G protein-coupled receptor heteromers are key players in substance use disorder

International audienceG protein-coupled receptors (GPCR) represent the largest family of membrane proteins in the human genome. Physical association between two different GPCRs is linked to functional interactions which generates a novel entity, called heteromer, with specific ligand binding and signaling properties. Heteromerization is increasingly recognized to take place in the mesocorticolimbic pathway and to contribute to various aspects related to substance use disorder. This review focuses on heteromers identified in brain areas relevant to drug addiction. We report changes at the molecular and cellular levels that establish specific functional impact and highlight behavioral outcome in preclinical models. Finally, we briefly discuss selective targeting of native heteromers as an innovative therapeutic option

Double fluorescent knock-in mice to investigate endogenous mu-delta opioid heteromer subscellular distribution.

The heteromerization of Mu (MOP) and delta (DOP) opioid receptors has been extensively studied in heterologous systems. These studies demonstrated significant functional interaction of MOP and DOP evidenced by new pharmacological properties and intracellular signalling in transfected cells co-expressing the receptors. Due to the lack of appropriate tools for receptor visualization, such as specific antibodies, the pharmacological and functional properties of MOP-DOP heteromers in cells naturally expressing these receptors remains poorly understood. To address endogenous MOP-DOP heteromer trafficking and signalling in vivo and in primary neuronal cultures, we generated a double knock-in mouse line expressing functional fluorescent versions of DOP and MOP receptors. This mouse model has successfully been used to map the neuroanatomic distribution of the receptors and to identify brain regions in which the MOP-DOP heteromers are expressed. Here, we describe a method to quantitatively and automatically analyze changes in the subcellular distribution of MOP-DOP heteromers in primary hippocampal culture from this mouse model. This approach provides a unique tool to address specificities of endogenous MOP-DOP heteromer trafficking

Heteromerization Modulates mu Opioid Receptor Functional Properties in vivo.

Mu opioid receptors modulate a large number of physiological functions. They are in particular involved in the control of pain perception and reward properties. They are also the primary molecular target of opioid drugs and mediate their beneficial analgesic effects, euphoric properties as well as negative side effects such as tolerance and physical dependence. Importantly, mu opioid receptors can physically associate with another receptor to form a novel entity called heteromer that exhibits specific ligand binding, signaling, and trafficking properties. As reviewed here, in vivo physical proximity has now been evidenced for several receptor pairs, subsequent impact of heteromerization on native mu opioid receptor signaling and trafficking identified and a link to behavioral changes established. Selective targeting of heteromers as a tool to modulate mu opioid receptor activity is therefore attracting growing interest and raises hopes for innovative therapeutic strategies.journal articlereview20182018 11 13importe

Heteromerization Modulates mu Opioid Receptor Functional Properties in vivo

Mu opioid receptors modulate a large number of physiological functions. They are in particular involved in the control of pain perception and reward properties. They are also the primary molecular target of opioid drugs and mediate their beneficial analgesic effects, euphoric properties as well as negative side effects such as tolerance and physical dependence. Importantly, mu opioid receptors can physically associate with another receptor to form a novel entity called heteromer that exhibits specific ligand binding, signaling, and trafficking properties. As reviewed here, in vivo physical proximity has now been evidenced for several receptor pairs, subsequent impact of heteromerization on native mu opioid receptor signaling and trafficking identified and a link to behavioral changes established. Selective targeting of heteromers as a tool to modulate mu opioid receptor activity is therefore attracting growing interest and raises hopes for innovative therapeutic strategies

Developmental exposure to ethinylestradiol and reproductive function in mice : neuroendocrine and behavioral effects

Les réseaux neuroendocrines qui contrôlent la reproduction sont mis en place pendant le développement sous l’action des stéroïdes sexuels endogènes. Toute perturbation de l’équilibre hormonal pendant ces phases critiques pourrait être à l’origine de troubles de la fonction de reproduction chez l’adulte. Ce travail vise à identifier l’impact d’une exposition développementale à un oestrogène de synthèse, l’éthinyloestradiol (EE2), sur les réseaux neuroendocrines et les conséquences physiologiques et comportementales chez l’adulte et sa descendance. Nos résultats ont montré que l’EE2 induit des perturbations des comportements sexuels chez les mâles et chez les femelles et une modification des réseaux hypothalamiques à GnRH et des neurones à calbindine qui contrôlent la physiologie et les comportements reproducteurs. Nous avons également montré que certains effets de l’EE2 sont transmis jusqu’à la quatrième génération, mettant ainsi en évidence le caractère transgénérationnel de ces perturbations. Ces résultats mettent en évidence la sensibilité des réseaux neuroendocrines aux perturbateurs endocriniens et la nécessité de prendre en compte ces paramètres dans l’évaluation de leurs effets sur la santé et la reproduction.Neuroendocrine networks controlling reproductive function are established during development by the action of endogenous sex steroids. Any disturbance in the hormone balance during these critical phases may cause several disorders in reproductive function in adulthood. This work aims at identifing the consequences of a developmental exposure to the synthetic pharmaceutical estrogen ethinylestradiol (EE2) on the neuroendocrine and behavioral outcomes of the reproductive function in adult individuals and their offspring. Our findings showed that EE2 induced disturbances of sexual behaviors in males and females and modified the GnRH and the calbindin hypothalamic networks of exposed animals. We also showed that some effects of EE2 were transmitted up to the fourth generation, pointing out the transgenerational character of certain effects. All these results highlight the sensitivity of neuroendocrine networks to endocrine disruptors and the need to consider these parameters in assessing their effects on health and reproduction

