title: Aggression and increased glutamate in the mPFC during withdrawal from intermittent alcohol in outbred mice.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Psychology, Tufts University, 530 Boston Avenue, Medford, MA, 02155, USA.
authors.forename: Lara S
authors.initials: LS
authors.lastname: Hwa
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Nathanson
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamoto
authors.forename: Jillian K
authors.initials: JK
authors.lastname: Tayeh
authors.forename: Allison R
authors.initials: AR
authors.lastname: Wilens
authors.forename: Elizabeth N
authors.initials: EN
authors.lastname: Holly
authors.forename: Emily L
authors.initials: EL
authors.lastname: Newman
authors.forename: Joseph F
authors.initials: JF
authors.lastname: DeBold
authors.forename: Klaus A
authors.initials: KA
authors.lastname: Miczek
mesh_terms: D000374:Aggression / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D000431:Ethanol / Q000009:adverse effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D008559:Memantine / Q000494:pharmacology; D051379:Mice; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012919:Social Behavior; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000523:psychology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D018698:Glutamic Acid; D007649:Ketamine; D008559:Memantine