Identification of Dopamine D1–D3 Receptor Heteromers

Marcellino, Daniel; Ferré, Sergi; Casadó, Vicent; Cortés, Antonio; Foll, Bernard Le; Mazzola, Carmen; Drago, Filippo; Saur, Oliver; Stark, Holger; Soriano, Aroa; Barnes, Chanel; Goldberg, Steven R.; Lluı́s, Carme; Fuxé, Kjell; Franco, Rafael

doi:10.1074/jbc.m710349200

Cited by 216 publications

(93 citation statements)

References 42 publications

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“…Previous studies have found that D1 containing neurons in striatum also express D3, while D2 expressing neurons mostly represent a separate neuronal population (41, 42). D1 and D3 receptors dimerize and form a receptor complex which is important in the development of addiction (43, 44). D3 receptors can also inhibit D1 signaling which may be responsible for the decrease in cocaine preference seen with increased D3 expression in the Npas2 mutant mice during the light cycle.…”

Section: Discussionmentioning

confidence: 99%

Direct Regulation of Diurnal Drd3 Expression and Cocaine Reward by NPAS2

Ozburn

Falcón

Twaddle

et al. 2015

Biological Psychiatry

119

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Background Circadian gene disruptions are associated with the development of psychiatric disorders, including addiction. However, the mechanisms by which circadian genes regulate drug reward remain poorly understood. Methods We used mice with a mutation in Npas2, and AAV-shRNA mediated knock-down of Npas2 and Clock in the nucleus accumbens (NAc). We performed conditioned place preference (CPP) assays for cocaine. We utilized cell sorting techniques, qPCR and chromatin immunoprecipitation (ChIP) assays followed by deep sequencing (ChIP-seq). Results Npas2 mutants exhibit decreased sensitivity to cocaine reward which can be recapitulated with a knock-down of NPAS2 specifically in the NAc, demonstrating the functional importance of NPAS2 in this region. Interestingly, reducing CLOCK (a homologue of NPAS2) expression in the NAc had no effect, suggesting an important distinction in NPAS2 and CLOCK function. Furthermore, we find that NPAS2 expression is restricted to Drd1 expressing neurons, (i.e. “direct” pathway circuitry) while CLOCK is ubiquitous. Moreover, NPAS2 and CLOCK have distinct temporal patterns of DNA binding, and we identified novel and unique binding sites for each protein. We identified the Drd3 dopamine receptor as a direct transcriptional target of NPAS2 and find that NPAS2 knock-down in the NAc disrupts its diurnal rhythm in expression. Chronic cocaine treatment likewise disrupts the normal rhythm in Npas2 and Drd3 expression in the NAc, which may underlie behavioral plasticity in response to cocaine. Conclusions Together, these findings identify an important and novel role for the circadian protein, NPAS2, in the NAc in the regulation of dopamine receptor expression and drug reward.

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Section: Discussionmentioning

confidence: 99%

Direct Regulation of Diurnal Drd3 Expression and Cocaine Reward by NPAS2

Ozburn

Falcón

Twaddle

et al. 2015

Biological Psychiatry

119

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“…Moreover, modeling studies of mammalian DA neurons suggest that tonic versus burst firing can result in differences in the relative occupancies of the different receptor subtypes [61, 62]. D3R and D1R can display functional interactions that are based on different hetero-dimer [63–65] or hetero-tetramer configurations [66]. In the hetero-tetrameric model, D1R and D3R co-activation leads to both antagonistic and synergistic interactions at the level of adenylyl-cyclase and MAPK activation, respectively [66].…”

Section: The Potential Role Of D1-d3 Receptor Interaction In Rlsmentioning

confidence: 99%

“…A2AR-D2R heteromers are selectively localized in the indirect MSN, which gives rise to the indirect pathway [90]. The direct MSN constitutes the direct efferent pathway and expresses D1R and D3R, which can potentially form D1R-D3R heteromers [63, 65]. D3R has a lower striatal expression than D1R, but it upregulates in animal models of L-dopa-induced dyskinesia and psychostimulants abuse [91, 92].…”

Section: Receptor Heteromerization and Relevance To Rlsmentioning

confidence: 99%

Connectome and molecular pharmacological differences in the dopaminergic system in restless legs syndrome (RLS): plastic changes and neuroadaptations that may contribute to augmentation

