Investigation of the Effects of Ketamine as a Promising Strategy for the Treatment of Alcohol Use Disorder: Behavioral Analysis and Molecular and Physiological Changes in Neuronal Ensembles.

• Grant number: 24/23801-3
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2025
• End date: April 30, 2027
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Fabio Cardoso Cruz
• Grantee: Fabio Cardoso Cruz
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Ethanol use disorder is a major public health problem in Brazil and worldwide, with high social and economic losses and costs. The complications related to this disorder affect not only the dependent individual but also the broader community, including family members. Although its relevance is evident, current treatments are not entirely effective, as approximately 80-90% of patients relapse into substance use. One neurobiological theory about substance use disorders suggests that addiction involves associative learning behaviors, where, with repeated substance use, individuals associate the drug's effects with environmental stimuli or cues where the substance is consumed. Over time, mere exposure to these environmental cues can trigger cravings and lead to relapse. Recent studies have shown that these associations are stored in small groups of selectively activated neurons, distributed across different brain regions and interconnected through strong synapses, known as neuronal ensembles. The formation of these associations involves neural plasticity at the synapses between neuronal ensembles. Numerous studies have demonstrated the therapeutic potential of ketamine in treating psychiatric disorders such as major depressive disorder, obsessive-compulsive disorder, depression, anxiety, and substance use disorders. Evidence suggests that ketamine may effectively and permanently remodel maladaptive memories, such as those related to drug use, rewriting the original appetitive information so that responses associated with these pathological memories are no longer expressed. While the results of ketamine treatment for psychiatric disorders are highly promising, its effects on the attenuation of pathological memories, as well as the underlying mechanisms, remain unclear. We propose that ketamine induces a state of heightened plasticity, modulating addiction-related engrams, thereby altering the physical representation of such memories. In the present study, we will investigate the pharmacological mechanisms involved in the action of ketamine on ethanol addiction-related memories in mice. To achieve this, we have divided the project into three main objectives: (I) We will analyze the behavioral effects of ketamine on the processes of reconsolidation and extinction of ethanol administration-related memories; (II) We will profile the gene expression induced by ketamine in neuronal ensembles using the technique of fluorescence-activated cell sorting (FACS) and qPCR; (III) We will analyze, in real-time, the activity of these specific neuronal groups under the action of ketamine using in vivo fiber photometry. This approach opens a therapeutic window for the use of ketamine in the reconsolidation of pathological memories or the acceleration of the extinction process of such memories, while also contributing to a better understanding of the mechanisms underlying its therapeutic effects. This work will provide valuable insights for future protocols and treatments for ethanol use disorder. (AU)