Reduced isolation-induced aggressiveness in mice following NAALADase inhibition.

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-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.

Accelerated Barnes maze test in mice for assessment of stress effects on memory.

Repeated restraint stress in rodents impairs spatial memory in a Y-maze test and induces hippocampal neuronal changes that last up to 5 d after the stressor ends. Our goal was to implement a Barnes maze spatial memory test in mice that could be used to validate our findings of social stress induced Y-maze impairment. We measured performance of mice in 5- and 9-day test paradigms previously used in rats and mice, respectively. Selecting features from each paradigm, we implemented a 5-d test (pre-training, training (4 trials/d/3 d) and probe testing for assessment of spatial memory in mice. Stress consisted of placing each test mouse in a stainless steel perforated box (25.5 cm x 21.5 cm x 16.5 cm) within an aggressor's home cage for 6 h/d for 21 d; direct agonistic encounters occurred randomly throughout stress periods. Barnes maze pre-training (habituation) was on day 21 of the stress exposures. In a preliminary experiment, mice that habituated following their last stressor performed poorly relative to unstressed and to those not habituated prior to the last stressor, as demonstrated by a greater latency to escape and more errors. We conclude that acute stress in a chronic stress paradigm may impair spatial memory acquisition.

A CRH1 antagonist into the amygdala of mice prevents defeat-induced defensive behavior.

Corticotropin-releasing hormone (CRH) is believed to play an important role in the regulation of behavioral responses to stress. CRH(1) receptor antagonists may reduce stress responsivity. Stress increases CRH in the amygdala, important in memory consolidation. We hypothesized that infusion of a CRH(1) antagonist into the amygdala following social defeat would prevent the development of generalized fear responses. Acute social defeat in mice increases defense towards intruders, even nonaggressive intruders, placed within their home cage. We infused the CRH(1) antagonist antalarmin (0.25 microg/125 nl) bilaterally into the amygdala of mice immediately after defeat and measured their response to a nonaggressive intruder stimulus mouse placed within their home cage 24 h after defeat. Defeated mice that received vehicle displayed high levels of crouch defensive posture and numerous flights from intruders, relative to nondefeated mice that received vehicle. Defeated mice that received antalarmin into the amygdala exhibited significantly less defensive posture than did vehicle-treated defeated mice. Display of defensive posture in antalarmin-treated mice approached that of vehicle-treated nondefeated mice. These findings support a role for CRH in the amygdala to promote consolidation of emotional memory and indicate that antagonism of CRH(1) receptors in the amygdala may prevent the development of exaggerated fear responses in stressed mice.

Vasopressin into the preoptic area increases grooming behavior in mice.

In mice, the neuropeptide arginine-8-vasopressin (AVP) induces excessive grooming, scratching, and hyperactivity when administered intracerebroventricularly. In hamsters, AVP infusion into the medial preoptic area/anterior hypothalamus (MPOA/AH) increases flank marking and flank mark grooming. We measured the behavioral effects of administration of AVP (0, 1, and 10 ng/250 nl) into the preoptic area (POA) of male C57BL/6 mice. Administration of AVP into the POA induced robust effects on grooming, including increased hindleg scratching and face washing. Rearing and olfactory investigation were inhibited by AVP into the POA. These findings indicate that the POA is one site in which AVP induces grooming behavior in mice.