The CRF<sub>1</sub> receptor mediates social behavior deficits induced by opiate withdrawal

Piccin, Alessandro; Contarino, Angelo

doi:10.1002/jnr.24697

Cited by 9 publications

(5 citation statements)

References 70 publications

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“…For instance, genetic inactivation of the CRF 2 receptor reduced sociability deficits associated with long-term cocaine withdrawal in male mice (Morisot et al, 2018). Moreover, genetic CRF 1 receptor-deficiency decreased opiate withdrawal-induced sociability deficits in female mice, as assessed one week after cessation of repeated morphine administration (Piccin and Contarino, 2022). The latter findings contrast with the present results of a lack of effect of antalarmin in female mice.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, genetic inactivation of the CRF 2 receptor (CRF 2 -/-) reduced sociability deficits and vulnerability to stress associated with long-term cocaine withdrawal in male mice (Morisot et al, 2018). Moreover, genetic inactivation of the CRF 1 receptor (CRF 1 -/-) decreased morphine withdrawal-induced sociability deficits in female mice and hostility-driven interest for a same-sex conspecific in male mice (Piccin and Contarino, 2022). Besides, extensive literature points out to the two closely related neuropeptides oxytocin (OXY) and arginine-vasopressin (AVP) as main substrates of social interaction, parenting behavior and intermale aggressiveness (Jurek and Neumann, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Disruption of the CRF₁receptor eliminates morphine-induced sociability deficits and firing of oxytocinergic neurons in male mice

Piccin,

Allain,

Baufreton

et al. 2024

Preprint

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Substance-induced social behavior deficits dramatically worsen the clinical outcome of substance use disorders; yet, the underlying mechanisms remain poorly understood. Herein, we investigated the role for the corticotropin-releasing factor receptor 1 (CRF1) in the acute sociability deficits induced by morphine and the related activity of oxytocin (OXY)- and arginine-vasopressin (AVP)-expressing neurons of the paraventricular nucleus of the hypothalamus (PVN). For this purpose, we used both the CRF1receptor-preferring antagonist compound antalarmin and the genetic mouse model of CRF1receptor-deficiency. Antalarmin completely abolished sociability deficits induced by morphine in male, but not in female, C57BL/6J mice. Accordingly, genetic CRF1receptor-deficiency eliminated morphine-induced sociability deficits in male mice.Ex vivoelectrophysiology studies showed that antalarmin also eliminated morphine-induced firing of PVN neurons in male, but not in female, C57BL/6J mice. Likewise, genetic CRF1receptor-deficiency reduced morphine-induced firing of PVN neurons in a CRF1gene expression-dependent manner. The electrophysiology results consistently mirrored the behavioral results, indicating a link between morphine-induced PVN activity and sociability deficits. Interestingly, in male mice antalarmin abolished morphine-induced firing in neurons co-expressing OXY and AVP, but not in neurons expressing only AVP. In contrast, in female mice antalarmin did not affect morphine-induced firing of neurons co-expressing OXY and AVP or only OXY, indicating a selective sex-specific role for the CRF1receptor in opiate-induced PVN OXY activity. The present findings demonstrate a major, sex-linked, role for the CRF1receptor in sociability deficits and related brain alterations induced by morphine, suggesting new therapeutic strategy for opiate use disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Disruption of the CRF₁receptor eliminates morphine-induced sociability deficits and firing of oxytocinergic neurons in male mice

Piccin,

Allain,

Baufreton

et al. 2024

Preprint

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“…Opioid withdrawal triggers severe social deficits in humans, including social isolation and aggression, which can perpetuate OUD as individuals are less likely to receive the support necessary to abstain from drug misuse [52][53][54] . The LS is well-implicated in social behaviors, including social interaction, aggression, mating, and pup-rearing 55 , but it is unknown whether LS-Nts neurons play a role in withdrawal-induced social deficits.…”

Section: Silencing Ls-nts Neurons Exacerbates Withdrawal-induced Pain...mentioning

confidence: 99%

Opioid-driven disruption of the septal complex reveals a role for neurotensin-expressing neurons in withdrawal