Earley¹,

Uhl

Clemens

et al. 2017

Sleep Medicine

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Restless Legs Syndrome (RLS) is primarily treated with levodopa and dopaminergics that target the inhibitory dopamine receptor subtypes D3 and D2. The initial success of this therapy led to the idea of a hypo-dopaminergic state as the mechanistic origin underlying RLS. However, multiple lines of evidence suggest that this simplified concept of a reduced dopamine function as the basis of RLS is incomplete. Moreover, long-term medication with the D2/D3 agonists leads to a reversal of the initial benefits of dopamine agonists and augmentation, which is a worsening of symptoms under therapy. The recent findings on the state of the dopamine system in RLS that support the notion that a dysfunction in the dopamine system may in fact give rise to a hyper-dopaminergic state is summaraized. Based on this data, the concept of a dynamic nature of the dopamine effects in a circadian context, is presented. The possible interactions of cell-adhesion molecules expressed by dopaminergic systems and their possible impact on RLS and augmentation are discussed. Genome-wide association studies (GWAS) indicate a significantly increased risk for RLS in populations with genomic variants of the cell adhesion molecule receptor type protein tyrosine phosphatase D (PTPRD), and PTPRD is abundantly expressed by dopamine neurons. PTPRD may play a role in the reconfiguration of neural circuits, including shaping the interplay of G protein-coupled receptor (GPCR) homomers and heteromers that mediate dopaminergic modulation. Recent animal model data support the concept that interactions between functionally-distinct dopamine receptor subtypes can re-shape behavioral outcomes and change with normal aging. Additionally, long-term activation of one dopamine receptor subtype can increase receptor expression of a different receptor subtype with opposing modulatory actions. Such dopamine receptor interactions at both spinal and supra-spinal levels appear to play important roles in RLS. In addition, these interactions can also extend to the adenosine A2A receptor, which is also prominently expressed in the striatum. Interactions between A2A and dopamine receptors and dopaminergic cell adhesion molecules, including PTPRD, may provide new pharmacological targets in treating RLS. In summary, new treatment options for RLS that include recovery from augmentation will have to take into account dynamic changes to the dopamine system that occur during the circadian cycle, plastic changes that can develop as a function of treatment or with aging, changes to the connectome based on alterations to cell adhesion molecules, and receptor interactions that may reach beyond the dopamine system itself.

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“…Moreover, D3 receptors may be upregulated in these places in the brains of cocaine and methamphetamine abusers (Staley and Mash, 1996; Boileau et al, 2012). It is also intriguing to consider that D1–D3 receptor heteromers (Marcellino et al, 2008, Ferre et al, 2014) in these discrete brain regions may play a role in drug memory reconsolidation. Despite a need for additional studies, our current results suggest that pharmacological blockade of either D1 or D3 receptors in the context of drug memory reconsolidation may be therapeutic for the treatment of cocaine craving and relapse in clinical settings.…”

Section: Discussionmentioning

confidence: 99%

Dopamine D1 and D3 receptors mediate reconsolidation of cocaine memories in mouse models of drug self-administration

Yan

Newman

2014

Neuroscience

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Memories of drug experience and drug-associated environmental cues can elicit drug-seeking and taking behaviors in humans. Disruption of reconsolidation of drug memories dampens previous memories and therefore may provide a useful way to treat drug abuse. We and others previously demonstrated that dopamine D1 and D3 receptors play differential roles in acquiring cocaine-induced behaviors. Moreover, D3 receptors contribute to the reconsolidation of cocaine-induced conditioned place preference. In the present study, we examined effects of manipulating D1 or D3 receptors on reconsolidation of cocaine memories in mouse models of drug self-administration. We found that pharmacological blockade of D1 receptors or a genetic mutation of the D3 receptor gene attenuated reconsolidation that lasted for at least 1 week after the memory retrieval. In contrast, with no memory retrieval, pharmacological antagonism of D1 receptors or the D3 receptor gene mutation did not significantly affect reconsolidation of cocaine memories. Pharmacological blockade of D3 receptors also attenuated reconsolidation in wild-type mice that lasted for at least 1 week after the memory retrieval. These results suggest that D1 and D3 receptors and related signaling mechanisms play key roles in reconsolidation of cocaine memories in mice, and that these receptors may serve as novel targets for the treatment of cocaine abuse in humans.

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Identification of Dopamine D1–D3 Receptor Heteromers

Cited by 216 publications

References 42 publications

Direct Regulation of Diurnal Drd3 Expression and Cocaine Reward by NPAS2

Direct Regulation of Diurnal Drd3 Expression and Cocaine Reward by NPAS2

Connectome and molecular pharmacological differences in the dopaminergic system in restless legs syndrome (RLS): plastic changes and neuroadaptations that may contribute to augmentation

Dopamine D1 and D3 receptors mediate reconsolidation of cocaine memories in mouse models of drug self-administration

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