GPR88 is a striatal-enriched orphan G protein-coupled receptor (GPCR) whose expression varies over development in the brain of rodents, monkeys and humans (Ghate et al., 2007; Massart et al., 2009; Van Waes et al., 2011; Massart et al., 2016). Gene association studies in humans have uncovered a link between GPR88 function and several psychiatric, neurodevelopmental or neurodegenerative disorders, including schizophrenia, bipolar disorder, speech delay and chorea (Alkufri et al., 2016; Del Zompo et al., 2014). In rodents, transcript levels of Gpr88 gene were found modified following exposure to various psychoactive drugs, such as mood stabilizers, antidepressants, methamphetamine, L-DOPA and drugs of abuse (Conti et al., 2007; Ogden et al., 2004; Brandish et al., 2005; Le Merrer et al., 2012; Becker et al., 2017). GPR88 thus appears a promising target for the development of innovative treatments for CNS pathologies. In mice, deletion of the Gpr88 gene alters primarily striatal physiology, striatum-centered brain networks and striatal-dependent behaviors, with notably severe deficits in motor coordination and skill learning, hyperactivity, stereotypies and altered reward-driven behaviors (Meirsman et al., 2016a; Meirsman et al., 2016b; Rainwater et al., 2017; Ben Hamida et al., 2018; Arefin et al., 2017; Quintana et al., 2012). GPR88 function, however, extends beyond striatal-mediated responses, in accordance with extra-striatal GPR88 expression (Ehrlich et al., 2018a) and widespread modifications in brain connectivity, gene expression and behavioral responses in Gpr88 null (Gpr88^-/-) mice (Meirsman et al., 2016a; Arefin et al., 2017). Thus, GPR88 has a major influence on brain physiology and controls a vast repertoire of behaviors; the molecular bases of this control, however, remains poorly understood, mostly due to the paucity of pharmacological tools available to manipulate its activity.

At structural level, GPR88 appears as an atypical GPCR. Although considered as part of the class A (rhodopsin) family of GPCRs, GPR88 is distantly related to any well-known receptor of this class (Surgand et al., 2006; Vassilatis et al., 2003; Joost and Methner, 2002; Kakarala and Jamil, 2014) and displays an unusually short C-terminus (14 amino acids) and large non-homologous third intracellular loop (67 amino acids). Moreover, based on the sequence of its putative transmembrane binding pocket, GPR88 clusters with class C GPCRs, for which the endogenous ligands bind in the large N-terminus domain (Surgand et al., 2006). Intensive efforts in deorphanizing GPR88 have remained vain (Bi et al., 2015; Decker et al., 2017; Dzierba et al., 2015; Jin et al., 2014); meanwhile, synthetic chemistry met significant difficulties in identifying potent agonists for this atypical receptor (Bi et al., 2015; Jin et al., 2014; Jin et al., 2018). With only a handful of synthetic ligands available to target GPR88, its pharmacology remains poorly explored. Although this receptor was shown to display constitutive and ligand-induced activity on Gαi/o/z inhibitory protein coupling in heterologous and native cells (Meirsman et al., 2016a; Dzierba et al., 2015; Jin et al., 2018), its ability to recruit β-arrestins and intracellular trafficking have not been investigated yet.

The atypical pharmacology of GPR88 questions the role of an endogenous ligand in its function. Interestingly, it was proposed that orphan GPCRs may influence the signaling of other GPCRs in a ligand-independent manner through hetero-oligomerization, as shown for GPR50 (Levoye et al., 2006a; Levoye et al., 2006b). Remarkably, we have evidenced in a previous study (Meirsman et al., 2016a) an increase in [³⁵S]-GTPγS binding of striatal membranes from Gpr88^-/- mice in response to stimulation by agonists of the muscarinic and opioid delta (δOR) and mu (μOR) receptors. Moreover, we noticed that behavioral features of these mutants intriguingly oppose several aspects of the phenotype of mice lacking δOR (Oprd1^-/-) and that pharmacological blockade of δOR ameliorate behavioral deficits in Gpr88 knockout mice. Together, these data suggest that GPR88 represses the activity of opioid and muscarinic receptors under physiological conditions, with significant consequences on δOR-mediated behavioral responses.

In the present study, we first investigated in vitro whether GPR88 was able to come in close physical proximity to the three opioid receptors, and if its co-expression with these receptors had an influence in their ability to activate G protein and β-arrestin-dependent signaling pathways. Having revealed a significant impact of GPR88 expression on µOR signaling, we then assessed behavioral responses to the µOR agonist morphine in mice lacking the Gpr88 gene. Intriguingly, the consequences of Gpr88 deletion on morphine-induced responses were different if not opposed depending on the behavior tested. Considering that morphine-induced responses involve other GPCRs beyond µOR, we extended our in vitro studies to various GPCRs with striatum-enriched versus non-neuronal expression. We unraveled the ability of GPR88, when co-expressed with multiple other GPCRs, to bias their signaling by repressing G protein-dependent activation when closely interacting with them and β-arrestin recruitment independently from physical proximity.

In the present study, we evidence for the first time physical proximity between GPR88 and the three opioid receptors, and a negative impact of GPR88 expression on opioid-receptor mediated G protein and β-arrestin recruitment in vitro, µOR-dependent signaling appearing the most severely affected. In mice, Gpr88 deletion produced different effects on morphine-induced (µOR-dependent) responses depending on the behavior assessed, exacerbating morphine-induced locomotor sensitization, withdrawal syndrome and supra-spinal analgesia while blunting morphine effects on spinal nociceptive responses and leaving CPP unchanged. Importantly, we also detected close proximity between GPR88 and multiple other GPCRs with enriched striatal expression but not with GPCRs not expressed in CNS neurons. GPR88 co-expression was able to inhibit G protein dependent signaling of most GPCRs from which it comes close, and only these. In contrast, such co-expression resulted in blunted β-arrestin recruitment by all GPCRs tested.

The first finding from this study is that GPR88 closely interacts with opioid receptors and that its expression impedes opioid signaling in vitro. Saturated BRET signals of GPR88 in presence of δOR, κOR and µOR indicate physical proximity with opioid receptors and suggest potential hetero-oligomerization. Remarkably, although GPR88 displayed similar saturated BRET signals in presence of the three opioid receptors, the orphan receptor seemed to have a differential influence on their signaling. GPR88 co-expression had only a modest impact on κOR-mediated G protein pathway activation compared to δOR and µOR. Conversely, δOR appeared to be the less affected among opioid receptors on its ability to recruit β-arrestins, as seen from agonist-induced β-arr2 recruitment and receptor internalization. Finally, µOR function seemed to be the most severely altered by GPR88 co-expression, on both G protein and β-arrestin-dependent pathways.

