Levetiracetam Attenuates Adolescent Stress-induced Behavioral and Electrophysiological Changes Associated With Schizophrenia in Adult Rats

Author(s)

Cavichioli, Andreza M. ; Santos-Silva, Thamyris ; Grace, Anthony A. ; Guimaraes, Francisco S. ; Gomes, Felipe, V

• Document type: Journal article
• Source: SCHIZOPHRENIA BULLETIN; v. 49, n. 1, p. 10-pg., 2022-08-21.

Abstract

Background and Hypothesis Stress during adolescence is a major risk factor for schizophrenia. We have found previously in rats that adolescent stress caused, in adulthood, behavioral changes and enhanced ventral tegmental area (VTA) dopamine system activity, which were associated with dysregulation of the excitatory-inhibitory (E/I) balance in the ventral hippocampus (vHip). Levetiracetam, an anticonvulsant drug, regulates the release of neurotransmitters, including glutamate, via SV2A inhibition. It also modulates parvalbumin interneuron activity via Kv3.1 channels. Therefore, levetiracetam could ameliorate deficits in the E/I balance. We tested whether levetiracetam attenuate the adolescent stress-induced behavioral changes, vHip hyperactivity, and enhanced VTA dopamine system activity in adult rats. Study Design Male Sprague-Dawley rats were subjected to a combination of daily footshock (postnatal day [PD] 31-40), and three 1 h-restraint stress sessions (at PD31, 32, and 40). In adulthood (PD62), animals were tested for anxiety responses (elevated plus-maze and light-dark box), social interaction, and cognitive function (novel object recognition test). The activity of vHip pyramidal neurons and VTA dopamine neurons was also recorded. Study Results Adolescent stress produced anxiety-like responses and impaired sociability and cognitive function. Levetiracetam (10 mg/kg) reversed these changes. Levetiracetam also reversed the increased VTA dopamine neuron population activity and the enhanced firing rate of vHip pyramidal neurons induced by adolescent stress. Conclusions These findings suggest that levetiracetam attenuates the adverse outcomes associated with schizophrenia caused by stress during adolescence. (AU)

• FAPESP's process: 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
• Grantee: Felipe Villela Gomes
• Support Opportunities: Research Grants - Young Investigators Grants
• 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