Abstract
Rationale
Disrupted social behavior, including occasional aggressive outbursts, is characteristic of withdrawal from long-term alcohol (EtOH) use. Heavy EtOH use and exaggerated responses during withdrawal may be treated using glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonists.
Objectives
The current experiments explore aggression and medial prefrontal cortex (mPFC) glutamate as consequences of withdrawal from intermittent access to EtOH and changes in aggression and mPFC glutamate caused by NMDAR antagonists memantine and ketamine.
Methods
Swiss male mice underwent withdrawal following 1–8 weeks of intermittent access to 20 % EtOH. Aggressive and nonaggressive behaviors with a conspecific were measured 6–8 h into EtOH withdrawal after memantine or ketamine (0–30 mg/kg, i.p.) administration. In separate mice, extracellular mPFC glutamate after memantine was measured during withdrawal using in vivo microdialysis.
Results
At 6–8 h withdrawal from EtOH, mice exhibited more convulsions and aggression and decreased social contact compared to age-matched water controls. Memantine, but not ketamine, increased withdrawal aggression at the 5-mg/kg dose in mice with a history of 8 weeks of EtOH but not 1 or 4 weeks of EtOH or in water drinkers. Tonic mPFC glutamate was higher during withdrawal after 8 weeks of EtOH compared to 1 week of EtOH or 8 weeks of water. Five milligrams per kilogram of memantine increased glutamate in 8-week EtOH mice, but also in 1-week EtOH and water drinkers.
Conclusions
These studies reveal aggressive behavior as a novel symptom of EtOH withdrawal in outbred mice and confirm a role of NMDARs during withdrawal aggression and for disrupted social behavior.
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Acknowledgments
This research was supported by NIH grants R01 AA013983 (KAM) and F31 AA021622 (LSH). The authors would like to acknowledge Justin Choi and Alexandra Kiesling for their behavioral research as well as Dr. Lucas Albrechet-Souza for assistance with histology.
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The authors declare no conflicts of interest.
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Hwa, L.S., Nathanson, A.J., Shimamoto, A. et al. Aggression and increased glutamate in the mPFC during withdrawal from intermittent alcohol in outbred mice. Psychopharmacology 232, 2889–2902 (2015). https://doi.org/10.1007/s00213-015-3925-y
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DOI: https://doi.org/10.1007/s00213-015-3925-y