Reduced isolation-induced aggressiveness in mice following NAALADase inhibition.
BACKGROUND
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-alpha-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.
Lumley
L A
LA
Department of Neurochemistry and Neuroendocrinology, Division of Neurosciences, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. lucille.lumley@na.amedd.army.mil
Robison
C L
CL
Slusher
B S
BS
Wozniak
K
K
Dawood
M
M
Meyerhoff
J L
JL
D000374:Aggression / Q000187:drug effects* / Q000502:physiology / Q000523:psychology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005977:Glutarates / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012934:Social Isolation / Q000523:psychology*; D005464:Fluorobenzenes; D005466:Fluorocarbons
D004791:Enzyme Inhibitors; D043425:Glutamate Carboxypeptidase II; D005977:Glutarates; C436737:(2-((pentafluorophenylmethyl)hydroxyphosphinyl) methyl)pentanedioic acid; D005464:Fluorobenzenes; D005466:Fluorocarbons