In order to better characterize the effects of GPR88 expression on opioid signaling, we focused on GPR88-µOR functional interactions. We first confirmed the inhibitory effect of GPR88 expression on G-protein dependent signaling of µOR, by evidencing a suppression of G_i/o protein-dependent µOR-induced phosphorylation of ERK in presence of GPR88. We then evaluated how µOR expression levels impact the effects of GPR88 co-expression on G-protein dependent signaling and β-arrestin recruitment by µOR. We observed a weakening of the inhibitory action of GPR88 on µOR-mediated G-protein dependent signaling when µOR expression increased over GPR88 expression. Thus, direct µOR-GPR88 interactions seem necessary for GPR88 to exert its inhibitory effects; moreover, the regular pace of the rightwards shift of µOR signaling dose response when GPR88 amounts increase suggests a 1:1 (or n/n) stoichiometry in this interaction. In contrast, increasing µOR amounts failed to fully restore µOR-mediated β-arrestin recruitment in presence of GPR88, suggesting that a pool of β-arrestins remained out of reach of µOR, regardless µOR expression levels. Therefore, GPR88 effects on µOR-mediated G-protein dependent signaling and β-arrestin recruitment likely involved different mechanisms of interaction. Interestingly, differential relative inhibitory effects of GPR88 on the signaling of the different opioid receptors (and other GPCR partners) possibly reflected differential sensitivity to variations in the expression of the partner receptor, G-protein signaling being more sensitive than β-arrestin recruitment to such variations. Finally, we tested whether agonist-induced activation of GPR88 influences its effects on µOR signaling in vitro. Activation of GPR88 by Compound 19 tended to exacerbate the inhibitory action of GPR88 on µOR-mediated G-protein dependent signaling, but had no detectable effect on β-arrestin recruitment by µOR. These results suggest that GPR88 is more efficient in blunting GPCR partner’s G-protein dependent signaling, but not β-arrestin recruitment, if in an active-like conformation.

The physiological consequences of GPR88 expression on opioid signaling are not straightforward to predict from in vitro experiments, as inhibition of G protein signaling argues for a reduction of (δOR and µOR) opioid signaling, whereas dampened β-arrestin recruitment suggests a retention of opioid receptors at the cell surface and maintained signaling but loss of β-arrestin-mediated functional effects. We took advantage of analyzing the phenotype of Gpr88 null mice to get insight into interactions between GPR88 and opioid signaling in vivo. Our previous findings of increased δOR-mediated G protein signaling in striatal membranes of Gpr88^-/- mice together with a phenotypic profile opposing that of mice lacking δOR (Le Merrer et al., 2013) and partially normalized by δOR antagonist administration (Meirsman et al., 2016a) plead for an excessive δOR activity in these animals, consistent with a main inhibitory impact of GPR88 on the G protein dependent signaling of this receptor. In the present study, we evaluated the in vivo consequences of Gpr88 deletion on µOR signaling by challenging knockout animals with morphine across several experimental paradigms. Morphine-induced responses in Gpr88^-/- knockouts were differentially modified depending on the behavior assessed, likely due to differences in the brain regions, signaling pathways and GPCR populations engaged to mediate these responses. The prominent factor influencing the effects of Gpr88 deletion, however, was likely the brain substrates underlying behavioral responses, and whether GPR88 is expressed in these structures under physiological conditions. Indeed, Gpr88 deletion exacerbated morphine-induced responses that involved µOR activation in brain regions where Gpr88 expression is usually enriched (Massart et al., 2016; Ehrlich et al., 2018a; Becker et al., 2008), namely locomotor activity and sensitization, depending on µOR signaling in the striatum (Tao et al., 2017; Charbogne et al., 2017), withdrawal symptoms involving µOR activity in the nucleus accumbens (Williams et al., 2001; Le Merrer et al., 2009) and supra-spinal analgesia measured in the hot-plate test, modulated notably by µOR activity in the central amygdala (Pavlovic et al., 1996; Pavlovic and Bodnar, 1998). In contrast, morphine-induced CPP and reinstatement were not modified in Gpr88^-/- mice. Interestingly, morphine-induced CPP involves primarily µOR signaling in the ventral tegmental area (Charbogne et al., 2017; Le Merrer et al., 2009) where GPR88 is scarcely expressed (Ehrlich et al., 2018a; Ehrlich et al., 2018b). This could account for unchanged morphine CPP in the absence of Gpr88 expression. Of note, Gpr88 null animals extinguished CPP faster than controls, in agreement with previously evidenced facilitation of hippocampus-dependent learning processes (Meirsman et al., 2016a). A second factor that plausibly influenced morphine-induced responses in Gpr88^-/- mice was the signaling pathway involved in µOR-mediated effects. Indeed, locomotor sensitization, markedly exacerbated in knockout mice, was evidenced to depend tightly on β-arrestin recruitment not only by µOR, but also by the D1 dopamine receptor (Tao et al., 2017; Urs et al., 2011; Borgkvist et al., 2008; Becker et al., 2001). As regards these behavioral responses, the phenotypic profile of Gpr88 mutant animals is thus consistent with a relief of GPR88 break on β-arrestin recruitment by µOR, and D1. Now focusing on nociception, morphine-induced analgesia was significantly reduced in the tail immersion test, which tackles spinal function (Ramabadran et al., 1989). Gpr88 expression in spinal cord is discrete (Massart et al., 2016; Becker et al., 2008). Its deletion, however, may have allowed massive µOR-mediated β-arrestin recruitment under morphine stimulation, which was shown to be detrimental to spinal morphine analgesia (Yang et al., 2011). Finally, behavioral responses to morphine in Gpr88^-/- mice may not be the consequence of GPR88 removal on µOR function only but also on the signaling of other GPCRs involved in the expression of these responses. Notably, morphine-induced locomotor sensitization involves striatal dopamine and cholinergic receptors (Tao et al., 2017; Valjent et al., 2005; Ruan et al., 2019), and the effects of GPR88 deletion on their pharmacology likely contributed to the exacerbation of this phenomenon in mutant animals. The involvement of multiple GPCR players in morphine-induced responses may have participated to our failure in detecting the expected increase in pERK/tERK ratio in Gpr88 knockout mice sensitized to morphine; modified kinetics of ERK phosphorylation in vivo versus in vitro, however, represents a more likely explanation for this failure. In conclusion, altered behavioral responses to morphine challenge in Gpr88 null mice are consistent with an inhibitory influence of GPR88 co-expression on µOR signaling, especially for behaviors engaging striatal regions, thus demonstrating the predictive value of in vitro experiments.

