Name: Gabriela Pandini Silote
Type: MSc dissertation
Publication date: 06/04/2016

Namesort descending Role
Vanessa Beijamini Harres Advisor *

Examining board:

Namesort descending Role
Luiz Carlos Schenberg Internal Examiner *
Sara Cristina Hott External Examiner *
Vanessa Beijamini Harres Advisor *

Summary: Ketamine is a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptor. Preclinical and clinical studies have suggested that ketamine has a rapid and relatively sustained antidepressant effect. The mechanism of action involved in this effect appears to be more complex than simply blocking NMDA receptors, involving the activation of α-amino-3-hydroxy-5-methylisoxazole-4- propionic acid (AMPA) receptors and brain derived neurotrophic factor (BDNF) signaling pathway and its receptor, tropomyosin-related kinase B (TrκB). Several antidepressants are effective in treating generalized anxiety disorder (GAD) and panic disorder (PD) only after chronic treatment, it is possible that ketamine may also exhibit a rapid and sustained anxiolytic or panicolytic effect. The elevated T maze (ETM) is an animal model for assessing in the same procedure, two types of anxiety: learned anxiety (inhibitory avoidance), related to the GAD, and innate anxiety (escape) related to PD. The aim of the study was to investigate the behavioral effects induced by ketamine in rats exposed to ETM, and the possible involvement of BDNF/TrκB signaling pathway in PAG on these effects. The results showed that ketamine (10 and 30 mg/kg) administered acutely did not change the behavior of rats on ETM. The anesthetic dose (80 mg/Kg), impaired the escape 1, which may suggest rapid panicolytic-like effect. When the ketamine 10mg/kg was administered 24 hours before the ETM, facilitated escape 1, which may suggest delayed panicogeniclike effect. The anesthetic dose of ketamine given 24 hours before test, facilitated avoidance, which suggests a late anxiogenic-like effect, at the same time, impaired escape 1, that suggest a sustained panicolytic-like effect. MK- 801 (0.05 mg/kg) 24 hours before the test did not change the behavior of the animals. When ketamine was administered directly into DPAG (dorsal periaqueductal grey matter) was observed that only the lowest dose (2µg) facilitated escape 1, which features a rapid panicogenic-like effect. Moreover, none of the administration schedules and doses used altered animals’ locomotor activity on the open field test. To investigate the involvement of the BDNF/TrκB signaling pathway in the effects of ketamine and MK-801 on anxiety on the ETM, tests were performed to quantify total TrκB and phosphorylated in the tyrosine 706/707 and 515 residues in rats’ PAG. Ketamine 80mg/kg and MK-801 0.05mg/kg administered acutely previously to collecting/heaping the PAG did not induce statistically significant change in the amount of pTrκB residues Y-706/707 and Y-515. The results showed that the ketamine 10 and 80 mg/kg, administered approximately 24 hours before to collecting/heaping of PAG, did not induce statistically significant change in the quantity of pTrκB Y- 706/707 and Y-515 residue. In conclusion, the results show that ketamine may have a slight effect in panic, but this effect depends on both the dose and the administration schedule. Even, at least the panicogenic effect of ketamine appears to involve the MCPD.

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