Translational research: pharmacogenomic analysis of the response to crack and cocaine addiction

• Grant number: 17/26225-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): April 01, 2018
• Effective date (End): November 30, 2021
• Field of knowledge: Biological Sciences - Pharmacology - Clinical Pharmacology
• Principal Investigator: Paulo Caleb Júnior de Lima Santos
• Grantee: Paola Palombo
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 13/09295-3 - Pharmacogenetic of cardiovascular system drugs focusing on implementation, AP.JP

Abstract

Dependence on cocaine, as well as crack, is a major public health problem in Brazil and in the world. A dopaminergic neurotransmission, the brain reward system, and the cholinergic system, more information about our mechanisms of reward, self-administration, and cocaine dependence. In this context, Prof. Dr. José Carlos Fernández Galduróz (Department of Psychobiology, Paulista School of Medicine, UNIFESP) conducted a pilot study with cocaine/crack cocaine-dependent patients medicated with biperidene (anticholinergics to relieve the side effects of antipsychotics). Patients report lower compulsion, decreased appetite, greater adherence to treatment, and decreased amounts of cocaine-crack. Corroborating with these clinical results, animal studies demonstrating that biperiden reduced an expression of place-conditioned preference and a memory consolidation of this drug. Thus, these evidences are successful, not easy to administer. Thus, the general objective of this project is to perform a study translated to understand the possible mechanisms of pharmacotherapeutic response or resistance to treatment with biperidene. To do this, use the pharmacogenomics tool, through rtPCR, to analyze possible associations of the gene expression of the drug's action target at the M1 muscarinic receptor and its genetic variant rs2067477. We will also evaluate the drug's response in the dopaminergic system, through the analysis of DRD1 genes and their genetic variants rs5326 and rs265981; DRD2 and its genetic variant rs1800497; COMT and its genetic variants rs4680 and rs4818, TH and DARPP32 with a prediction of whether or not biperiden treatment is successful. In addition, using a model of self-administration of drugs of abuse, a microdialysis technique and a gene silencing methodology, with the aid of viral vectors and microRNAs, were used to validate these pharmacogenomic targets in an animal model. (AU)