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Study of the effects of pretreatment with canabidiol and the induction of post-discharge on single hippocampal synaptic plasticity changes produced by ketamine via CA1-mPFC in anesthetized rats in vivo

Grant number: 11/04467-5
Support type:Scholarships in Brazil - Master
Effective date (Start): August 01, 2011
Effective date (End): April 30, 2013
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:João Pereira Leite
Grantee:Matheus Teixeira Rossignoli
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Psychotic disorders affect about 20% of patients suffering from temporal lobe epilepsy (TLE) and are result of poorly understood dysfunction present in multiple levels of neurobiological organization. In experimental models, ministration of NMDA receptor antagonists such as ketamine (KET) generates clear changes in synaptic efficacy in CA1-medial prefrontal cortex (mPFC) pathway, and behavioral abnormalities, such as hyperlocomotion, working memory impairment and deficit in pre-pulse inhibition in acoustic startle response (PPI). Several studies related to psychiatric disorders in animal models and clinics point cannabidiol (CBD) as a possible antiepileptic, antipsychotic and anxiolytic. Moreover, the CBD appears to have an important role in circuits involving the mPFC, being able even to reverse hiperlocomotion generated by administration of KET in mice. The induction of a single post-discharge (AD) by high frequency electrical stimulation in the hippocampus produces behavioral abnormalities similar to those observed in rodents under the effect of KET. These data provide further evidence on a possible overlap between the neural circuits underlying the TLE and psychosis. Despite the evidence of these data, there are no studies reporting the possible modulation of the CBD, AD and KET on induction of short term synaptic plasticity under the model of paired-pulse facilitation by (PPF), and on the induction and maintenance of long-term potentiation (LTP) in CA1-mPFC pathway. Therefore, the objective of this project is to describe and compare the effects of treatment with KET, CBD and AD on: (1) the basal field post-synaptic potentials (fPSPs) mPFC evoked by electrical stimulation CA1, (2) synaptic plasticity (PPF and LTP models) induced on the same hippocampus-cortical projections, and (3) the local field potentials (LFPs) recorded simultaneously in the dorsal hippocampus and mPFC. Additionally, we test the hypothesis that pretreatment with CBD or AD could attenuate the previously described effects of KET on basal fPSPs CA1-mPFC pathway. All experiments will be performed in vivo with urethane anesthetized rats. It is expected that this project can contribute to a better understanding on the mechanisms involved in psychiatric comorbidity (especially psychosis) associated to TLE. Additionally, we intend to provide further evidence on the possible role of antipsychotic CBD and possible therapeutic properties of hippocampal AD when applied prior to treatment with KET (experimental model of psychosis). (AU)