic stimulation of D1-or D2-MSN projections to the VP revealed that virtually all VP neurons respond to optically evoked D2 inputs from the NAcore, and about one-half the cells respond to D1 stimulation (Kupchik et al, 2015).…”

Section: A Nucleus Accumbens Corementioning

confidence: 99%

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The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

et al. 2016

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Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections

Cited by 399 publications

References 25 publications

The Direct and Indirect Pathways of the Nucleus Accumbens are not What You Think

The Direct and Indirect Pathways of the Nucleus Accumbens are not What You Think

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

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

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