Effects of GL-II-73, a positive allosteric modulator of alpha 5-containing GABAa receptors, on locomotor activity in mice

• Grant number: 23/10784-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: February 01, 2024
• End date: July 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Felipe Villela Gomes
• Grantee: Lucas Vieira Faria Machado
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 18/17597-3 - The impact of stress on the dopamine system depends on the state of the critical period of neuroplasticity: implications for depression and schizophrenia and for the study of new drug targets, AP.JP

Abstract

Evidence point to changes in the excitatory-inhibitory balance in different psychiatric disorders, such as depression, anxiety, and schizophrenia. This imbalance seems to result from the functional loss of GABAergic interneurons expressing parvalbumin in different brain regions, including the ventral hippocampus, leading to increased activity of glutamatergic pyramidal neurons. Thus, there is the possibility of using modulator drugs of this excitatory-inhibitory balance as a new form of treatment for psychiatric disorders. In this context, positive allosteric modulators of GABAA receptors containing the ±5 subunit (GABAA-±5) have gained prominence, given the relatively high and restricted presence of these receptors in glutamatergic neurons in the hippocampus, allowing the modulation of their activity in situations of imbalances in the excitatory-inhibitory balance. In this context, GL-II-73, a positive allosteric modulator of GABAA-±5 receptor, stands out, for studies in rodents conducted in our laboratory have indicated that this drug has potential anxiolytic, antidepressant, and antipsychotic effects. However, these effects were accompanied by an increase in locomotor activity. Thus, the objective of this project is to conduct an extensive analysis of the effects of GL-II-73 on locomotor activity. It will evaluate: 1) the locomotor effect of GL-II-73 in animals exposed to a novel environment and, 2) after habituation to this environment, 3) whether GL-II-73 promotes locomotor sensitization and alters hyperlocomotion induced by an NMDA receptor antagonist and amphetamine. Additionally, since increased psychomotor activity is associated with the potentiation of dopaminergic activity, it will be evaluated whether 5) GL-II-73 alters the activity of dopaminergic neurons in the ventral tegmental area through in vivo electrophysiology, and 6) whether the increase in locomotor activity induced by GL-II-73 involves the activation of D1 and D2 dopamine receptors. We expect to elucidate the effects of this new positive allosteric modulator of GABAA-±5 receptors on locomotor activity.