Further confirming such predictive value, in vivo administration of Compound 19 markedly inhibited morphine-induced stimulation of locomotor activity in wild-type mice, resulting in opposed effects compared to Gpr88 deletion on this parameter. GPR88 activation, however, had no influence on the amplitude of locomotor sensitization measured upon repeated morphine administration. Interestingly, while acute stimulant effects of morphine were shown to involve both G protein activation and β-arrestin recruitment by µOR (and D1 receptors), sensitization, as mentioned above, relies essentially on the latter (Tao et al., 2017; Urs et al., 2011; Girault et al., 2007). In light of Compound 19’s effects on morphine-induced locomotor responses, it thus seems that pharmacological activation of GPR88 in vivo can potentiate the inhibitory effects of GPR88 on µOR-dependent G protein activation, but not β-arrestin recruitment, in agreement with in vitro results (Figure 2—figure supplement 2). Whether this applies to other GPCR partners of GPR88, however, would deserve further investigation. Of note, these results further argue for the inhibitory effects of GPR88 on the G-protein dependent signaling of a partner GPCR requiring GPR88 to be in an active-like conformation, as previously described for many interacting GPCRs (Vilardaga et al., 2008; Goudet et al., 2005; Pin et al., 2019).

A second major finding from this study is that GPR88 can bias the signaling of multiple GPCRs beyond opioid receptors. In vitro, we detected physical proximity between GPR88 and muscarinic M1 and M4, dopamine D2, adenosine A_2A and GPR12 receptors, suggesting that GPR88 can form hetero-oligomers with them. Such close interactions are plausible in vivo as all these partner receptors share a common enriched expression in the striatum and extended amygdala, notably in medium spiny GABAergic neurons (Ferré et al., 2007; Surmeier et al., 2007; Pellissier et al., 2018; Ignatov et al., 2003), where GPR88 is also expressed. In contrast, we could not evidence proximity between GPR88 and dopamine D1 receptor, another GPCR with enriched striatal expression, and two GPCRs not known to be expressed in CNS neurons, the vasopressin V2R and chemokine CXCR4 receptors. Interestingly, these last results suggest that GPR88 forms close associations with other GPCRs in a selective manner. Further studies will aim at determining the molecular interface involved in interactions between GPR88 and other GPCRs.

At functional level, GPR88 dampened agonist-induced G protein pathway activation of most receptors to which it comes close, with the exception of adenosine A_2A receptors. These in vitro effects are consistent with our previous observation of facilitated δOR, µOR and muscarinic receptor agonist-induced [³⁵S]-GTPγS binding in striatal membranes from Gpr88^-/- mice (Meirsman et al., 2016a). Regarding G protein dependent pathway, therefore, close proximity appears necessary, although not sufficient, to predict an inhibitory effect of GPR88. This result suggests that GPR88 exerts its influence on G protein recruitment through hetero-oligomerization, either by triggering conformational changes of the target partner less favorable to G protein coupling, as proposed for the angiotensin II AT₂ receptor (AbdAlla et al., 2001), or by steric hindrance of this coupling, as shown for the orphan receptor GPR50 (Levoye et al., 2006a). Interestingly, GPR88 displays an atypically long third intracellular loop, which may impede G protein recruitment at partner GPCRs. Focusing now on β-arrestins, our in vitro work evidenced the ability of GPR88 to hinder their recruitment by all the GPCRs that we examined in the present study, independently from its physical proximity to these target receptors. Interestingly, previous reports have evidenced the ability of two GPCRs, the vasopressin V2R and neurokinin NK1 receptors, upon activation by a selective agonist, to sequester β-arrestins in endosomes and dampen their recruitment by a partner GPCR (Klein et al., 2001; Schmidlin et al., 2002). GPR88 fulfills two conditions required to exert a similar effect on β-arrestin trafficking, under basal conditions: it demonstrates high affinity for β-arrestins (Figure 6D) and displays, besides localization at cell membrane, a substantial, patchy, intracellular expression (Massart et al., 2016), suggesting its presence in vesicular compartments, where it colocalizes with β-arrestins (Figure 6E). Interestingly, the failure of high levels of µOR expression to rescue µOR-mediated β-arrestin recruitment in presence of GPR88 is also consistent with GPR88 maintaining an intracellular pool of β-arrestins out of reach of its partner GPCRs (Figure 2D). Thus, a likely mechanism by which GPR88 inhibits the recruitment of β-arrestins at other GPCRs is by sequestering the formers in intracellular compartments, and this effect appears to affect GPCRs in a non-selective manner, as we could not find a co-expressed receptor for which it was not observed. Of note, CXCR4, which shares with GPR88 a high basal affinity for β-arrestins (Figure 6D) but shows a higher ratio of membrane versus intracellular expression (Watts et al., 2013), was not able to interfere with agonist-induced β-arrestin recruitment at µOR (Figure 6A), further highlighting the peculiarity of GPR88 action.

Experimental evidence supports the physiological relevance of previous in vitro findings. Indeed, mice lacking GPR88 were shown to display a diminished locomotor response to the stimulant effects of the dopamine D1 agonist SKF81297 (Quintana et al., 2012), matching with the increase in G protein dependent activation of D1 receptors that we detected in presence of GPR88. Reduced D1 receptor activation in the striatum of Gpr88^-/- animals may have contributed to decreased alcohol reward in a CPP paradigm (Ben Hamida et al., 2018; Cole et al., 2018), not observed for morphine CPP as it was possibly compensated by facilitated µOR signaling, and reduced foraging efficiency in these animals (Rainwater et al., 2017). Of note and as mentioned above, increased β-arrestin recruitment at D1 receptor likely played a crucial role in the facilitation of morphine-induced locomotor sensitization that we observed in Gpr88 null mice. Moreover, in these animals, the effects of D2 receptor activation on striatum-dependent locomotion, stereotypic behavior and catalepsy were shown to be exacerbated (Quintana et al., 2012; Logue et al., 2009), consistent with decreased signaling when GPR88 is co-expressed with the D2 receptor in vitro. Thus in vitro evidence that GPR88 interferes with dopamine receptor activity accurately predict pharmacologically-induced behavioral responses in vivo. More interestingly, these data further argue for a critical role of GPR88 in modulating the physiology of dopaminoceptive neuronal populations, primarily in the striatum and amygdala (Meirsman et al., 2016a; Ben Hamida et al., 2018; Quintana et al., 2012), where it would dampen GPCR activity. As a corollary of this, induction of Gpr88 expression may represent an adaptive modulatory mechanism in these populations, in accordance with the propensity of psychoactive drugs targeting dopaminoceptive substrates to stimulate Gpr88 transcription (Conti et al., 2007; Ogden et al., 2004; Brandish et al., 2005; Le Merrer et al., 2012; Becker et al., 2017). GPR88 could thus play a protective buffering role whenever striatal GPCRs are excessively activated, a role that may be lost or compromised in neuropsychiatric conditions (Alkufri et al., 2016; Del Zompo et al., 2014; Ben Hamida et al., 2018).

In conclusion, the orphan receptor GPR88 dampens the signaling of multiple GPCRs, the consequences of such inhibition depending on their location in the CNS and the signaling pathways involved. This study further highlights the interest of GPR88 as a promising target to treat various CNS disorders, together with the complexity of its pharmacology. Future investigations might consider developing, besides ligands modulating GPR88 activity, novel compounds able to interfere with its ability to closely interact with other GPCRs, or to sequester β-arrestins, in order to influence opioid function and/or striatal physiology.

