Reduced isolation-induced aggressiveness in mice following NAALADase inhibition

L. A. Lumley, C. L. Robison, Barbara Slusher, K. Wozniak, M. Dawood, J. L. Meyerhoff

Research output: Contribution to journalArticle

Abstract

Rationale: Long-term individual housing increases aggressive behavior in mice, a condition termed isolation-induced aggression; this aggressiveness is reduced by some antidepressants and anxiolytics. NMDA antagonists also inhibit isolation-induced aggression in mice. The enzyme N-acetylated-a-linked acidic dipeptidase (NAALADase) hydrolyzes the neurotransmitter N- acetylaspartylglutamate (NAAG) to form glutamate and N-acetylaspartate; NAAG acts as a partial NMDA agonist as well as a full agonist at the presynaptic metabotropic glutamate receptor 3 (mGluR3), where it acts to reduce glutamate release. Objective: We postulated that NAALADase inhibition would reduce isolation-induced aggression in mice. Methods: We tested whether acute exposure to the NAALADase inhibitor 2-[[hydroxy[2,3,4,5,6-pentafluorophenyl)methyl] phosphinyl]methyl] pentanedioic acid (GPI-5232), administered 30 min prior to a social interaction test, would inhibit aggressive behavior in SJL mice that had been individually housed long term. Results: Administration of GPI-5232 (30 mg/kg, IP) inhibited initiation of aggressive behavior, indicated by greater latencies to display tail-rattling, attack and biting, and by fewer mice initiating aggressive behavior, compared to mice that received vehicle. In addition, GPI-5232 treated mice had fewer tail-rattling responses to a non-aggressive conspecific. Conclusions: The effectiveness of GPI-5232 in this animal model suggests that NAALADase inhibition may be a novel therapeutic approach to reduce or inhibit heightened aggressiveness, and possibly to treat aggressive behavior associated with psychiatric disorders.

Original languageEnglish (US)
Pages (from-to)375-381
Number of pages7
JournalPsychopharmacology
Volume171
Issue number4
DOIs
StatePublished - Feb 2004
Externally publishedYes

Fingerprint

Aggression
N-Methylaspartate
Tail
Glutamic Acid
Anti-Anxiety Agents
Interpersonal Relations
Inhibition (Psychology)
dipeptidase
Antidepressive Agents
Neurotransmitter Agents
Psychiatry
Animal Models
Acids
Enzymes
N-acetyl-1-aspartylglutamic acid
Therapeutics

Keywords

  • Aggression
  • Aggressive behavior
  • Glutamate
  • Isolation
  • Mice
  • NAAG
  • NAALADase

ASJC Scopus subject areas

  • Pharmacology

Cite this

Lumley, L. A., Robison, C. L., Slusher, B., Wozniak, K., Dawood, M., & Meyerhoff, J. L. (2004). Reduced isolation-induced aggressiveness in mice following NAALADase inhibition. Psychopharmacology, 171(4), 375-381. https://doi.org/10.1007/s00213-003-1610-z

Reduced isolation-induced aggressiveness in mice following NAALADase inhibition. / Lumley, L. A.; Robison, C. L.; Slusher, Barbara; Wozniak, K.; Dawood, M.; Meyerhoff, J. L.

In: Psychopharmacology, Vol. 171, No. 4, 02.2004, p. 375-381.

Research output: Contribution to journalArticle

Lumley, LA, Robison, CL, Slusher, B, Wozniak, K, Dawood, M & Meyerhoff, JL 2004, 'Reduced isolation-induced aggressiveness in mice following NAALADase inhibition', Psychopharmacology, vol. 171, no. 4, pp. 375-381. https://doi.org/10.1007/s00213-003-1610-z
Lumley, L. A. ; Robison, C. L. ; Slusher, Barbara ; Wozniak, K. ; Dawood, M. ; Meyerhoff, J. L. / Reduced isolation-induced aggressiveness in mice following NAALADase inhibition. In: Psychopharmacology. 2004 ; Vol. 171, No. 4. pp. 375-381.
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