Simon,

Fleming,

Senthilkumar

et al. 2024

Preprint

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Because opioid withdrawal is an intensely aversive experience, persons with opioid use disorder (OUD) often relapse to avoid it. The lateral septum (LS) is a forebrain structure that is important in aversion processing, and previous studies have linked the lateral septum (LS) to substance use disorders. It is unclear, however, which precise LS cell types might contribute to the maladaptive state of withdrawal. To address this, we used single-nucleus RNA-sequencing to interrogate cell type specific gene expression changes induced by chronic morphine and withdrawal. We discovered that morphine globally disrupted the transcriptional profile of LS cell types, but Neurotensin-expressing neurons (Nts; LS-Nts neurons) were selectively activated by naloxone. Using two-photon calcium imaging and ex vivo electrophysiology, we next demonstrate that LS-Nts neurons receive enhanced glutamatergic drive in morphine-dependent mice and remain hyperactivated during opioid withdrawal. Finally, we showed that activating and silencing LS-Nts neurons during opioid withdrawal regulates pain coping behaviors and sociability. Together, these results suggest that LS-Nts neurons are a key neural substrate involved in opioid withdrawal and establish the LS as a crucial regulator of adaptive behaviors, specifically pertaining to OUD.

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“…In female mice, CRF-R1 activity eliminates social behavior deficits associated with opiate withdrawal (Piccin and Contarino, 2020a) and CRF receptors signaling in dorsal raphe nucleus regulates and enhance maternal care (Kijama et al, 2021). Interestingly, Piccin and Contarino (2020b) reported initial evidence about how both receptors, CRF-R1 and CRF-R2 have a sex-linked role when a pharmacological approach was used in male and female mice.…”

Section: New Insights Of Crf Receptorsmentioning

confidence: 99%

Transcriptional Regulation, Signaling Pathways, and Subcellular Localization of Corticotropin-Releasing Factor Receptors in the Central Nervous System

et al. 2022

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Corticotropin releasing factor (CRF) receptors, CRF-R1 and CRF-R2, are differentially distributed in body tissues and although respond differentially to stimuli due to their association with different signaling pathways, both receptors have a fundamental role in the response and adaptation to stressful stimuli. Here, we summarize the reported data on different forms of CRF-R1 and CRF-R2 regulation as well as on their subcellular localization. While the presence of R1 has been described at pre-and postsynaptic sites, R2 is mainly associated with postsynaptic densities. Different studies have provided valuable information on how these receptors regulate responses at central level, elucidating different and sometimes synergistic roles in response to stress, but despite their high sequence identity, both receptors have been described to be differentially regulated both by their ligands and by transcriptional factors. To date, and from the point of view of their promoter sequences, it has not yet been reported how the different consensus sites identified in silico could be modulating the transcriptional regulation and expression of the receptors under different conditions which strongly limits the fully understanding of their differential functions, providing a wide field to increase and expand the study of the regulation and role of CRF receptors in the CRF system.

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The CRF₁ receptor mediates social behavior deficits induced by opiate withdrawal

Cited by 9 publications

References 70 publications

Disruption of the CRF₁receptor eliminates morphine-induced sociability deficits and firing of oxytocinergic neurons in male mice

Disruption of the CRF₁receptor eliminates morphine-induced sociability deficits and firing of oxytocinergic neurons in male mice

Opioid-driven disruption of the septal complex reveals a role for neurotensin-expressing neurons in withdrawal

Transcriptional Regulation, Signaling Pathways, and Subcellular Localization of Corticotropin-Releasing Factor Receptors in the Central Nervous System

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The CRF1 receptor mediates social behavior deficits induced by opiate withdrawal

Cited by 9 publications

References 70 publications

Disruption of the CRF1receptor eliminates morphine-induced sociability deficits and firing of oxytocinergic neurons in male mice

Disruption of the CRF1receptor eliminates morphine-induced sociability deficits and firing of oxytocinergic neurons in male mice

Opioid-driven disruption of the septal complex reveals a role for neurotensin-expressing neurons in withdrawal

Transcriptional Regulation, Signaling Pathways, and Subcellular Localization of Corticotropin-Releasing Factor Receptors in the Central Nervous System

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The CRF₁ receptor mediates social behavior deficits induced by opiate withdrawal

Disruption of the CRF₁receptor eliminates morphine-induced sociability deficits and firing of oxytocinergic neurons in male mice

Disruption of the CRF₁receptor eliminates morphine-induced sociability deficits and firing of oxytocinergic neurons in male mice