All data generated or analysed during this study are included in the manuscript and supporting files.

1. 1. AbdAlla S
   2. Lother H
   3. Abdel-tawab AM
   4. Quitterer U

   (2001) The angiotensin II AT2 receptor is an AT1 receptor antagonist

   The Journal of Biological Chemistry 276:39721–39726.

   https://doi.org/10.1074/jbc.M105253200

   • PubMed
   • Google Scholar
2. 1. Alkufri F
   2. Shaag A
   3. Abu-Libdeh B
   4. Elpeleg O

   (2016) Deleterious mutation in GPR88 is associated with chorea, speech delay, and learning disabilities

   Neurology Genetics 2:e64.

   https://doi.org/10.1212/NXG.0000000000000064

   • PubMed
   • Google Scholar
3. 1. Arefin TM
   2. Mechling AE
   3. Meirsman AC
   4. Bienert T
   5. Hübner NS
   6. Lee HL
   7. Ben Hamida S
   8. Ehrlich A
   9. Roquet D
   10. Hennig J
   11. von Elverfeldt D
   12. Kieffer BL
   13. Harsan LA

   (2017) Remodeling of sensorimotor brain connectivity in Gpr88-Deficient mice

   Brain Connectivity 7:526–540.

   https://doi.org/10.1089/brain.2017.0486

   • PubMed
   • Google Scholar
4. 1. Ayoub MA
   2. See HB
   3. Seeber RM
   4. Armstrong SP
   5. Pfleger KD

   (2013) Profiling epidermal growth factor receptor and heregulin receptor 3 heteromerization using receptor tyrosine kinase heteromer investigation technology

   PLOS ONE 8:e64672.

   https://doi.org/10.1371/journal.pone.0064672

   • PubMed
   • Google Scholar
5. 1. Becker A
   2. Grecksch G
   3. Kraus J
   4. Peters B
   5. Schroeder H
   6. Schulz S
   7. Höllt V

   (2001) Loss of locomotor sensitisation in response to morphine in D1 receptor deficient mice

   Naunyn-Schmiedeberg's Archives of Pharmacology 363:562–568.

   https://doi.org/10.1007/s002100100404

   • PubMed
   • Google Scholar
6. 1. Becker JA
   2. Befort K
   3. Blad C
   4. Filliol D
   5. Ghate A
   6. Dembele D
   7. Thibault C
   8. Koch M
   9. Muller J
   10. Lardenois A
   11. Poch O
   12. Kieffer BL

   (2008) Transcriptome analysis identifies genes with enriched expression in the mouse central extended amygdala

   Neuroscience 156:950–965.

   https://doi.org/10.1016/j.neuroscience.2008.07.070

   • PubMed
   • Google Scholar
7. 1. Becker JAJ
   2. Kieffer BL
   3. Le Merrer J

   (2017) Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol

   Addiction Biology 22:1205–1217.

   https://doi.org/10.1111/adb.12405

   • PubMed
   • Google Scholar
8. 1. Ben Hamida S
   2. Mendonça-Netto S
   3. Arefin TM
   4. Nasseef MT
   5. Boulos L-J
   6. McNicholas M
   7. Ehrlich AT
   8. Clarke E
   9. Moquin L
   10. Gratton A
   11. Darcq E
   12. Harsan LA
   13. Maldonado R
   14. Kieffer BL

   (2018) Increased Alcohol Seeking in Mice Lacking Gpr88 Involves Dysfunctional Mesocorticolimbic Networks

   Biological Psychiatry 84:202–212.

   https://doi.org/10.1016/j.biopsych.2018.01.026

   • Google Scholar
9. 1. Berrendero F
   2. Kieffer BL
   3. Maldonado R

   (2002) Attenuation of nicotine-induced antinociception, rewarding effects, and dependence in mu-opioid receptor knock-out mice

   The Journal of Neuroscience 22:10935–10940.

   https://doi.org/10.1523/JNEUROSCI.22-24-10935.2002

   • PubMed
   • Google Scholar
10. 1. Bi Y
    2. Dzierba CD
    3. Fink C
    4. Garcia Y
    5. Green M
    6. Han J
    7. Kwon S
    8. Kumi G
    9. Liang Z
    10. Liu Y
    11. Qiao Y
    12. Zhang Y
    13. Zipp G
    14. Burford N
    15. Ferrante M
    16. Bertekap R
    17. Lewis M
    18. Cacace A
    19. Westphal RS
    20. Kimball D
    21. Bronson JJ
    22. Macor JE

    (2015) The discovery of potent agonists for GPR88, an orphan GPCR, for the potential treatment of CNS disorders

    Bioorganic & Medicinal Chemistry Letters 25:1443–1447.

    https://doi.org/10.1016/j.bmcl.2015.02.038

    • Google Scholar
11. 1. Borgkvist A
    2. Valjent E
    3. Santini E
    4. Hervé D
    5. Girault JA
    6. Fisone G

    (2008) Delayed, context- and dopamine D1 receptor-dependent activation of ERK in morphine-sensitized mice

    Neuropharmacology 55:230–237.

    https://doi.org/10.1016/j.neuropharm.2008.05.028

    • PubMed
    • Google Scholar
12. 1. Borroto-Escuela DO
    2. Flajolet M
    3. Agnati LF
    4. Greengard P
    5. Fuxe K

    (2013) Bioluminescence resonance energy transfer methods to study G protein-coupled receptor-receptor tyrosine kinase heteroreceptor complexes

    Methods in Cell Biology 117:141–164.

    https://doi.org/10.1016/B978-0-12-408143-7.00008-6

    • PubMed
    • Google Scholar
13. 1. Brandish PE
    2. Su M
    3. Holder DJ
    4. Hodor P
    5. Szumiloski J
    6. Kleinhanz RR
    7. Forbes JE
    8. McWhorter ME
    9. Duenwald SJ
    10. Parrish ML
    11. Na S
    12. Liu Y
    13. Phillips RL
    14. Renger JJ
    15. Sankaranarayanan S
    16. Simon AJ
    17. Scolnick EM

    (2005) Regulation of gene expression by lithium and depletion of inositol in slices of adult rat cortex

    Neuron 45:861–872.

    https://doi.org/10.1016/j.neuron.2005.02.006

    • PubMed
    • Google Scholar
14. 1. Charbogne P
    2. Gardon O
    3. Martín-García E
    4. Keyworth HL
    5. Matsui A
    6. Mechling AE
    7. Bienert T
    8. Nasseef MT
    9. Robé A
    10. Moquin L
    11. Darcq E
    12. Ben Hamida S
    13. Robledo P
    14. Matifas A
    15. Befort K
    16. Gavériaux-Ruff C
    17. Harsan LA
    18. von Elverfeldt D
    19. Hennig J
    20. Gratton A
    21. Kitchen I
    22. Bailey A
    23. Alvarez VA
    24. Maldonado R
    25. Kieffer BL

