Hisashi Kuribara

Accumulation of Filamentous Tau in the Cerebral Cortex of Human Tau R406W Transgenic Mice

Missense mutations of the tau gene cause autosomal dominant frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), an illness characterized by progressive personality changes, dementia, and parkinsonism. There is prominent frontotemporal lobe atrophy of the brain accompanied by abundant tau accumulation with neurofibrillary tangles and neuronal cell loss. Using a hamster prion protein gene expression vector, we generated several independent lines of transgenic (Tg) mice expressing the longest form of the human four-repeat tau with the R406W mutation associated with FTDP-17. The TgTauR406W 21807 line showed tau accumulation beginning in the hippocampus and amygdala at 6 months of age, which subsequently spread to the cortices and subcortical areas. The accumulated tau was phosphorylated, ubiquitinated, conformationally changed, argyrophilic, and sarcosyl-insoluble. Activation of GSK-3beta and astrocytic induction of mouse tau were observed. Astrogliosis and microgliosis correlated with prominent tau accumulation. Electron microscopic examination revealed the presence of straight filaments. Behavioral tests showed motor disturbances and progressive acquired memory loss between 10 to 12 months of age. These findings suggested that TgTauR406W mice would be a useful model in the study of frontotemporal dementia and other tauopathies such as Alzheimers disease (AD).

Modification of morphine sensitization by opioid and dopamine receptor antagonists: evaluation by studying ambulation in mice

The repeated administration of morphine (10 mg/kg s.c.) at 3- to 4-day intervals caused sensitization to its ambulation-increasing effect. A mu-opioid receptor antagonist naloxone (0.03-1 mg/kg s.c.), and dopamine D1 and D2 receptor antagonists SCH 23390; R-(+)-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl (0.01-0.1 mg/kg s.c.) and YM-09151-2 (nemonapride); cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4- methylaminobenzamide (0.003-0.1 mg/kg s.c.), respectively, dose dependently reduced the ambulation increase caused by morphine as well as the sensitization to morphine, when one of them was combined with morphine in the repeated administration. Treatment with SCH 23390 or YM-09151-2, but not naloxone, 3 h after each morphine administration tended to enhance the morphine sensitization. Furthermore, when YM-09151-2 (0.1 mg/kg) was repeatedly administered to the morphine-naive mice 5 times at 3- to 4-day intervals, these mice showed a significant increase in morphine sensitivity. Although the morphine sensitization was partially reversible, repeated (5 times) treatment of the morphine-sensitized mice with SCH 23390 (0.1 mg/kg) resulted in a further enhancement in morphine sensitivity. The same treatment with YM-09151-2 (0.03 and 0.1 mg/kg) tended to increase the sensitivity. These results suggest that, in terms of ambulation in mice, an enhancement of dopaminergic neurotransmission through the agonistic action on mu-opioid receptors is responsible for induction of morphine sensitization.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopamine Antagonists Can Inhibit Methamphetamine Sensitization, But Not Cocaine Sensitization, When Assessed by Ambulatory Activity in Mice

Abstract— The repeated subcutaneous administration of methamphetamine (2 mg kg−1) and cocaine (10 mg kg−1) at 3–4 day intervals induced sensitization to their ambulation‐increasing effects in mice. Subcutaneous administration of SCH 23390 (R‐(+)‐7‐chloro‐8‐hydroxy‐1‐phenyl‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepine; 0·003–0·03 mg kg−1) and YM‐09151–2 (cis‐N‐(1‐benzyl‐2‐methylpyrrolidin‐3‐yl)‐5‐chloro‐2‐methoxy‐4‐methylaminobenzamide; 0·003–0·03 mg kg−1), the selective dopamine D1 and D2 antagonists, respectively, reduced dose‐dependently the acute ambulation‐increasing effect of methamphetamine. The development of methamphetamine sensitization was inhibited when it was administered in combination with either SCH 23390 or YM‐09151–2 in the repeated administration schedule. Although SCH 23390 (0·01–0·1 mg kg−1) and YM‐09151–2 (0·01–0·1 mg kg−1) also reduced the ambulation‐increasing effect of cocaine (10 mg kg−1), neither drug inhibited the cocaine sensitization. Mice given cocaine with SCH 23390 (0·03 mg kg−1) or YM‐09151–2 (0·03 and 0·1 mg kg−1) showed higher sensitivity than those given cocaine alone. The present results suggest that, although both the dopamine D1 and D2 antagonists reduce the acute stimulant effects of both methamphetamine and cocaine, they are only effective for inhibition of the methamphetamine sensitization. Mechanisms other than the dopaminergic system appear to be involved in the cocaine sensitization.

