When orexins meet cannabinoids: Bidirectional functional interactions

Berrendero, Fernando; Flores, África; Robledo, Patricia

doi:10.1016/j.bcp.2018.08.040

Cited by 24 publications

(27 citation statements)

References 113 publications

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“…A direct role of eCBs has been proposed in the formation of episodic memory 5 , 34 whereas Cannabis consumption may interfere with the formation of new memories 35 . The biosynthesis of the eCB, 2-arachidonoylglycerol (2-AG) via diacylglycerol lipase α (DAGLα), and subsequently the signaling of CB1 receptors, are stimulated by OxA 36 , a neuropeptide produced by neurons in the lateral perifornical area of the hypothalamus (LH) and involved in the sleep/wake cycle, arousal, appetite, and energy homeostasis and acting via the G q/11 protein-coupled orexin receptor-1 (Ox1-R) and orexin receptor-2 37 , 38 . OxA is emerging as a regulator of neurogenesis and hippocampal plasticity 38 – 41 .…”

Section: Introductionmentioning

confidence: 99%

Orexin-A and endocannabinoids are involved in obesity-associated alteration of hippocampal neurogenesis, plasticity, and episodic memory in mice

et al. 2021

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The mammalian brain stores and distinguishes among episodic memories, i.e. memories formed during the personal experience, through a mechanism of pattern separation computed in the hippocampal dentate gyrus. Decision-making for food-related behaviors, such as the choice and intake of food, might be affected in obese subjects by alterations in the retrieval of episodic memories. Adult neurogenesis in the dentate gyrus regulates the pattern separation. Several molecular factors affect adult neurogenesis and exert a critical role in the development and plasticity of newborn neurons. Orexin-A/hypocretin-1 and downstream endocannabinoid 2-arachidonoylglycerol signaling are altered in obese mice. Here, we show that excessive orexin-A/2-arachidonoylglycerol/cannabinoid receptor type-1 signaling leads to the dysfunction of adult hippocampal neurogenesis and the subsequent inhibition of plasticity and impairment of pattern separation. By inhibiting orexin-A action at orexin-1 receptors we rescued both plasticity and pattern separation impairment in obese mice, thus providing a molecular and functional mechanism to explain alterations in episodic memory in obesity.

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Section: Introductionmentioning

confidence: 99%

Orexin-A and endocannabinoids are involved in obesity-associated alteration of hippocampal neurogenesis, plasticity, and episodic memory in mice

et al. 2021

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“…Several works support the idea that there is an interplay between cannabinoid and orexin systems, reviewed by Berrendero et al . ( 23 ) and Flores et al . ( 39 ).…”

Section: Discussionmentioning

confidence: 95%

“…The CB1R and OX2R have presented an overlapping distribution area in some regions of the CNS, based on anatomical studies ( 20 21 22 ); thus could be said that they can mutually regulate several physiological functions such as reward, nociception, food intake and energy balance, as reviewed by Berrendero et al . ( 23 ). Moreover, bioluminescence energy transfer assay showed that both OX1R and OX2R are capable of forming homo- and heteromeric complexes with one another and with the CB1R ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

Mutual assistance of nucleus accumbens cannabinoid receptor-1 and orexin receptor-2 in response to nicotine

Fartootzadeh

Alaei

Reisi

2021

Research in Pharmaceutical Sciences

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Background and purpose: The nucleus accumbens (NAc) express both orexin-2 receptor (OX2R) and cannabinoid receptor type 1 (CB1R). Orexin and cannabinoid regulate the addictive properties of nicotine. In this study, the effect of the CB1R blockade on the electrical activity of NAc neurons in response to nicotine, and its probable interaction with the OX2R in this event, within this area, were examined via the single-unit recording. Experimental approach: The spontaneous firing rate of NAc was initially recorded for 15 min, and then 5 min before subcutaneous injection of nicotine (0.5 mg/kg)/saline, AM251 and TCS-OX2-29 were injected into the NAc. Neuronal responses were recorded for 70 min, after nicotine administration. Findings/Results: Nicotine excited the NAc neurons significantly and intra-NAc microinjection of AM251 (25 and 125 ng/rat), as a selective CB1R antagonist, prevented the nicotine-induced increases of NAc neuronal responses. Moreover, microinjection of AM251 (125 ng/rat), before saline injection, could not affect the percentage of change of the neuronal response. Finally, simultaneous intra-NAc administration of the effective or ineffective doses of AM251 and TCS-OX2-29 (a selective antagonist of OX2R) prevented the nicotine- induced increases of NAc neuronal responses, so that there was a significant difference between the group received ineffective doses of both antagonists and the AM251 ineffective dose. Conclusion and implications: The results suggest that the CB1R can modulate the NAc reaction to the nicotine, and it can be concluded that there is a potential interplay between the OX2R and CB1R in the NAc, in relation to nicotine.

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“…In the brains of nd- fads2 −/− mice, the two novel endocannabinoids took over the function of AEA and 2-AG in the retrograde action as ligands of presynaptic CB1 on orexinergic neurons in different areas of brain (lateral hypothalamus, hippocampus, arcuate nucleus. The release of inhibitory GABAergic inputs promotes increased appetite and feeding and increased body fat mass, resulting in obesity, and excitatory glutamatergic inputs, suppressing hunger and induce hypophagy (14, 35, 36).…”

Section: Discussionmentioning

confidence: 99%

Novel CB1-ligands maintain homeostasis of the endocannabinoid system in ω3- and ω6-long-chain-PUFA deficiency

Hammels

Binczek

Schmidt‐Soltau

et al. 2019

Journal of Lipid Research

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Mammalian ω3- and ω6-PUFAs are synthesized from essential fatty acids (EFAs) or supplied by the diet. PUFAs are constitutive elements of membrane architecture and precursors of lipid signaling molecules. EFAs and long-chain (LC)-PUFAs are precursors in the synthesis of endocannabinoid ligands of G i/o protein-coupled cannabinoid receptor (CB)1 and CB2 in the endocannabinoid system, which critically regulate energy homeostasis as the metabolic signaling system in hypothalamic neuronal circuits and behavioral parameters. We utilized the auxotrophic fatty acid desaturase 2-deficient ( fads2 −/− ) mouse, deficient in LC-PUFA synthesis, to follow the age-dependent dynamics of the PUFA pattern in the CNS-phospholipidome in unbiased dietary studies of three cohorts on sustained LC-PUFA-free ω6-arachidonic acid- and DHA-supplemented diets and their impact on the precursor pool of CB1 ligands. We discovered the transformation of eicosa-all cis -5,11,14-trienoic acid, uncommon in mammalian lipidomes, into two novel endocannabinoids, 20:3 5,11,14 -ethanolamide and 2-20:3 5,11,14 -glycerol. Their function as ligands of CB1 has been characterized in HEK293 cells. Labeling experiments excluded Δ8-desaturase activity and proved the position specificity of FADS2. The fads2 −/− mutant might serve as an unbiased model in vivo in the development of novel CB1 agonists and antagonists.

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When orexins meet cannabinoids: Bidirectional functional interactions

Cited by 24 publications

References 113 publications

Orexin-A and endocannabinoids are involved in obesity-associated alteration of hippocampal neurogenesis, plasticity, and episodic memory in mice

Orexin-A and endocannabinoids are involved in obesity-associated alteration of hippocampal neurogenesis, plasticity, and episodic memory in mice

Mutual assistance of nucleus accumbens cannabinoid receptor-1 and orexin receptor-2 in response to nicotine

Novel CB1-ligands maintain homeostasis of the endocannabinoid system in ω3- and ω6-long-chain-PUFA deficiency

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