    (2017) Mu opioid receptors in Gamma-Aminobutyric acidergic forebrain neurons moderate motivation for heroin and palatable food

    Biological Psychiatry 81:778–788.

    https://doi.org/10.1016/j.biopsych.2016.12.022

    • PubMed
    • Google Scholar
15. 1. Cole SL
    2. Robinson MJF
    3. Berridge KC

    (2018) Optogenetic self-stimulation in the nucleus accumbens: d1 reward versus D2 ambivalence

    PLOS ONE 13:e0207694.

    https://doi.org/10.1371/journal.pone.0207694

    • PubMed
    • Google Scholar
16. 1. Conti B
    2. Maier R
    3. Barr AM
    4. Morale MC
    5. Lu X
    6. Sanna PP
    7. Bilbe G
    8. Hoyer D
    9. Bartfai T

    (2007) Region-specific transcriptional changes following the three antidepressant treatments electro convulsive therapy, sleep deprivation and fluoxetine

    Molecular Psychiatry 12:167–189.

    https://doi.org/10.1038/sj.mp.4001897

    • PubMed
    • Google Scholar
17. 1. Decker AM
    2. Gay EA
    3. Mathews KM
    4. Rosa TC
    5. Langston TL
    6. Maitra R
    7. Jin C

    (2017) Development and validation of a high-throughput calcium mobilization assay for the orphan receptor GPR88

    Journal of Biomedical Science 24:23.

    https://doi.org/10.1186/s12929-017-0330-3

    • PubMed
    • Google Scholar
18. 1. Del Zompo M
    2. Deleuze JF
    3. Chillotti C
    4. Cousin E
    5. Niehaus D
    6. Ebstein RP
    7. Ardau R
    8. Macé S
    9. Warnich L
    10. Mujahed M
    11. Severino G
    12. Dib C
    13. Jordaan E
    14. Murad I
    15. Soubigou S
    16. Koen L
    17. Bannoura I
    18. Rocher C
    19. Laurent C
    20. Derock M
    21. Faucon Biguet N
    22. Mallet J
    23. Meloni R

    (2014) Association study in three different populations between the GPR88 gene and major psychoses

    Molecular Genetics & Genomic Medicine 2:152–159.

    https://doi.org/10.1002/mgg3.54

    • PubMed
    • Google Scholar
19. 1. Dzierba CD
    2. Bi Y
    3. Dasgupta B
    4. Hartz RA
    5. Ahuja V
    6. Cianchetta G
    7. Kumi G
    8. Dong L
    9. Aleem S
    10. Fink C
    11. Garcia Y
    12. Green M
    13. Han J
    14. Kwon S
    15. Qiao Y
    16. Wang J
    17. Zhang Y
    18. Liu Y
    19. Zipp G
    20. Liang Z
    21. Burford N
    22. Ferrante M
    23. Bertekap R
    24. Lewis M
    25. Cacace A
    26. Grace J
    27. Wilson A
    28. Nouraldeen A
    29. Westphal R
    30. Kimball D
    31. Carson K
    32. Bronson JJ
    33. Macor JE

    (2015) Design, synthesis, and evaluation of phenylglycinols and phenyl amines as agonists of GPR88

    Bioorganic & Medicinal Chemistry Letters 25:1448–1452.

    https://doi.org/10.1016/j.bmcl.2015.01.036

    • PubMed
    • Google Scholar
20. 1. Ehrlich AT
    2. Semache M
    3. Bailly J
    4. Wojcik S
    5. Arefin TM
    6. Colley C
    7. Le Gouill C
    8. Gross F
    9. Lukasheva V
    10. Hogue M
    11. Darcq E
    12. Harsan LA
    13. Bouvier M
    14. Kieffer BL

    (2018a) Mapping GPR88-Venus illuminates a novel role for GPR88 in sensory processing

    Brain Structure & Function 223:1275–1296.

    https://doi.org/10.1007/s00429-017-1547-3

    • PubMed
    • Google Scholar
21. 1. Ehrlich AT
    2. Maroteaux G
    3. Robe A
    4. Venteo L
    5. Nasseef MT
    6. van Kempen LC
    7. Mechawar N
    8. Turecki G
    9. Darcq E
    10. Kieffer BL

    (2018b) Expression map of 78 brain-expressed mouse orphan GPCRs provides a translational resource for neuropsychiatric research

    Communications Biology 1:102.

    https://doi.org/10.1038/s42003-018-0106-7

    • PubMed
    • Google Scholar
22. 1. Ferré S
    2. Agnati LF
    3. Ciruela F
    4. Lluis C
    5. Woods AS
    6. Fuxe K
    7. Franco R

    (2007) Neurotransmitter receptor heteromers and their integrative role in 'local modules': the striatal spine module

    Brain Research Reviews 55:55–67.

    https://doi.org/10.1016/j.brainresrev.2007.01.007

    • PubMed
    • Google Scholar
23. 1. Fujita W
    2. Gomes I
    3. Devi LA

    (2014) Revolution in GPCR signalling: opioid receptor heteromers as novel therapeutic targets: iuphar review 10

    British Journal of Pharmacology 171:4155–4176.

    https://doi.org/10.1111/bph.12798

    • PubMed
    • Google Scholar
24. 1. Ghate A
    2. Befort K
    3. Becker JA
    4. Filliol D
    5. Bole-Feysot C
    6. Demebele D
    7. Jost B
    8. Koch M
    9. Kieffer BL

    (2007) Identification of novel striatal genes by expression profiling in adult mouse brain

    Neuroscience 146:1182–1192.

    https://doi.org/10.1016/j.neuroscience.2007.02.040

    • PubMed
    • Google Scholar
25. 1. Girault JA
    2. Valjent E
    3. Caboche J
    4. Hervé D

    (2007) ERK2: a logical AND gate critical for drug-induced plasticity?