Correlation between antiavoidance activities of antipsychotic drugs in rats and daily clinical doses.

Effects of oral antipsychotic drugs, 12 phenothiazines, 3 thioxanthenes, 5 butyrophenones and 8 other derivatives on Sidman and discriminated avoidance responses in rats were investigated and compared to their clinical doses routinely used PO. Almost all drugs except sulpiride and clozapine suppressed the avoidance responses with a dose-dependent decrease in the response rate (lever-pressing) and increase in the shock rate in the Sidman avoidance performance or a decrease in both the response and avoidance rates in the discriminated one. Sulpiride (80-640 mg/kg) produced no marked change in the avoidance responses. Clozapine (2.5-10 mg/kg) increased the shock rate or decreased the avoidance rate without eliciting any change in the response rate. The avoidance-suppressing activities of the antipsychotic drugs were well correlated with their clinical daily doses. However, the avoidance-suppressing effects of carpipramine, clocapramine, thiothixene and sulpiride were relatively less potent, while that of clotiapine was more potent than in the clinical activities. The potencies of the avoidance-suppressing effects of each drug on the Sidman and the discriminated avoidance responses were almost identical except for triflupromazine, pimozide, thioridazine, spiclomazine and propericiazine. The former two drugs suppressed the Sidman avoidance response more than the discriminated avoidance response. However, the latter three drugs suppressed the discriminated avoidance response more markedly than the Sidman avoidance response. The present results suggest that the avoidance response in rats is applicable in evaluating the clinical efficacies of antipsychotic drugs.

The Anxiolytic Effect of Two Oriental Herbal Drugs in Japan Attributed to Honokiol from Magnolia Bark

An improved elevated plus‐maze test in mice revealed that seven daily treatments with two differnt traditional Chinese medicines, known as Kampo medicines in Japan, Hange‐koboku‐to (composed of extracts of 5 plants) and Saiboku‐to (composed of extracts of 10 plants), produced an anxiolytic effect, and the effect was mainly due to the presence of honokiol derived from magnolia. This study was carried out to evaluate the anxiolytic potential of honokiol, Hange‐koboku‐to and Saiboku‐to, which were prescribed with two different magnolia samples: Kara‐koboku (Magnoliae officinalis) (KA) or Wa‐koboku (Magnoliae obovata) (WA).

Effects of dopamine antagonism on methamphetamine sensitization: evaluation by ambulatory activity in mice.

SCH 23390 (SCH: 0.001-0.03 mg/kg SC) and YM-09151-2 (YM: 0.001-0.03 mg/kg SC), the selective dopamine D1 and D2 antagonists, respectively, reduced dose-dependently the ambulation-increasing effect of methamphetamine (MAP: 2 mg/kg SC) in mice. The sensitization to MAP was inhibited when it was administered in combination with SCH (0.003-0.03 mg/kg) or YM (0.003-0.03 mg/kg) in the repeated administration regimen. The inhibitory action of YM on the MAP sensitization was more prominent than that of SCH. However, the repeated treatment with either SCH or YM could not ameliorate the established MAP sensitization. Rather, the repeated treatment with the highest dose of YM (0.03 mg/kg) increased the MAP sensitivity in both the MAP-sensitized and drug-naive mice. SCH had no such action. The present results suggest that the dopamine D2 receptors are more intimately involved than the dopamine D1 receptors in the increased sensitivity to MAP induced by the repeated treatment with MAP itself, behavioral sensitization, or dopamine antagonists, denervation supersensitivity.

