Enhancing Addiction Severity Prediction by Modulating GABAergic Activity in the Central Amygdala of RATTACA Rats

University Of California, San Diego, La Jolla CA

Investigators

Abstract

Project Summary/Abstract Cocaine Use Disorder (CUD) represents a significant public health challenge, characterized by a complex interplay of genetic, environmental, and individual factors, and limited treatment options. Despite advances in understanding the genetic underpinnings of addiction vulnerability, a critical gap remains in elucidating the neurobiological mechanisms underlying addiction susceptibility, particularly regarding pre-existing cellular differences. The present study aims to investigate pre-existing differences in GABAergic and glutamatergic transmission within the central amygdala (CeA) and their potential contribution to individual differences in addiction susceptibility. We employ a novel method called RATTACA, which leverages extensive genotype and phenotype data to enable polygenic trait prediction in naïve rats, allowing for the selection of animals with predicted high and low cocaine addiction-like behaviors before exposure to cocaine. Specific Aim 1 focuses on characterizing and comparing basal GABAergic and glutamatergic transmission in the CeA of rats with high and low predicted susceptibility to CUD. Specific Aim 2 examines the hypothesis that cocaine differentially modulates GABAergic and glutamatergic transmission in the CeA of rats with high and low predicted susceptibility to CUD by applying cocaine ex vivo and performing electrophysiological recordings. Preliminary data demonstrate that animals with a predicted high cocaine addiction-like behavior phenotype exhibit a higher level of tonic GABA release compared to animals predicted to have low cocaine addiction-like behaviors, with cocaine reducing GABA release only in the predicted high rats. These findings underscore the potential of our approach to investigate pre-existing individual differences at the cellular level, which may contribute to the observed individual differences in addiction-like behaviors. This study will provide insights into the role of GABAergic and glutamatergic transmission in the CeA in addiction vulnerability and inform potential therapeutic targets for CUD and other substance use disorders.