Investigation of sex-specific mechanisms underlying anti-stress nociceptin and norepinephrine interactions on synaptic transmission and neuronal functions in the central amygdala in ethanol dependence and withdrawal

• Grant number: 23/09647-9
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: January 04, 2024
• End date: January 03, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Fabio Cardoso Cruz
• Grantee: Alexia dos Anjos Santos
• Supervisor: Marisa Roberto
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Institution abroad: Scripps Research Institute, San Diego, United States
• Associated to the scholarship: 21/00838-0 - Investigation of the participation of hippocampal projections to infralimbic cortex and nucleus acumbens in the context-induced reinstatement of ethanol seeking, BP.DR

Abstract

Alcohol Use Disorder (AUD) is a chronic condition characterized by compulsive alcohol-seeking behavior, negative impact on various aspects of life, and the development of a negative emotional state associated with withdrawal. The central amygdala (CeA) receives both pro- and anti-stress signals and plays a role in negative reinforcement processes that contribute to alcohol use and relapse. The nociceptin peptide and its receptor (NOP) are densely expressed in the CeA and have anti-stress effects by counteracting the activity of corticotropin-releasing factor (CRF) and blocking relapse driven by negative reinforcement in AUD. Additionally, the CeA is influenced by the release of norepinephrine (NE), and dysfunctions in the NE system have been implicated in conditions such as stress, anxiety, and alcohol dependence. Furthermore, the anti-stress neuropeptide nociceptin counteracts the pro-stress effects of NE by reducing GABA release in the CeA. In this study, we aim to investigate the sex-specific mechanisms underlying the interactions between the anti-stress effects of nociceptin and norepinephrine on GABAergic transmission in the CeA during ethanol dependence and withdrawal. Male and female rats will be exposed to CIE vapor paradigm, and brain slices will be collected for in situ hybridization (ISH) and whole-cell patch-clamp recordings. In Experiment 1, we will use ISH to determine the proportion of cells expressing Pnoc (pre-nociceptin) and Oprl1 (NOP) and their colocalization with GABA neuronal marker (Gad2) in the CeA of alcohol Dep and WD relative to naïves. In Experiment 2, we will apply nociceptin followed by NE, and vice versa, to investigate the effect of ethanol dependence and withdrawal on the modulatory actions of the interaction between nociceptin and NE on synaptic transmission in the CeA of male and female rats. (AU)