Role of cannabinoid CB1 receptors in modulating neural circuits involved in the interaction between maternal separation stress and ethanol intake in mice

• Grant number: 19/24073-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2020
• End date: May 31, 2024
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Fabio Cardoso Cruz
• Grantee: Cristiane Aparecida Favoretto
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 18/15505-4 - Neurobiology study of relapse to alcohol and cocaine seeking: identification of plasticity in neuronal ensembles that encodes addiction-related memories, AP.JP2
• Associated scholarship(s): 22/10168-5 - Impacts of chronic intermittent ethanol vapor and stress exposure on striatal D1 medium spiny neurons: modulation by CB1 cannabinoid receptors, BE.EP.PD

Abstract

Ethanol-use disorders represent a serious public health issue in Brazil and worldwide, and are one of the main risk factors associated with development of disease, disability and death. Early onset of ethanol use, its use pattern, and chronic exposure to stress during childhood are vulnerability factors highly associated with the development of ethanol dependence. Changes in dopaminergic system function promoted by repeated ethanol use and / or exposure to stressors are possibly one of the mechanisms underlying behavioral transition from controlled drug use to abuse and dependence. In the dorsal striatum, the endocannabinoid (eCB) system presents an important modulating function of dopaminergic system through 2-arachidonylglycerol action on CB1 receptors, present, among other sites, in medium spiny neurons that express D1 (D1 MSNs), which are neuronal cells widely involved in responses to drugs of abuse, including ethanol, and stress. ECB signaling via CB1 receptors has also been implicated in responses to ethanol and stress. For example, studies have indicated that systemic treatment with CB1 receptor antagonists has been able to reduce ethanol intake and reinstatement of ethanol seeking behavior in rodents. In addition, exposure to neonatal stress promoted increased ethanol intake, correlated with increased CB1 receptors expression in limbic brain areas. Therefore, we propose to evaluate, in adolescent mice, behavioral and neurobiological changes associated to voluntary ethanol intake promoted by previous exposure to neonatal stress of Maternal Separation (MS). In addition, we will investigate the involvement of CB1 receptors in modulating neural circuits involved in responses to MS stress and ethanol intake. For this, male C57BL/6J mice will be exposed to a MS protocol during the neonatal period and their voluntary ethanol intake, neuronal activation levels and CB1 receptors expression will be analyzed in brain areas associated with reward pathways and, through RNAscope technique, in D1 MSNs of dorsal striatum. In addition, by combining the use of transgenic Cre mice and local injection of small interference RNA (siRNA, for selective inhibition of CB1 receptors), we propose to identify whether CB1 receptors expressed in dorsal striatal D1 MSNs, are specifically involved in the interaction between stress and ethanol intake. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MORAIS-SILVA, GESSYNGER; FAVORETTO, CRISTIANE APARECIDA; PAGLIUSI, MARCO; LEGATES, TARA A.. Editorial: Advances in the involvement of brain cellular subpopulations and pathways in distress and stress-related disorders. FRONTIERS IN NEUROSCIENCE, v. 17, p. 3-pg., 2023-08-29. (21/13291-0, 20/08363-9, 22/10168-5, 19/24073-3, 20/15216-2)

FAVORETTO, C. A.; BERTAGNA, N. B.; RIGHI, T.; RODOLPHO, B. T.; ANJOS-SANTOS, A.; SILVA, F. B. R.; BIANCHI, P. C.; CRUZ, F. C.. Impacts of maternal separation stress on ethanol-related responses, anxiety-and depressive-like behaviors in adolescent mice. Neuroscience Letters, v. 809, p. 12-pg., 2023-05-23. (19/24073-3, 18/15505-4)

FAVORETTO, CRISTIANE APARECIDA; PAGLIUSI, MARCO; MORAIS-SILVA, GESSYNGER. Involvement of brain cell phenotypes in stress-vulnerability and resilience. FRONTIERS IN NEUROSCIENCE, v. 17, p. 14-pg., 2023-07-05. (21/13291-0, 20/08363-9, 22/10168-5, 19/24073-3, 20/15216-2)