Effects of levetiracetam on behavioral e electrophysiological changes resembling schizophrenia induced by adolescent stress

Author(s)

Andreza Manzato Cavichioli

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2022-02-17

Examining board members

Felipe Villela Gomes; Fabrício de Araújo Moreira; Fernando Eduardo Padovan Neto

• Advisor: Felipe Villela Gomes

Abstract

Introduction: among all psychiatric disorders, schizophrenia is considered the most disabling. It is known that socioenvironmental risk factors, such as stress, play a critical role in schizophrenia development. Studies indicate that the exposure to stress during critical periods of development, such as adolescence, results in a hyperdopaminergic state indicated by an increased activity of the dopaminergic system in the ventral tegmental area (VTA) similar to what is seen in schizophrenia patients and animal models for the study of this disorder. As in animal models and suggested to occur in patients with schizophrenia, the adolescent stress-induced hyperdopaminergic state was associated with a dysfunction in the excitatory-inhibitory (E/I) balance in the ventral hippocampus (VH), with functional loss of parvalbumin (PV)-containing interneurons GABAergic e increase in the activity of pyramidal glutamatergic neurons. Thus, drugs that act through the modulation of the E/I balance have emerged as interesting pharmacological tools for the treatment of disorders associated with E/I balance impairments. Levetiracetam, an anticonvulsant, seems to be capable of modulating the E/I balance through the modulation of the synaptic protein SV2A, regulating the release of neurotransmitters such as GABA and glutamate, and Kv3.1 potassium channels that are crucial for the activity of PV interneurons. Thus, we hypothesize that the acute treatment with levetiracetam in adult animals attenuates deficits in the E/I balance e, consequently, behavioral e electrophysiological changes induced by stress in adolescence. Aims: To assess whether treatment with levetiracetam in adulthood attenuates behavioral changes e hyperactivity of pyramidal neurons in VH e dopaminergic neurons in VTA induced by adolescent stress. Methods: Male Sprague-Dawley rats were submitted to a stress protocol between postnatal days (PND) 31 e 40, a period corresponding to adolescence. When they reached adulthood (PND 65), the animals were submitted to the following behavioral tests: experimental block 1 of experiments - elevated plus-maze (EPM), object recognition (NOR) and locomotor response to amphetamine (LRA); block 2 of experiments - light-dark test (LD) and social interaction (SI). One week later, the animals were submitted to in vivo electrophysiological recordings of VTA dopaminergic neurons. In a third block of experiments, the in vivo electrophysiological recording of pyramidal neurons e interneurons in the VH was performed. The animals received 10 mg/kg (i.p) of levetiracetam or saline 30 minutes before each behavioral test e electrophysiological recordings. Results: Stress during adolescence decreases exploration of animals in the EPM, caused an anxiety-like effect in the LD test, decreased interaction time in the SI test and also resulted in cognitive impairments in the NOR test. Acute treatment with levetiracetam attenuated/reversed all these behavioral deficits, except for the changes in the EPM. Stress during adolescence did not change LRA, but, unexpectedly, we observed an increased locomotor response to amphetamine in stressed animals treated with levetiracetam. Electrophysiological recordings indicated that stress during adolescence led to an increase in the firing rate of pyramidal neurons in the VH, as well as an increase in the number of spontaneously active dopaminergic neurons in the VTA. Levetiracetam treatment reversed the hyperactivity of both pyramidal and dopaminergic neurons. Furthermore, treatment with levetiracetam also increased the firing rate of GABAergic interneurons in the VH of stressed animals compared to saline-treated stressed animals. Conclusion: These findings suggest that levetiracetam attenuates behavioral and electrophysiological changes related to schizophrenia in the adult animal that were induced by exposure to stress during adolescence. (AU)

• FAPESP's process: 20/04241-6 - Kv3.1 channel as a new target for schizophrenia treatment
• Grantee: Andreza Manzato Cavichioli
• Support Opportunities: Scholarships in Brazil - Master