    Current Opinion in Pharmacology 7:77–85.

    https://doi.org/10.1016/j.coph.2006.08.012

    • PubMed
    • Google Scholar
26. 1. Goudet C
    2. Kniazeff J
    3. Hlavackova V
    4. Malhaire F
    5. Maurel D
    6. Acher F
    7. Blahos J
    8. Prézeau L
    9. Pin JP

    (2005) Asymmetric functioning of dimeric metabotropic glutamate receptors disclosed by positive allosteric modulators

    Journal of Biological Chemistry 280:24380–24385.

    https://doi.org/10.1074/jbc.M502642200

    • PubMed
    • Google Scholar
27. 1. Haley TJ
    2. McCORMICK WG

    (1957) Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse

    British Journal of Pharmacology and Chemotherapy 12:12–15.

    https://doi.org/10.1111/j.1476-5381.1957.tb01354.x

    • PubMed
    • Google Scholar
28. 1. Heiman M
    2. Schaefer A
    3. Gong S
    4. Peterson JD
    5. Day M
    6. Ramsey KE
    7. Suárez-Fariñas M
    8. Schwarz C
    9. Stephan DA
    10. Surmeier DJ
    11. Greengard P
    12. Heintz N

    (2008) A translational profiling approach for the molecular characterization of CNS cell types

    Cell 135:738–748.

    https://doi.org/10.1016/j.cell.2008.10.028

    • PubMed
    • Google Scholar
29. 1. Ho H
    2. Both M
    3. Siniard A
    4. Sharma S
    5. Notwell JH
    6. Wallace M
    7. Leone DP
    8. Nguyen A
    9. Zhao E
    10. Lee H
    11. Zwilling D
    12. Thompson KR
    13. Braithwaite SP
    14. Huentelman M
    15. Portmann T

    (2018) A guide to Single-Cell transcriptomics in adult rodent brain: the medium spiny neuron transcriptome revisited

    Frontiers in Cellular Neuroscience 12:159.

    https://doi.org/10.3389/fncel.2018.00159

    • PubMed
    • Google Scholar
30. 1. Ignatov A
    2. Lintzel J
    3. Hermans-Borgmeyer I
    4. Kreienkamp HJ
    5. Joost P
    6. Thomsen S
    7. Methner A
    8. Schaller HC

    (2003) Role of the G-protein-coupled receptor GPR12 as high-affinity receptor for sphingosylphosphorylcholine and its expression and function in brain development

    The Journal of Neuroscience 23:907–914.

    https://doi.org/10.1523/JNEUROSCI.23-03-00907.2003

    • PubMed
    • Google Scholar
31. 1. Jin C
    2. Decker AM
    3. Huang XP
    4. Gilmour BP
    5. Blough BE
    6. Roth BL
    7. Hu Y
    8. Gill JB
    9. Zhang XP

    (2014) Synthesis, pharmacological characterization, and structure-activity relationship studies of small molecular agonists for the orphan GPR88 receptor

    ACS Chemical Neuroscience 5:576–587.

    https://doi.org/10.1021/cn500082p

    • PubMed
    • Google Scholar
32. 1. Jin C
    2. Decker AM
    3. Makhijani VH
    4. Besheer J
    5. Darcq E
    6. Kieffer BL
    7. Maitra R

    (2018) Discovery of a potent, selective, and Brain-Penetrant small molecule that activates the orphan receptor GPR88 and reduces alcohol intake

    Journal of Medicinal Chemistry 61:6748–6758.

    https://doi.org/10.1021/acs.jmedchem.8b00566

    • PubMed
    • Google Scholar
33. 1. Joost P
    2. Methner A

    (2002) Phylogenetic analysis of 277 human G-protein-coupled receptors as a tool for the prediction of orphan receptor ligands

    Genome Biology 3:research0063.1.

    https://doi.org/10.1186/gb-2002-3-11-research0063

    • Google Scholar
34. 1. Kakarala KK
    2. Jamil K

    (2014) Sequence-structure based phylogeny of GPCR Class A Rhodopsin receptors

    Molecular Phylogenetics and Evolution 74:66–96.

    https://doi.org/10.1016/j.ympev.2014.01.022

    • Google Scholar
35. 1. Klein U
    2. Müller C
    3. Chu P
    4. Birnbaumer M
    5. von Zastrow M

    (2001) Heterologous inhibition of G protein-coupled receptor endocytosis mediated by receptor-specific trafficking of beta-arrestins

    Journal of Biological Chemistry 276:17442–17447.

    https://doi.org/10.1074/jbc.M009214200

    • PubMed
    • Google Scholar
36. 1. Le Merrer J
    2. Becker JA
    3. Befort K
    4. Kieffer BL

    (2009) Reward processing by the opioid system in the brain

    Physiological Reviews 89:1379–1412.

    https://doi.org/10.1152/physrev.00005.2009

    • PubMed
    • Google Scholar
37. 1. Le Merrer J
    2. Befort K
    3. Gardon O
    4. Filliol D
    5. Darcq E
    6. Dembele D
    7. Becker JA
    8. Kieffer BL

    (2012) Protracted abstinence from distinct drugs of abuse shows regulation of a common gene network

    Addiction Biology 17:1–12.

    https://doi.org/10.1111/j.1369-1600.2011.00365.x

    • PubMed
    • Google Scholar
38. 1. Le Merrer J
    2. Rezai X
    3. Scherrer G
    4. Becker JA
    5. Kieffer BL

    (2013) Impaired hippocampus-dependent and facilitated striatum-dependent behaviors in mice lacking the δ opioid receptor

    Neuropsychopharmacology 38:1050–1059.

    https://doi.org/10.1038/npp.2013.1

    • PubMed
    • Google Scholar
39. 1. Levoye A
    2. Dam J
    3. Ayoub MA
    4. Guillaume J-L
    5. Couturier C
    6. Delagrange P
    7. Jockers R

    (2006a) The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization

    The EMBO Journal 25:3012–3023.

    https://doi.org/10.1038/sj.emboj.7601193

    • Google Scholar
40. 1. Levoye A
    2. Dam J
    3. Ayoub MA
    4. Guillaume JL
    5. Jockers R

    (2006b) Do orphan G-protein-coupled receptors have ligand-independent functions? New insights from receptor heterodimers

    EMBO Reports 7:1094–1098.

    https://doi.org/10.1038/sj.embor.7400838

    • PubMed
    • Google Scholar
41. 1. Logue SF
    2. Grauer SM
    3. Paulsen J
    4. Graf R
    5. Taylor N
    6. Sung MA
    7. Zhang L
    8. Hughes Z
    9. Pulito VL
    10. Liu F
    11. Rosenzweig-Lipson S
    12. Brandon NJ
    13. Marquis KL
    14. Bates B
    15. Pausch M

    (2009) The orphan GPCR, GPR88, modulates function of the striatal dopamine system: a possible therapeutic target for psychiatric disorders?

