A participação dos receptores D2 e 5-HT2 e a influência do ambiente sobre a resposta locomotora induzida por cetamina

Abstract

Ketamine, a non-competitive NMDA receptor antagonist had its use restricted in human medicine because of its side effects attributed to subanesthetic doses. Currently, this drug is used as an experimental model of schizophrenia and also recreationally. Considering the contribution of behavioral sensitization to the study of antipsychotic effects and drug addiction, the present study was subdivided into 4 experiments. Experiment 1 (exp1) aimed to evaluate the development and expression of behavioral sensitization induced by subanesthetic doses (30 and 50 mg/kg) of ketamine. In experiments 2 and 3 (exp2 and exp3), the objectives were to investigate the role of the D2 and the 5-HT2 antagonists, raclopride and ketanserin, respectively. Finally, experiment 4 (exp4) aimed to evaluate the ability of ketamine to produce both conditioned and contextually sensitized locomotor responses. Initially, adult Swiss mice were submitted to 3 consecutive days of habituation in the open field for 60 (exp1) or 20 (exp2-3-4) minutes each day. After the habituation phase, each experiment followed its specific procedures. As for exp 1, seven consecutive days of exposure to 30 or 50 mg/kg ketamine demonstrated that 30 mg/kg produced the development of a sensitized locomotor response and, after 5 days of withdrawal, this same dose expressed a sensitized locomotor response. Based on these effects and on the lack of differences between males and females, for the next set of experiments we selected 30 mg/kg of ketamine to be administered in males. In exp2, 7 consecutive days of ketamine preceded by raclopride exposure indicated that the D2 blockade prevented both the development and expression of ketamine-induced behavioral sensitization, even in the absence of raclopride locomotor effects. Consistently, exp3 showed that the prevention of both responses occurred when ketamine was preceded by the 5-HT2 antagonist, ketanserin. Finally, in exp 4, the experimental protocol that included 7 consecutive days of injections unpaired and paired to the test environment demonstrated that ketamine paired to the open field produced a conditioned locomotor response following a challenge with saline, even after 2 days of ketamine withdrawal. In addition, it was shown that ketamine, when paired to the open field produced context-dependent behavioral sensitization. In summary, 30 mg/kg of ketamine developed and expressed a sensitized locomotor response, which was inhibited both by D2 and 5-HT2 antagonism. Interestingly the same dose interacted with environmental factors, resulting in a conditioned locomotor response and a context-dependent sensitization. Therefore, this study suggests a key role of both D2 and 5-HT2 receptors and the environmental context in the ketamine-induced behavioral sensitization.