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Context-Specific Tolerance and Pharmacological Changes in the Infralimbic Cortex-Nucleus Accumbens Shell Pathway Evoked by Ketamine

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Abstract

Like other drugs, ketamine is abused due to its ability to act as a positive reinforcer in the control of behavior, just as natural reinforcers do. Besides, through Pavlovian conditioning, tolerance to drug effects can become conditioned to specific contextual cues showing that environmental stimuli can act as powerful mediators of craving and relapse. In the present study, we shall investigate the effects of long-term ketamine administration and withdrawal on behavioral measures and emotionality, the drug-context-specific influence on the tolerance to the sedative effects of an anesthetic dose of ketamine, and the neuropharmacological events underlying this phenomenon, in rats conditioned with 10 mg/kg of ketamine and later challenged with a dose of ketamine of 80 mg/kg in a familiar and non-familiar environment. Variations in dopamine and serotonin efflux in the infralimbic cortex-nucleus accumbens shell circuitry (IL-NAcSh) was further recorded in the same conditions. Our results highlight that besides its well-known reinforcing properties, ketamine also shares the ability to induce behavioral and pharmacological conditioned tolerance, associated with increases in cortical (IL), and decreases in striatal (NAcSh) dopamine release. To our knowledge, we are presenting the first set of behavioral and neurochemical data showing that, like other drugs of abuse, ketamine can induce learned context-specific tolerance.

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Acknowledgements

This work was supported by FAPESP (Proc. no. 2014/23690-5, 2017/18268-0). M.J. Nobre is the recipient of a Productivity Research Grant from CNPq (303144/2015-7). G.K. Silva- Cardoso holds a master scholarship from FAPESP (2015/17568-5). We declare that the sponsors have not been involved in or influenced the design, collection, analysis, or interpretation of study data, nor the writing of the report or the decision to submit it for publication. Moreover, the authors declare that they have no known competing for financial interest or personal relationships that could have appeared to influence the work reported in this paper.

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  1. Departamento de Psicologia, Uni-FACEF, Franca, SP, 14401-135, Brasil

    Manoel Jorge Nobre

  2. Laboratório de Psicobiologia, Departamento de Psicologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo (USP), Av. Bandeirantes, 3900, Ribeirão Preto, SP, 14040-901, Brasil

    Gleice Kelli Silva-Cardoso & Manoel Jorge Nobre

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Silva-Cardoso, G.K., Nobre, M.J. Context-Specific Tolerance and Pharmacological Changes in the Infralimbic Cortex-Nucleus Accumbens Shell Pathway Evoked by Ketamine. Neurochem Res 46, 1686–1700 (2021). https://doi.org/10.1007/s11064-021-03300-6

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