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NMDA receptor antagonism: escalation of aggressive behavior in alcohol-drinking mice

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Abstract

Rationale

Memantine is a potential treatment for alcoholic patients, yet few studies investigate the effect of concurrent treatment with memantine and ethanol on aggression. We evaluated aggressive behavior following ethanol consumption and treatment with glutamatergic drugs to characterize interactions between these compounds.

Objective

This study aimed to use rodent models of aggression to examine interactions between glutamatergic compounds and ethanol.

Materials and methods

Once male CFW mice reliably self-administered 1 g/kg ethanol or water, they were assessed for aggression in resident–intruder confrontations. Alternatively, aggression was evaluated following a social-instigation procedure. Animals were then injected with memantine, ketamine, neramexane, MTEP, or LY379268 before aggressive confrontations. Effects of the pharmacological manipulations on salient aggressive and non-aggressive behaviors were analyzed.

Results

Moderate doses of memantine, neramexane, and MTEP interacted with ethanol to increase the frequency of attack bites while ketamine did not. The highest dose of LY379268, an mGluR2/3 agonist, reduced both aggressive and non-aggressive behaviors after water and ethanol self-administration. Attack bites increased with social instigation and decreased with administration of high doses of MTEP and LY379268. Memantine and MTEP both reduced attack bite frequency in the instigation condition without reducing locomotor behavior.

Conclusions

Memantine and neramexane interacted with ethanol to heighten aggression. The binding characteristics of these compounds allow for ‘partial trapping’ by which some NMDARs are unblocked between depolarizations. We propose that this feature may contribute to the differential aggression-heightening interactions between these compounds and ethanol. MTEP also interacted with ethanol to escalate aggression, possibly through inhibition of mGluR5 modulation of NMDARs.

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Acknowledgments

Special thanks to Keisha Dodman, Georgia Gunner, Nishani Hewage, Lara Hwa, Tom Sopko, and Kate Woodard for their expert and dedicated assistance.

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Authors and Affiliations

  1. Psychology Department, Tufts University, Medford, MA, 02155, USA

    Emily L. Newman, Adam Chu, Brittany Bahamón, Joseph F. DeBold & Klaus A. Miczek

  2. National Institute of Genetics, Michima City, Japan

    Aki Takahashi

  3. Neuroscience Department, Tufts University, Boston, MA, 02111, USA

    Klaus A. Miczek

  4. Tufts University, 530 Boston Avenue (Bacon Hall), Medford, MA, 02155, USA

    Klaus A. Miczek

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  1. Emily L. Newman
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  2. Adam Chu
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  3. Brittany Bahamón
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  4. Aki Takahashi
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  5. Joseph F. DeBold
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  6. Klaus A. Miczek
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Correspondence to Klaus A. Miczek.

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Funded by National Institute on Alcoholism and Alcohol Abuse AA013983.

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Newman, E.L., Chu, A., Bahamón, B. et al. NMDA receptor antagonism: escalation of aggressive behavior in alcohol-drinking mice. Psychopharmacology 224, 167–177 (2012). https://doi.org/10.1007/s00213-012-2734-9

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