Behavioral and neurochemical changes in subcortical systems underlying the context-dependent tolerance expression induced by the dissociative anesthetic ketamine

Author(s)

Gleice Kelli Ribeiro da Silva Cardoso

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (PCARP/BC)
• Defense date: 2017-10-20

Examining board members

Manoel Jorge Nobre do Espírito Santo; Norberto Cysne Coimbra; Julia Maria dos Santos; Renata Ferreira Sgobbi

• Advisor: Manoel Jorge Nobre do Espírito Santo

Abstract

The anesthetic ketamine, widely consumed by young club and rave people in, has a strong dissociative effect, which is one reason for its use. Despite this, little is known about its reinforcing effects as well as the result of discontinuation of its consumption after chronic ingestion. Ingested continuously shows tolerance to the sedative effect. Based on previous preclinical and clinical studies that describe the ability of ketamine to induce relaxation and euphoria, despite its well-known sedative effect, that the hypothesis that ketamine tolerance, even at higher doses, will emerge,and it will be noted strengthening effect of the drug. This study aimed to determine whether the sedative effects of ketamine can be conditioned to environmental cues such as other drugs of abuse. We evaluated the effects of staggered doses of chronic ketamine administration on the motor and emotional reactivity of rats. We also investigated the existence of context-induced conditioned tolerance in previously treated rats. The analysis of the effects of ketamine on motor and emotional behavior was performed with the use of an open field (e-activity monitor). The animals received a single daily injection of ketamine or placebo for 14 days at different doses (10, 20, 40 and 80 mg / kg). For the place-based preference protocol, the animals were submitted to a baseline of three consecutive sessions with free access to a box of two contexts, and were conditioned in the context that presented the shorter residence time for 4 days for 1 hour, receiving a Daily injection of placebo or ketamine (10, 20, 40, and 80 mg / kg), the test was performed after drug-free treatment for drug-boosted / aversion assessment paired with contextual clues. For the conditioned tolerance protocol the animals were submitted to a dose of ketamine or placebo (10 mg / kg, 1x day) for 4 days and then tested. Two visual and tactile differentiated chambers were used, the conditioning chamber and the test chamber. The analysis of the changes promoted by the drug in the behavioral reactivity of the animals was performed using an open field (electronic activity monitor) in different contexts, after the administration of an overdose (80 m / kg). Therefore the experimental groups were divided into A x A or A x B. The changes induced by administration of the 10 mg / kg ketamine dose in the infra-limbic (IL) and nucleus accumbens shell (NAcSh) serotonergic and dopaminergic systems, Encephalic regions involved in the motivational aspects of drug use and abuse were evaluated using in vivo microdialysis and high pressure chromatography techniques. All experiments were conducted with the consent of CEUA (FFCLRP-USP, protocol 16.5.736.59.1). For data analysis, one or two-factor ANOVA was used, followed when necessary by the Tukey-HSD test, with p established at <0.05. The results indicate that similar to other drugs of abuse, we found an increased tolerance to contextual clue-induced sedative effects for ketamine. In addition, prolonged use of ketamine increases the time spent in the center of the monitor in a dose-dependent manner, a well-known measure of low reactivity behavior in rodents. This increase does not appear to be due to the sedative effects of ketamine, since immobility (time) has decreased as doses increase in the ketamine pretreated groups. In addition, the speed, distance traveled and ambulation did not differ in relation to the placebo group. The results also indicate the existence of conditioned tolerance to the sedative effects of ketamine without impairment of the motor response, as well as significant alterations in the dopamine and serotonin tonus that differ if the animals are tested during the effect or with 24 hours of abstinence. In conclusion, our study points to the anti-aversive effects of higher doses of ketamine. This effect appears to be accompanied by pharmacological tolerance to the sedative effects of ketamine which may help explain the use of higher doses of this drug for recreational purposes in humans. In this way, ketamine shares some common characteristics with other drugs of abuse, such as the installation of context-dependent tolerance and associated neurochemical changes (marked depression in AD and 5-HT levels in NAcSh) during exposure to a previously paired context With the effects of the drug. (AU)

• FAPESP's process: 15/17568-5 - Changes on cortical neurochemistry associated with the expression of contextual conditioned tolerance of rats submitted to chronic treatment with the dissociative anesthetic ketamine
• Grantee: Gleice Kelli Ribeiro da Silva Cardoso
• Support Opportunities: Scholarships in Brazil - Master