Honokiol, a putative anxiolytic agent extracted from Magnolia bark, has no diazepam-like side-effects in mice

Use of the elevated plus-maze experiment and activity and traction tests in mice have revealed that seven daily treatments with 0.2 mg kg(-1) and higher doses of honokiol, a neolignane derivative extracted from Magnolia bark, had an anxiolytic effect without change in motor activity or muscle tone. Diazepam, 1 mg kg(-1), had the same anxiolytic potential as 0.2 mg kg(-1) honokiol but induced muscle relaxation. The aim of this study was to determine whether honokiol had diazepam-like side-effects. Mice treated with 1-10 mg kg(-1) diazepam, but not those treated with 0.1-2 mg kg(-1) honokiol, for 12 days showed withdrawal symptoms characterized by hyperactivity and running-fit when they were challenge-administered intraperitoneal flumazenil (10 mg kg(-1)) 24 h after the last treatment with diazepam. Oral diazepam (0.5-2 mg kg(-1), 10 min before) dose-dependently prolonged hexobarbital (100 mg kg(-1), i.p.)-induced sleeping, disrupted learning and memory, and inhibited (+)-bicuculline (40 mg kg(-1), i.p.)-induced death. Honokiol (0.2-20 mg kg(-1), p.o., 3 h before) had no such effects. The prolongation by diazepam (1 mg kg(-1)) of hexobarbital-induced sleeping was not modified by honokiol (0.2-20 mg kg(-1)). These results suggest that honokiol is less likely than diazepam to induce physical dependence, central depression and amnesia at doses eliciting the anxiolytic effect. It is also considered that honokiol might have no therapeutic effect in the treatment of convulsion.

Effects of interdose interval on ambulatory sensitization to methamphetamine, cocaine and morphine in mice

To determine the minimum interdose interval for induction of ambulatory sensitization to methamphetamine, cocaine and morphine, 3 sets of 5 groups of mice were treated with either methamphetamine (2 mg/kg s.c.), cocaine (10 mg/kg s.c.) or morphine (10 mg/kg s.c.) 3 times at intervals of 3, 6, 12, 24 or 48 h, and then 2 times at intervals of 3 days in all groups. During the first 3 administrations of both methamphetamine and cocaine, interdose intervals of 3-12 h did not produce a significant change in the ambulatory stimulation. However, 3 repeated administrations of morphine with interdose intervals of 3 and 6 h, but not 12 h, caused tolerance to the ambulatory stimulant effect. The administration of all drugs with interdose intervals of 24 and 48 h produced ambulatory sensitization. Furthermore, following the fourth and fifth administrations of each drug, all groups of mice demonstrated sensitization. These results indicate that an interdose interval of 24 h or longer is required for induction of ambulatory sensitization to methamphetamine, cocaine and morphine.

Automatic measurement of drinking in rats: effects of hypophysectomy.

A new apparatus for the continuous measurement of drinking in the rats was assembled. The principle of the device is as follows: a cartridge which makes water drops (0.05 ml) is inserted between a water tank and a drinking spout. When a rat drinks, water falls into the cartridge drop by drop and the number of drops is electrically counted. The total count of drops per day, as well as counts at definite intervals, can be atuomatically printed out. To test apparatus reliability and applicability, drinking behavior in hypophysectomized rats was investigated in the light and dark phases, alternating every 12 hr. Activity and feeding in these phases were also observed. In the sham-operated rats, the total daily water intake was 30-40 ml, which corresponded to 10-15% of the body weight, and 85-95% of the total daily drinking counts were recorded in the dark phase. In the hypophysectomized rats, a large amount of water was drunk immediately after the operation. However, the high rate of drinking rapidly returned to near the normal level within a few days. Drinking in the dark phase decreased to about 75% of the total daily, but synchronization with the light-dark cycle was still maintained. The daily patterns of activity and eating ran nearly parallel with the drinking behavior. These results indicate that our drinkometer could have extensive applications within many fields of research.

Decreased level of brain acetylcholine and memory disturbance in APPsw mice

To clarify whether amyloid beta protein (Abeta) amyloidosis induces a disturbance of cholinergic system leading to long-term memory deficits, we continuously examined memory disturbance using the passive-avoidance task, and measured Abeta burden and concentrations of acetylcholine in the brain of APPsw transgenic mice. Repetitive retention trials of the passive-avoidance task showed that the long-term memory impairment in APPsw mice appeared from approximately 7.75 months old and progressively advanced. Significant decreases in acetylcholine levels were found in the brains of 10-month-old mice. A few senile plaques appeared in the cerebral cortex and the hippocampus at 8 months old, and increased in size and number with aging. The concentrations of brain Abeta40/42(43) gradually increased from 8 months old and exponentially increased thereafter. Advance of long-term memory disturbance was closely correlated with Abeta40/42(43) burden. These findings suggested that Abeta accumulation induced long-term memory impairment and disturbance of the cholinergic system, and that the passive-avoidance task and measuring acetylcholine were useful methods for evaluating this mouse model as well as Abeta accumulation.