EXPLORING THE USE OF KETAMINE AS A THERAPEUTIC STRATEGY FOR ALCOHOL USE DISORDER: MOLECULAR, NEURAL NETWORK, AND BEHAVIORAL ANALYSIS

• Grant number: 24/17960-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2025
• End date: February 28, 2027
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Fabio Cardoso Cruz
• Grantee: Rafaella Valete Nunes Paiva
• 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

Abstract

Ethanol use disorder is a major public health problem in Brazil and worldwide. The social and economic losses and costs are extremely high. The complications related to this disorder not only affect the dependent individual but also the entire community, including family members and victims of violence and accidents. Although relevant, the treatments currently used are not fully effective, as about 80-95% of patients relapse into using this substance. One of the neurobiological theories on substance dependence proposes that addiction involves associative learning behaviors, where, with repeated use of the substance of abuse, the individual associates the drug's effect with stimuli or cues from the environment where the substance is being consumed. Over time, merely being exposed to these environmental cues could trigger cravings and lead the individual to relapse into drug use. Recent studies have shown that these associations are stored by small, selectively activated neural groups distributed across different brain regions and interconnected through strong synapses, known as neuronal ensembles. The formation of these associations would involve neural plasticity in 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 could effectively and permanently remodel maladaptive memories, such as those related to drug use, by rewriting the original appetitive information so that the responses associated with these pathological memories are no longer expressed. Although the results of treating psychiatric disorders with ketamine are very promising, its effects on attenuating pathological memories, as well as the mechanisms underlying such effects, remain unknown. Thus, in the present study, we will investigate the pharmacological mechanisms involved in ketamine's action on ethanol dependence-related memories in mice. To achieve this, we divided this project into three major areas: (I) we will analyze the behavioral effects of ketamine on the processes of reconsolidation and extinction of ethanol administration-related memories; (II) we will trace, in the neuronal ensembles, the gene expression profile induced by ketamine through 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. We propose that ketamine induces a state of high plasticity, modulating the addiction-related engram and thus acting by attenuating/modifying the physical representation of such memories. This approach opens a window of opportunity to modify pathological memories using ketamine, in addition to understanding the mechanisms behind ketamine's therapeutic effects. This work will provide valuable insights for future protocols and treatments of ethanol use disorder. (AU)