Role of direct and indirect ventral striatal pathways in context-induced reinstatement of alcohol seeking

• Grant number: 16/25894-2
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): April 01, 2017
• Effective date (End): July 31, 2022
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Fabio Cardoso Cruz
• Grantee: Caroline Riberti Zaniboni
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 13/24986-2 - The role of neuronal ensembles in context-induced reinstatement of ethanol seeking: pharmacogenetic, optogenetic and molecular investigation, AP.JP
• Associated scholarship(s): 19/13128-1 - Alcohol and the gut-brain axis: investigating post ingestive and gustatory effects on the striatum, BE.EP.DR

Abstract

Alcohol addiction is a complex behavioral phenomenon and is considered a world health problem. High rate of relapse is observed in alcohol addiction. One of the main problems for treating ethanol addiction is high rates of relapse to drug use. In human addicts, environmental stimuli previously associated with drug use can evoke relapse to drug after prolonged abstinence. Learned associations play an important role in addiction. With repeated drug use, addicts learn to associate drug effects with stimuli or cues in the drug environment, such as drug paraphernalia, context, and people. Over time, these cues can promote drug craving and relapse. These drug-related cues are complex combinations of different stimuli that are recognized with a high degree of resolution. Thus, any neural mechanism capable of encoding these learned associations must have a comparably high degree of resolution. We hypothesize that these strongly activated patterns of neurons, in nucleus accumbens direct and indirect pathways form neuronal ensembles that encode learned associations between alcohol effects and environmental cues associated with these effects. Many laboratories model drug relapse in rodents using a context-induced reinstatement procedure. In this procedure, rodents learn to associate particular contexts with drug-taking. At a later time, investigators can re-expose rodents to the drug-associated context and examine its effects on relapse to drug seeking. We will investigate whether context-induced reinstatement of alcohol seeking is mediated by projections from nucleus accumbens to substantia nigra pars reticulate and projections from nucleus accumbens to ventral pallidus globus and we will look for unique molecular alterations in these synapses, which could be involved with this behavior. For that we will train rats to self-administer ethanol in context A and extinguished lever pressing in a distinct context B. On test day, the context-induced reinstatement of ethanol seeking will be tested putting the rats back in the ethanol context (A). To assess a causal role for neural ensembles in these pathways in context-induced reinstatement, we will use imunohistochemistry, immunofluorescence and disconnection manipulation (ipsilateral versus contralateral injections). Next, we will use a procedure that uses flow citometry to analyze behaviorally activated synaptoneurosomes (preparation which contain the presynaptic terminal attached to post-synaptic density) in order to identify unique molecular alterations that are distinct from those in non-activated synapses. We hope that our preclinical procedure for context-induced reinstatement could find new targets for ethanol relapse treatment.