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The majority of patients with Alzheimer's disease (AD) and other forms of senile dementia display various psychiatric symptoms, such as aggression, agitation, irritability, and hallucinations at some point during the course of their illness. These are collectively known as the behavioral and psychological symptoms of dementia (BPSD). The BPSD are a major cause of distress to family members and caregivers. 1) Furthermore, the presence of BPSD may have a negative impact on the course of the disease.2,3) Atypical antipsychotics are often chosen to treat BPSD, such as psychosis, aggression, and agitation, in patients with dementia. 4) However, effective drug therapy for BPSD has not been established. Recently, the traditional Japanese medicine Yokukansan (YKS, Yi-gan san in Chinese) has been demonstrated to improve BPSD, such as aggression, agitation, irritability, and hallucinations, in a randomized, single-blind, placebo-controlled study.5) However, the psychopharmacologic effects of YKS remain unexplored.The aggressive behavior of animals can be influenced by stress such as social isolation. For example, mouse-killing behavior (muricide) is induced in male Wistar rats by chronic isolation.6) The social isolation also induces aggression in male mice. 7,8) Moreover, supine restraint stress induces aggression, which is expressed as biting a wooden stick. 9)N-Methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine (PCP) and MK-801, have been used as pharmacologic models of schizophrenia. NMDA receptor antagonists produce positive, negative and disorganization symptoms of schizophrenia in healthy individuals.10) In rodents, NMDA receptor blockers induce hyperlocomotion. 11)On the other hand, methamphetamine-induced hyperlocomotion has been used as a classic dopaminergic model for the identification of antipsychotics.In the present study, we investigated the effect of YKS on social isolation-induced aggressive behavior and methamphetamine-or MK-801-induced hyperlocomotion in rodents. MATERIALS AND METHODSAnimals Naïve 7-week-old male Wistar rats and 5-week-old male ddY mice were obtained from Kyudo, Saga, Japan. Animals were housed either in social isolation (1 rat per cage) or in social groups (5 rats per cage) for 11-13 weeks prior to rat behavioral testing, and in groups of 5 per cage for 1-2 weeks for mice, under standardized lighting conditions (lights on 07:00-19:00) at a constant temperature (23Ϯ2°C) with food and water available ad libitum. All procedures regarding animal care and use were performed in compliance with the regulations established by the Experimental Animal Care and Use Committee of Fukuoka University.Drugs YKS (Tsumura & Co., Tokyo, Japan) was dissolved in distilled water. Quetiapine (AstraZeneca, Wilmington, DE, U.S.A.) was suspended in 0.5% CMC-Na. Methamphetamine (Dainippon Pharmaceutical Co., Ltd., Osaka, Japan), MK-801 (Research Biochemicals Inc., Natick, MA, U.S.A.), and risperidone (Janssen Research Foundation, Beerse, Belgium) were dissolved in saline. YKS, quetiapine, and ...

These results suggest that GABAergic mechanism is involved in marble-burying behavior, and that valproate, carbamazepine and lamotrigine reduce marble-burying behavior. Moreover, valproate reduces marble-burying behavior via a GABA(A) receptor-dependent mechanism.

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Abstract. In the present study, we examined the effect of N-acetyl-L-cysteine (NAC), a glutamate-modulating agent, on marble-burying behavior in mice. Fluvoxamine (30 mg/kg, p.o.) and mirtazapine (3 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity. Similarity, NAC (150 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity. On the other hand, the antioxidant α-tocopherol (10, 30, and 100 mg/kg, p.o.) had no effect on the marble-burying behavior. These results suggest that the glutamatergic system is involved in the marble-burying behavior, and NAC may be useful for treatment of OCD.