Biomedical subjects
Publications and source records attributed to B Gao.
The nucleotide sequence of the ApoH cDNA encoding the bovine apolipoprotein H (ApoH) has been determined. The deduced protein, which contains a 19-amino-acid (aa) signal peptide and the 326-aa mature ApoH, shows 89% and 86% homology with human and rat ApoH, respectively.
Many functions of the 70-kDa heat-shock proteins (hsp70s) appear to be regulated by bound nucleotide. In this study we examined the nucleotide binding properties of purified bovine brain uncoating ATPase, one of the constitutively expressed members of the hsp70 family. We found that uncoating ATPase purified by ATP-agarose column chromatography retained one ADP molecule bound per enzyme molecule which could not be removed by extensive dialysis. Since this bound ADP exchanged rapidly with free ADP or ATP, the inability to remove the bound nucleotide was not due to slow dissociation but rather to strong binding of the nucleotide to the uncoating ATPase. In confirmation of this view, equilibrium dialysis experiments suggested that the dissociation constants for both ADP and ATP were less than 0.1 microM. Schmid et al. (Schmid, S. L., