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Opioid Receptor Heteromer in the Nucleus Accumbens

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Opioid Receptor Heteromer in the Nucleus Accumbens Molecular Psychiatry (2014) 19, 986–994 & 2014 Macmillan Publishers Limited All rights reserved 1359-4184/14 www.nature.com/mp ORIGINAL ARTICLE Antidepressant-like and anxiolytic-like effects following activation of the m-d opioid receptor heteromer in the nucleus accumbens N Kabli1,2, T Nguyen1, G Balboni3, BF O’Dowd1,2 and SR George1,2,4 Treatment-resistant major depressive disorder remains inadequately treated with currently available antidepressants. Opioid receptors (ORs) are involved in the pathophysiology of depression yet remain an untapped therapeutic intervention. The m-d OR heteromer represents a unique signaling complex with distinct properties compared with m- and d-OR homomers; however, its role in depression has not been characterized. As there are no ligands exclusively targeting the m-d heteromer, we devised a strategy to selectively antagonize the function of the m-dOR complex using a specific interfering peptide derived from the dOR distal carboxyl tail, a sequence implicated in m-dOR heteromerization. In vitro studies using a minigene expressing this peptide demonstrated a loss of the unique pharmacological and trafficking properties of d-agonists at the m-d heteromer, with no effect on m-ord-OR homomers, and a dissociation of the m-dOR complex. Intra-accumbens administration of the TAT-conjugated interfering peptide abolished the antidepressant-like and anxiolytic-like actions of the d-agonist UFP-512 (H-Dmt-Tic-NH-CH(CH2-COOH)-Bid) measured in the forced swim test, novelty-induced hypophagia and elevated plus maze paradigms in rats. UFP-512’s antidepressant-like and anxiolytic-like actions were abolished by pretreatment with either mOR or dOR antagonists. Overall, these findings demonstrate that the m-d heteromer may be a potential suitable therapeutic target for treatment-resistant depression and anxiety disorders. Molecular Psychiatry (2014) 19, 986–994; doi:10.1038/mp.2013.115; published online 24 September 2013 Keywords: anhedonia; emotion; G-protein coupled receptor; heterooligomer; mood; ventral striatum INTRODUCTION potent antidepressant-like and anxiolytic-like effects in animal 17–25 Treatment-resistant major depression remains a significant health, models. Further, the analgesic effects of d-agonists are social and economic burden that is inadequately treated with attenuated or abolished in mOR-gene-deleted animals and 26,27 currently available antidepressant medications that modulate following pretreatment with mOR antagonists, supporting the serotonergic and noradrenergic neurotransmission.1 Thus, pharma- notion that these ligands may in fact recruit the m-d OR heteromer cological agents with alternative mechanisms of action are critically for certain actions. Second, animals in which the genes for the mOR, needed and necessary to address this unmet therapeutic need. dOR or Gaz (the inhibitory G-protein to which the m-d heteromer Opioid receptors (ORs) and their endogenous ligands are couples selectively) are deleted display depressive-like and involved in the pathophysiology of major depression, yet remain anxiogenic behavior.28 Finally, recent studies localize the m-d an untapped potential therapeutic intervention.2–4 However, heteromer to brain nuclei implicated in mood and emotional although m-opioid agonists such as morphine have been used in processing, including the nucleus accumbens (NAc),29 a subcortical the clinic to successfully manage refractory depression, their brain region whose activity is reduced in patients with major clinical utility is limited by the development of tolerance and depressive disorders.30,31 Furthermore, direct activation of the NAc adverse side effects ensuing from mOR activation.5–11 m-and with deep brain stimulation has shown promise in ameliorating d-ORs have been shown to form a heteromeric receptor complex depression and anxiety in patients.32,33 Thus, overall, several lines possessing unique pharmacological and signalling properties.12–15 of evidence support exploring the activation of the m-d heteromer The m-d heteromer displays less of the functional desensitization in the NAc in models of depression and anxiety. and downregulation that limit the therapeutic utility of drugs In this study, we investigated the function of the m-d heteromer targeting the mOR,12,14 rendering the m-d receptor complex a and its role in regulating depressive-like and anxiogenic behavior promising therapeutic target. by determining its involvement in the mood-elevating properties Although the pharmacological and molecular profile of the m-d of d-agonists. In the absence of selective ligands exclusively heteromer in vitro is being elucidated, its physiological role in vivo targeting the m-d heteromer, we devised a novel strategy to is largely unknown. Exploring the m-d heteromer as a therapeutic selectively antagonize the function of the m-d receptor complex target for treatment-resistant major depression is supported by through physical disruption. To this end, we designed a specific behavioral, genetic and biochemical findings. First, d-opioid interfering peptide aimed at the distal carboxyl tail domain of the agonists, which we and others have shown to bind to and activate dOR, which has been implicated as a site of interaction between the m-d heteromer and regulate its intracellular trafficking,12,16 have m- and d-ORs. After validating the use of the peptide to dissociate 1Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, ON, Canada; 2Departments of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 3Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy and 4Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. Correspondence: Dr SR George, Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Medical Sciences Building Rm 4358, 1 King’s College Circle, Toronto, Ontario, M5S 1A8, Canada. E-mail: [email protected] Received 11 March 2013; revised 16 July 2013; accepted 18 July 2013; published online 24 September 2013 m-d heteromer mediates antidepressant-like action N Kabli et al 987 the m-d heteromer in vitro, we administered it in vivo into the NAc Intact cell internalization assay as a TAT-conjugate in order to interrogate the role of the m-d mOR binding was performed on intact cells stably expressing ORs using the 3 heteromer in the antidepressant-like and anxiolytic-like effects of hydrophilic selective m-agonist [ H]-DAMGO at its KD (2 nM) as described 12 UFP-512 (H-Dmt-Tic-NH-CH(CH2-COOH)-Bid), a d-agonist with high previously. Cells were treated with 1 mM agonist or saline vehicle for 1 h at subnanomolar affinity at the m-d heteromer.12 Overall, our findings 37 1C. In separate experiments, cells were pretreated with either 100 nM of the d-antagonist naltrindole or the m-antagonist CTOP. The disappearance indicate that activation of the m-d heteromer in the NAc by UFP- 3 512 produced antidepressant-like and anxiolytic-like actions, of [ H]-DAMGO binding sites on the cell surface served as an indicator of mOR internalization. which were completely abolished by dissociating the m-d heteromer or antagonizing either one of its component receptors. Animals Adult male Sprague Dawley rats weighing 250–350 g (Charles River, MATERIALS AND METHODS St Constant, Que´bec, Canada) were housed in pairs (and singly-housed following surgery) in a temperature-controlled room with corn chip Drugs bedding and free access to rodent chow and water. Rats were maintained 2 4 Naltrindole hydrochloride, deltorphin II, DAMGO ([D-Ala , N-MePhe , under a standard 12-h/12-h light/dark cycle. Testing was performed during 2 5 Gly-ol]-enkephalin), DPDPE ([D-Pen , D-Pen ]enkephalin), imipramine the light cycle. Animal protocols were approved by the University of and fluoxetine were purchased from Sigma (Saint Louis, MO, USA). CTOP Toronto Animal Care Committee and were in accordance with the (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) was purchased from Tocris guidelines set by the Canadian Council on Animal Care. (Ellisville, MO, USA). UFP-512 was synthesized by Balboni et al.34 Stereotaxic surgery Expression in mammalian cells Rats were mounted on a stereotaxic frame under isoflurane anesthesia. Human embryonic kidney 293T cells stably expressing m- and/or d-ORs Stainless steel guide cannulae were implanted bilaterally into the NAc (AP (density of 150–175 fmol mg À 1 per receptor and 150–350 fmol mg À 1 þ 1.6, ML þ 3.0, DV À 6.9) at a 101 angle from the midline or into the when both receptors were co-expressed) were generated as described lateral cerebral ventricle (AP À 0.8, ML þ 1.4, DV À 3.6) at 901 angle to the previously.12 skull using co-ordinates from.35 Guide cannulae were positioned 1 mm anterior to the NAc to prevent tissue damage at the target site. Cannulae were secured onto the skull using stainless steel screws and dental cement Minigene constructs with the insertion of dummy stylets to maintain patency. Rats were Complementary DNA fragments expressing either the distal 16 or 22 allowed to recover, and behavioral testing was conducted 7 days following amino acids of the dOR carboxyl tail were subcloned into pcDNA3.1. The surgery. Placement of guide cannulae was verified by brain sectioning and Transformer site-directed mutagenesis kit (Clontech, Mountain View, CA, histological examination at the end of the experiment. USA) was used to insert the hemaglutinin epitope (YPYDVPDYA) at the NH2-terminal of the dOR carboxyl tail fragment using the same approach TAT fusion peptides previously described.13,14 Cells were transfected using LipofectAMINE (Invitrogen, Burlington, ON, Canada) according to the manufacturer’s A peptide derived from the distal portion of the dOR carboxyl tail 0 0 protocols. (5 -VTACTPSDGPGGGAAA-3 ) identified as a m-d heteromerization interac- tion interface was conjugated to the HIV protein transduction domain TAT (50-YGRKKRRQRRR-30) to create a TAT fusion peptide for transduction into Cell membrane preparation neurons.36 A scrambled sequence of the same 16 amino acids was used as Membrane fractions (crude P2 fraction) and cell lysates were prepared control.
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