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Reduced isolation-induced aggressiveness in mice following NAALADase inhibition

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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-α-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.

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Acknowledgements

Research was supported by DAMD-17-98-1-8634 to J.L. Meyerhoff, and DAMD-17-0041 between Guilford Pharmaceuticals Inc. and WRAIR. The views of the authors do not purport to reflect the position of the Department of the Army or the Department of Defense (paragraph 4-3), AR 360-5.

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Authors and Affiliations

  1. Department of Neurochemistry and Neuroendocrinology, Division of Neurosciences, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA

    L. A. Lumley, C. L. Robison, M. Dawood & J. L. Meyerhoff

  2. Guilford Pharmaceuticals Inc., Baltimore, MD, 21224, USA

    B. S. Slusher & K. Wozniak

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  1. L. A. Lumley
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  2. C. L. Robison
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  3. B. S. Slusher
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  4. K. Wozniak
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  5. M. Dawood
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  6. J. L. Meyerhoff
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Correspondence to L. A. Lumley.

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Lumley, L.A., Robison, C.L., Slusher, B.S. et al. Reduced isolation-induced aggressiveness in mice following NAALADase inhibition. Psychopharmacology 171, 375–381 (2004). https://doi.org/10.1007/s00213-003-1610-z

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  • DOI: https://doi.org/10.1007/s00213-003-1610-z

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