Scholarship 24/01368-6 - Pânico, Sistema endocanabinoide - BV FAPESP
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Exploring the role of the orexinergic system and its interaction with cannabinoid receptors in the Dorsal Periaqueductal Gray Matter: implications for modulating panic-associated defensive responses.

Grant number: 24/01368-6
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Start date until: July 01, 2024
End date until: June 30, 2026
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal Investigator:Norberto Cysne Coimbra
Grantee:Paloma Molina Hernandes
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Panic disorder (PD) is a severe and often disabling psychiatric condition whose neurobiology is not yet fully understood. Existing clinical and preclinical evidence suggests a critical role of orexin (ORX) in the pathophysiology of PD. Studies have demonstrated that systemic treatment with the type 1 orexinergic receptor antagonist (OX1R) attenuated behavioral and autonomic responses induced in rats by the injection of sodium lactate. However, the neural systems through which ORX exerts its modulatory effects on panic remain poorly understood. The present study aims to investigate the role of the orexinergic system in the dorsal periaqueductal gray (SCPd), a mesencephalic structure considered a primary neural substrate in the genesis of defensive behaviors exhibited by rodents exposed to an imminent aversive situation. Initially, we will evaluate the effects of intra-SCPd administration of the OX1R antagonist, SB 334867, and orexin-A (OXA) in mice using two experimental models associating the escape response with panic: the polygonal arena for snake panic test and the beetle mania task. Subsequently, we will investigate the origin of orexinergic connections to SCPd from hypothalamic nuclei and the effects of optogenetic activation of this pathway on the organization and expression of panic-related behaviors. Finally, aiming to clarify the neurochemical mechanisms underlying the orexinergic system's modulation of behavioral responses, we will investigate the role of cannabinoid receptors 1 (CB1) in SCPd in mediating behavioral consequences resulting from the stimulation of the hypothalamic orexinergic pathway to SCPd, as previous findings have observed that the blockade of OX1R and CB1 by their respective antagonists attenuated the anxiogenic effect triggered by OXA in anxiety tests. Our hypothesis posits that in situations of intense fear/panic, the orexinergic HL-SCPd pathway is recruited, eliciting defensive responses. Additionally, we propose that inhibiting OX1R and CB1 receptors has the potential to attenuate these defense responses.

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