    Molecular and Cellular Neuroscience 42:438–447.

    https://doi.org/10.1016/j.mcn.2009.09.007

    • PubMed
    • Google Scholar
42. 1. Massart R
    2. Guilloux JP
    3. Mignon V
    4. Sokoloff P
    5. Diaz J

    (2009) Striatal GPR88 expression is confined to the whole projection neuron population and is regulated by dopaminergic and glutamatergic afferents

    European Journal of Neuroscience 30:397–414.

    https://doi.org/10.1111/j.1460-9568.2009.06842.x

    • PubMed
    • Google Scholar
43. 1. Massart R
    2. Mignon V
    3. Stanic J
    4. Munoz-Tello P
    5. Becker JA
    6. Kieffer BL
    7. Darmon M
    8. Sokoloff P
    9. Diaz J

    (2016) Developmental and adult expression patterns of the G-protein-coupled receptor GPR88 in the rat: establishment of a dual nuclear-cytoplasmic localization

    Journal of Comparative Neurology 524:2776–2802.

    https://doi.org/10.1002/cne.23991

    • PubMed
    • Google Scholar
44. 1. Matthes HW
    2. Maldonado R
    3. Simonin F
    4. Valverde O
    5. Slowe S
    6. Kitchen I
    7. Befort K
    8. Dierich A
    9. Le Meur M
    10. Dollé P
    11. Tzavara E
    12. Hanoune J
    13. Roques BP
    14. Kieffer BL

    (1996) Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene

    Nature 383:819–823.

    https://doi.org/10.1038/383819a0

    • PubMed
    • Google Scholar
45. 1. Meirsman AC
    2. Le Merrer J
    3. Pellissier LP
    4. Diaz J
    5. Clesse D
    6. Kieffer BL
    7. Becker JA

    (2016a) Mice lacking GPR88 show motor deficit, improved spatial learning, and low anxiety reversed by Delta opioid antagonist

    Biological Psychiatry 79:917–927.

    https://doi.org/10.1016/j.biopsych.2015.05.020

    • PubMed
    • Google Scholar
46. 1. Meirsman AC
    2. Robé A
    3. de Kerchove d'Exaerde A
    4. Kieffer BL

    (2016b) GPR88 in A2AR neurons enhances Anxiety-Like behaviors

    eNeuro 3:ENEURO.0202-16.2016.

    https://doi.org/10.1523/ENEURO.0202-16.2016

    • PubMed
    • Google Scholar
47. 1. Ogden CA
    2. Rich ME
    3. Schork NJ
    4. Paulus MP
    5. Geyer MA
    6. Lohr JB
    7. Kuczenski R
    8. Niculescu AB

    (2004) Candidate genes, pathways and mechanisms for bipolar (manic-depressive) and related disorders: an expanded convergent functional genomics approach

    Molecular Psychiatry 9:1007–1029.

    https://doi.org/10.1038/sj.mp.4001547

    • PubMed
    • Google Scholar
48. 1. Pavlovic ZW
    2. Cooper ML
    3. Bodnar RJ

    (1996) Opioid antagonists in the periaqueductal gray inhibit morphine and beta-endorphin analgesia elicited from the amygdala of rats

    Brain Research 741:13–26.

    https://doi.org/10.1016/S0006-8993(96)00880-3

    • PubMed
    • Google Scholar
49. 1. Pavlovic ZW
    2. Bodnar RJ

    (1998) Opioid supraspinal analgesic synergy between the amygdala and periaqueductal gray in rats

    Brain Research 779:158–169.

    https://doi.org/10.1016/S0006-8993(97)01115-3

    • PubMed
    • Google Scholar
50. 1. Pellissier LP
    2. Pujol CN
    3. Becker JAJ
    4. Le Merrer J

    (2018) Delta opioid receptors: learning and motivation

    Handbook of Experimental Pharmacology 247:227–260.

    https://doi.org/10.1007/164_2016_89

    • PubMed
    • Google Scholar
51. 1. Pin JP
    2. Kniazeff J
    3. Prézeau L
    4. Liu JF
    5. Rondard P

    (2019) GPCR interaction as a possible way for allosteric control between receptors

    Molecular and Cellular Endocrinology 486:89–95.

    https://doi.org/10.1016/j.mce.2019.02.019

    • PubMed
    • Google Scholar
52. 1. Quintana A
    2. Sanz E
    3. Wang W
    4. Storey GP
    5. Güler AD
    6. Wanat MJ
    7. Roller BA
    8. La Torre A
    9. Amieux PS
    10. McKnight GS
    11. Bamford NS
    12. Palmiter RD

    (2012) Lack of GPR88 enhances medium spiny neuron activity and alters motor- and cue-dependent behaviors

    Nature Neuroscience 15:1547–1555.

    https://doi.org/10.1038/nn.3239

    • PubMed
    • Google Scholar
53. 1. Rainwater A
    2. Sanz E
    3. Palmiter RD
    4. Quintana A

    (2017) Striatal GPR88 modulates foraging efficiency

    The Journal of Neuroscience 37:7939–7947.

    https://doi.org/10.1523/JNEUROSCI.2439-16.2017

    • PubMed
    • Google Scholar
54. 1. Ramabadran K
    2. Bansinath M
    3. Turndorf H
    4. Puig MM

    (1989) Tail immersion test for the evaluation of a nociceptive reaction in mice methodological considerations

    Journal of Pharmacological Methods 21:21–31.

    https://doi.org/10.1016/0160-5402(89)90019-3

    • PubMed
    • Google Scholar
55. 1. Ruan H
    2. Sun J
    3. Liu X
    4. Liu L
    5. Cui R
    6. Li X

    (2019) Cholinergic M₄ receptors are involved in morphine-induced expression of behavioral sensitization by regulating dopamine function in the nucleus accumbens of rats

    Behavioural Brain Research 360:128–133.

    https://doi.org/10.1016/j.bbr.2018.12.009

    • PubMed
    • Google Scholar
56. 1. Schmidlin F
    2. Déry O
    3. Bunnett NW
    4. Grady EF

    (2002) Heterologous regulation of trafficking and signaling of G protein-coupled receptors: beta-arrestin-dependent interactions between neurokinin receptors

    PNAS 99:3324–3329.

    https://doi.org/10.1073/pnas.052161299

    • PubMed
    • Google Scholar
57. 1. Surgand JS
    2. Rodrigo J
    3. Kellenberger E
    4. Rognan D

    (2006) A chemogenomic analysis of the transmembrane binding cavity of human G-protein-coupled receptors

    Proteins: Structure, Function, and Bioinformatics 62:509–538.

    https://doi.org/10.1002/prot.20768

    • PubMed
    • Google Scholar
58. 1. Surmeier DJ
    2. Ding J
    3. Day M
    4. Wang Z
    5. Shen W

    (2007) D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons

    Trends in Neurosciences 30:228–235.

    https://doi.org/10.1016/j.tins.2007.03.008

    • Google Scholar
59. 1. Tao Y-M
    2. Yu C
    3. Wang W-S
    4. Hou Y-Y
    5. Xu X-J
    6. Chi Z-Q
    7. Ding Y-Q
    8. Wang Y-J
    9. Liu J-G

    (2017) Heteromers of μ opioid and dopamine D₁ receptors modulate opioid-induced locomotor sensitization in a dopamine-independent manner

    British Journal of Pharmacology 174:2842–2861.

    https://doi.org/10.1111/bph.13908

    • Google Scholar
60. 1. Urs NM
    2. Daigle TL
    3. Caron MG

    (2011) A dopamine D1 receptor-dependent β-arrestin signaling complex potentially regulates morphine-induced psychomotor activation but not reward in mice

