Attenuation of benzodiazepine-induced passive avoidance deficit by post-training administration of muscimol: interaction with the cholinergic neuronal system

We examined the involvement of GABAergic neuronal systems in benzodiazepine-induced passive avoidance deficit. Chlordiazepoxide impaired the passive avoidance response dose dependently when it was given prior to training. Post-training administration of muscimol improved the performance of chlordiazepoxide-pretreated mice. The effects of muscimol were antagonized completely by the GABAA antagonist, bicuculline, and the muscarinic acetylcholine receptor antagonist, scopolamine, but not by the benzodiazepine receptor antagonist, flumazenil, when the latter was administered immediately after training. It appears from these results that the GABAergic neuronal system plays an important role in the benzodiazepine-induced passive avoidance deficit by interacting with the cholinergic neuronal system.     

Dissection of fission yeast microtubule associating protein p93Dis1: regions implicated in regulated localization and microtubule interaction

Background : Fission yeast microtubule associating protein (MAP) p93^Dis1 functions for sister chromatid separation: dis1 mutants fail to separate chromosomes, while the spindle elongates but without cyclin destruction. p93^Dis1 localizes along microtubules in interphase cytoplasm, but shifts to the spindle pole body (SPB) and spindle microtubules upon the entry into mitosis. In this study, regions of p93^Dis1 were dissected to examine their role.
Results : Nitrocellulose filter blotting shows that recombinant Dis1 binds to bovine brain microtubules in vitro . A basic central region rich in S, T and P is essential for this association. However, the whole p93^Dis1 with N- and C-termini containing a conserved repeat motif and heptad repeats, respectively, is necessary for normal microtubule association in vivo . The N-truncated region also binds to microtubules but only to the portions near the SPBs. Overproduction phenotypes indicate that p93^Dis1 greatly affects spindle formation and cell morphogenesis. The central region is essential but, by itself, not sufficient for generating such effects.
Conclusions : We propose that p93^Dis1 consists of three regions which carry distinct properties for localization: the N-region for cell cycle dependent localization, the central region for direct microtubule association, and the C-region for SPB and nuclear localization. The essential role of p93^Dis1 is carried out in the C-region, while the N-region acts as a regulator.     

Effects of DM-9384, a pyrrolidone derivative, on alcohol- and chlordiazepoxide-induced amnesia in mice

The effects of N-(2,6-dimethyl-phenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide (DM-9384), a new pyrrolidone derivative, were investigated on ethanol- and chlordiazepoxide (CDP)-induced amnesia animal model using the passive avoidance task in comparison with aniracetam, another pyrrolidone derivative. Pretraining administration of DM-9384 attenuated ethanol- and CDP-induced amnesia, whereas aniracetam failed to do so. The effects of DM-9384 on CDP-induced amnesia were antagonized by bicuculline, a GABAA receptor antagonist, but not by scopolamine, a muscarinic acetylcholine receptor antagonist and flumazenil, a benzodiazepine receptor antagonist. These results suggest that DM-9384 attenuates CDP-induced amnesia by interacting with the GABAergic neuronal system.     

Effects of vinconate, a novel vinca alkaloid, on spatial learning deficits induced by the basal forebrain lesion in rats.

We investigated the effects of vinconate, a novel vinca alkaloid, on spatial learning deficits induced by the basal forebrain (BF) lesion in rats. Bilateral BF lesions were produced by injecting ibotenic acid (6 micrograms/0.5 microliter/side). In BF-lesioned rats, impairment of spatial learning in escaping onto the platform during training and decrease in spatial bias during the spatial probe trial in Morris's water maze task were both observed. Vinconate (5 and 10 mg/kg) treatment shortened the increase of escape latency to the platform in BF-lesioned rats and significantly reversed the decrease in spatial bias induced by the BF lesion. Vinconate (10 mg/kg) attenuated the decrease in choline acetyltransferase activity in the frontoparietal cortex caused by the BF lesion. The present study suggests that vinconate has an antiamnesic effect on the BF-lesion-induced amnesia by ameliorating the dysfunction in cholinergic neurons.     

Behavioral pharmacological action of Ca-4-(3,5-dihydroxy-3-methylpenthylamido) butyrate (mevalonic GABA, MV-GABA)

The behavioral pharmacological effects of Ca-4-(3,5-dihydroxy-3-methylpenthylamido) butyrate (mevalonic-GABA, MV-GABA), a new GABA derivative were studied in comparison with those of Ca-hopantenate (HOPA) in mice. MV-GABA had no effect on the general behavior and electric shock-induced fighting behavior. The dosage of MV-GABA which caused locomotor hypoactivity produced an impairment of the rotarod performance. MV-GABA inhibited the hyperactivity induced by a dopamine (DA) agonist (methamphetamine) and acetylcholine (ACh) antagonists (scopolamine and atropine) at a dose which did not affect locomotor activity in normal mice. MV-GABA prolonged the pentobarbital-Na-induced sleeping time, and it prolonged the latencies until convulsion and death after administration of strychnine. MV-GABA and HOPA antagonized the electroconvulsive shock-induced amnesia in the passive avoidance response of mice. These results suggest that MV-GABA has effects on the central nervous systems, in particular, ACh and DA neural systems. The actions of MV-GABA were qualitatively similar to those of HOPA except for the effect on the DA neural system.     

Climbing exercise increases bone mass and trabecular bone turnover through transient regulation of marrow osteogenic and osteoclastogenic potentials in mice.

To investigate the relationship between the effects of bone turnover and bone marrow cell development in bone cells, we developed a mouse voluntary climbing exercise model. Climbing exercise increased bone volume and transient osteogenic potential of bone marrow. This model would be suitable for investigating the mechanistic roles of mechanical loading. INTRODUCTION: The relationship between bone mass gain and local bone formation and resorption in mechanically loaded bone is not well understood. MATERIALS AND METHODS: Sixty-five C57BL/6J mice, 8 weeks of age, were assigned to five groups: a baseline control and two groups each of ground control and climbing exercise mice for 2 and 4 weeks. Mice were housed in a 100-cm tower and had to climb toward a bottle placed at the top to drink water. RESULTS: Compared with the ground control, bone mineral density of the left femur increased in the climbing mice at 4 weeks. At 2 and 4 weeks, bone formation rate (BFR/BS) of periosteal surface, the cross-sectional area, and moment of inertia were increased in the climbing mice, whereas BFR/BS and eroded surface (ES/BS) of endosteal surface did not differ. The trabecular bone volume (BV/TV) of the proximal tibia increased in climbing mice, and osteoclast surface (Oc.S/BS) and osteoclast number decreased at 2 weeks. At 4 weeks, there were increases in BV/TV and parameters of bone formation, including mineralized surface, mineral apposition rate, and bone formation rate. In marrow cell cultures from the tibia, the number of alkaline phosphatase+ colony forming units-fibroblastic and the area of mineralized nodule formation in climbing mice were increased, and the number of osteoclast-like TRACP+ multinucleated cells was lower at 2 weeks. At 4 weeks, these parameters recovered to the levels of the ground controls. CONCLUSION: Our results indicate that climbing increased trabecular bone volume and reduced bone resorption, with a subsequent increase in bone formation. Intermittent climbing downregulates marrow osteoclastogenic cells and upregulates osteogenic cells initially, but further exercise seemed to desensitize them. Cortical envelopes were enlarged earlier, but the response seems to differ from trabecular bone.