G protein-coupled receptor heteromers are key players in substance use disorder.

G protein-coupled receptors (GPCR) represent the largest family of membrane proteins in the human genome. Physical association between two different GPCRs is linked to functional interactions which generates a novel entity, called heteromer, with specific ligand binding and signaling properties. Heteromerization is increasingly recognized to take place in the mesocorticolimbic pathway and to contribute to various aspects related to substance use disorder. This review focuses on heteromers identified in brain areas relevant to drug addiction. We report changes at the molecular and cellular levels that establish specific functional impact and highlight behavioral outcome in preclinical models. Finally, we briefly discuss selective targeting of native heteromers as an innovative therapeutic option.journal articlereviewresearch support, non-u.s. gov't2019 112018 09 29importe

Developmental exposure to 17-alpha-ethynilestradiol alters behavioral and neural outcomes in adult male mice

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Developmental exposure to Ethinylestradiol affects transgenerationally sexual behavior and neuroendocrine networks in male mice

Remerciements : Plateforme Phénotypage - Endocrinologie. INRA, UMR PRC 0085, 37380 Nouzilly, Centre Val de LoireDr Fouchécourt for the discussion on the hCG injection protocol, Dr Martini for her participation in testing mouse behavior and Ms. Torchy for the kisspeptin studyReproductive behavior and physiology in adulthood are controlled by hypothalamic sexually dimorphic neuronal networks which are organized under hormonal control during development. These organizing effects may be disturbed by endocrine disrupting chemicals (EDCs). To determine whether developmental exposure to Ethinylestradiol (EE2) may alter reproductive parameters in adult male mice and their progeny, Swiss mice (F1 generation) were exposed from prenatal to peripubertal periods to EE2 (0.1–1 μg/kg/d). Sexual behavior and reproductive physiology were evaluated on F1 males and their F2, F3 and F4 progeny. EE2-exposed F1 males and their F2 to F4 progeny exhibited EE2 dose-dependent increased sexual behavior, with reduced latencies of first mount and intromission, and higher frequencies of intromissions with a receptive female. The EE2 1 μg/kg/d exposed animals and their progeny had more calbindin immunoreactive cells in the medial preoptic area, known to be involved in the control of male sexual behavior in rodents. Despite neuroanatomical modifications in the Gonadotropin-Releasing Hormone neuron population of F1 males exposed to both doses of EE2, no major deleterious effects on reproductive physiology were detected. Therefore EE2 exposure during development may induce a hypermasculinization of the brain, illustrating how widespread exposure of animals and humans to EDCs can impact health and behaviors

Developmental exposure to ethinylestradiol affects reproductive physiology, the GnRH neuroendocrine network and behaviors in female mouse

Remerciements :Plateforme d'Imagerie Cellulaire. INRA, UMR PRC 0085, 37380 Nouzilly, Centre Tours Val de LoireDuring development, environmental estrogens are able to induce an estrogen mimetic action that may interfere with endocrine and neuroendocrine systems. The present study investigated the effects on the reproductive function in female mice following developmental exposure to pharmaceutical ethinylestradiol (EE2), the most widespread and potent synthetic steroid present in aquatic environments. EE2 was administrated in drinking water at environmentally relevant (ENVIR) or pharmacological (PHARMACO) doses [0.1 and 1 μg/kg (body weight)/day respectively], from embryonic day 10 until postnatal day 40. Our results show that both groups of EE2-exposed females had advanced vaginal opening and shorter estrus cycles, but a normal fertility rate compared to CONTROL females. The hypothalamic population of GnRH neurons was affected by EE2 exposure with a significant increase in the number of perikarya in the preoptic area of the PHARMACO group and a modification in their distribution in the ENVIR group, both associated with a marked decrease in GnRH fibers immunoreactivity in the median eminence. In EE2-exposed females, behavioral tests highlighted a disturbed maternal behavior, a higher lordosis response, a lack of discrimination between gonad-intact and castrated males in sexually experienced females, and an increased anxiety-related behavior. Altogether, these results put emphasis on the high sensitivity of sexually dimorphic behaviors and neuroendocrine circuits to disruptive effects of EDCs