    Neuropsychopharmacology 36:551–558.

    https://doi.org/10.1038/npp.2010.186

    • PubMed
    • Google Scholar
61. 1. Valjent E
    2. Pascoli V
    3. Svenningsson P
    4. Paul S
    5. Enslen H
    6. Corvol JC
    7. Stipanovich A
    8. Caboche J
    9. Lombroso PJ
    10. Nairn AC
    11. Greengard P
    12. Hervé D
    13. Girault JA

    (2005) Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum

    PNAS 102:491–496.

    https://doi.org/10.1073/pnas.0408305102

    • PubMed
    • Google Scholar
62. 1. Valjent E
    2. Bertran-Gonzalez J
    3. Aubier B
    4. Greengard P
    5. Hervé D
    6. Girault JA

    (2010) Mechanisms of locomotor sensitization to drugs of abuse in a two-injection protocol

    Neuropsychopharmacology 35:401–415.

    https://doi.org/10.1038/npp.2009.143

    • PubMed
    • Google Scholar
63. 1. Van Waes V
    2. Tseng KY
    3. Steiner H

    (2011) GPR88 - a putative signaling molecule predominantly expressed in the striatum: cellular localization and developmental regulation

    Basal Ganglia 1:83–89.

    https://doi.org/10.1016/j.baga.2011.04.001

    • PubMed
    • Google Scholar
64. 1. Vassilatis DK
    2. Hohmann JG
    3. Zeng H
    4. Li F
    5. Ranchalis JE
    6. Mortrud MT
    7. Brown A
    8. Rodriguez SS
    9. Weller JR
    10. Wright AC
    11. Bergmann JE
    12. Gaitanaris GA

    (2003) The G protein-coupled receptor repertoires of human and mouse

    PNAS 100:4903–4908.

    https://doi.org/10.1073/pnas.0230374100

    • PubMed
    • Google Scholar
65. 1. Vilardaga JP
    2. Nikolaev VO
    3. Lorenz K
    4. Ferrandon S
    5. Zhuang Z
    6. Lohse MJ

    (2008) Conformational cross-talk between alpha2A-adrenergic and mu-opioid receptors controls cell signaling

    Nature Chemical Biology 4:126–131.

    https://doi.org/10.1038/nchembio.64

    • PubMed
    • Google Scholar
66. 1. Watts AO
    2. van Lipzig MM
    3. Jaeger WC
    4. Seeber RM
    5. van Zwam M
    6. Vinet J
    7. van der Lee MM
    8. Siderius M
    9. Zaman GJ
    10. Boddeke HW
    11. Smit MJ
    12. Pfleger KD
    13. Leurs R
    14. Vischer HF

    (2013) Identification and profiling of CXCR3-CXCR4 chemokine receptor heteromer complexes

    British Journal of Pharmacology 168:1662–1674.

    https://doi.org/10.1111/bph.12064

    • PubMed
    • Google Scholar
67. 1. Williams JT
    2. Christie MJ
    3. Manzoni O

    (2001) Cellular and synaptic adaptations mediating opioid dependence

    Physiological Reviews 81:299–343.

    https://doi.org/10.1152/physrev.2001.81.1.299

    • PubMed
    • Google Scholar
68. 1. Yang CH
    2. Huang HW
    3. Chen KH
    4. Chen YS
    5. Sheen-Chen SM
    6. Lin CR

    (2011) Antinociceptive potentiation and attenuation of tolerance by intrathecal β-arrestin 2 small interfering RNA in rats

    British Journal of Anaesthesia 107:774–781.

    https://doi.org/10.1093/bja/aer291

    • PubMed
    • Google Scholar

Author details

1. Thibaut Laboute

   Deficits of Reward GPCRs and Sociability, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France

   Contribution

   Conceptualization, Resources, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Contributed equally with

   Jorge Gandía

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0870-1891

2. Jorge Gandía

   Deficits of Reward GPCRs and Sociability, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France

   Contribution

   Conceptualization, Resources, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - review and editing

   Contributed equally with

   Thibaut Laboute

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1711-8075

3. Lucie P Pellissier

   1. Deficits of Reward GPCRs and Sociability, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France
   2. Biology and Bioinformatics of Signalling Systems, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Nouzilly, France

   Contribution

   Conceptualization, Formal analysis, Investigation, Visualization, Methodology, Writing - original draft

   Competing interests

   No competing interests declared

4. Yannick Corde

   Deficits of Reward GPCRs and Sociability, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France

   Contribution

   Formal analysis, Validation, Investigation, Visualization

   Competing interests

   No competing interests declared

5. Florian Rebeillard

   Cellular Biology and Molecular Pharmacology of central Receptors, Centre de Psychiatrie et Neurosciences, Inserm UMR_S894 - Université Paris Descartes, Sorbonne Paris Cité, Paris, France

   Contribution

   Resources, Investigation

   Competing interests

   No competing interests declared

6. Maria Gallo

   Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona Biomedical Research Park, Barcelona, Spain

   Contribution

   Resources, Investigation

   Competing interests

   No competing interests declared

7. Christophe Gauthier

   Biology and Bioinformatics of Signalling Systems, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Nouzilly, France

   Contribution

   Resources, Investigation

   Competing interests

   No competing interests declared

8. Audrey Léauté

   Deficits of Reward GPCRs and Sociability, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France

   Contribution

   Investigation

   Competing interests

   No competing interests declared

9. Jorge Diaz

   Cellular Biology and Molecular Pharmacology of central Receptors, Centre de Psychiatrie et Neurosciences, Inserm UMR_S894 - Université Paris Descartes, Sorbonne Paris Cité, Paris, France

   Contribution

   Resources, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

10. Anne Poupon

    Biology and Bioinformatics of Signalling Systems, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Nouzilly, France

    Contribution

    Resources

    Competing interests

    No competing interests declared

11. Brigitte L Kieffer

    1. Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, Canada
    2. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, Inserm U1258, Université de Strasbourg, 1 rue Laurent Fries, Illkirch, France

    Contribution

    Conceptualization, Resources, Formal analysis, Investigation, Methodology, Writing - review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-8809-8334

12. Julie Le Merrer

    1. Deficits of Reward GPCRs and Sociability, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France
    2. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, Inserm U1258, Université de Strasbourg, 1 rue Laurent Fries, Illkirch, France

    Contribution

    Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing

    Contributed equally with

    Jérôme AJ Becker

    For correspondence

    julie.le-merrer@inra.fr

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-8670-4273

13. Jérôme AJ Becker

    1. Deficits of Reward GPCRs and Sociability, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France
    2. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, Inserm U1258, Université de Strasbourg, 1 rue Laurent Fries, Illkirch, France

    Contribution

    Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing

    Contributed equally with

    Julie Le Merrer

    For correspondence

    jerome.becker@inra.fr

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-0039-0067

• 5,126

  views

• 622

  downloads

• 19

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.