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Suppression of Methamphetamine Self-Administration by Ketamine Pre-treatment Is Absent in the Methylazoxymethanol (MAM) Rat Model of Schizophrenia

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Abstract

Ketamine may prove to be a potential candidate in treating the widespread drug addiction/substance abuse epidemic among patients with schizophrenia. Clinical studies have shown ketamine to reduce cocaine and heroin cravings. However, the use of ketamine remains controversial as it may exacerbate the symptoms of schizophrenia. Therefore, the aim of this study is to characterize the effects of ketamine on drug addiction in schizophrenia using the methylazoxymethanol (MAM) acetate rat model on operant IV methamphetamine (METH) self-administration. MAM was administered intraperitoneally (22 mg/kg) on gestational day 17. Locomotor activity test and later IV self-administration (IVSA) were then performed in the male offspring followed by a period of forced abstinence and relapse of METH taking. After reaching stable intakes in the relapse phase, ketamine (5 mg/kg) was administered intraperitoneally 30 min prior to the self-administration session. As documented previously, the MAM rats showed a lack of habituation in the locomotor activity test but developed stable maintenance of METH self-administration with no difference in operant behaviour to control animals. Results show that ketamine treatment significantly reduced the METH intake in the control animals but not in MAM animals. Ketamine effect on METH self-administration may be explained by increased glutamatergic signalling in the prefrontal cortex caused by the N-methyl-D-aspartate antagonism and disinhibition of GABA interneurons which was shown to be impaired in the MAM rats. This mechanism may at least partly explain the clinically proven anti-craving potential of ketamine and allow development of more specific anti-craving medications with fewer risks.

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Acknowledgements

This work was supported by project No. 3SGA5789 financed from the SoMoPro II Programme that has acquired a financial grant from the People Programme (Marie Curie Action) of the Seventh Framework Programme of EU according to the REA Grant Agreement No. 291782 and was further co-financed by the South-Moravian Region. This publication reflects only the author’s views and the Union is not liable for any use that may be made of the information contained therein. This research was also carried out under the project CEITEC 2020 (LQ1601) with financial support from the Ministry of Education, Youth and Sports of the Czech Republic under the National Sustainability Programme II and with the support of the Specific University Research Grant “Experimental and translational pharmacological research and development” number MUNI/A/1063/2016 with the support of the Specific University Research Grant, as provided by the Ministry of Education, Youth and Sports of the Czech Republic in the year 2017. Further support was provided by funds from the Faculty of Medicine MU to junior researcher Jana Ruda-Kucerova. The authors are grateful to Jaroslav Nadenicek for support in behavioural testing and excellent animal care. The language corrections were kindly done by Tony Fong (University of Waterloo, Ontario, Canada).

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Ruda-Kucerova, J., Babinska, Z., Stark, T. et al. Suppression of Methamphetamine Self-Administration by Ketamine Pre-treatment Is Absent in the Methylazoxymethanol (MAM) Rat Model of Schizophrenia. Neurotox Res 32, 121–133 (2017). https://doi.org/10.1007/s12640-017-9718-9

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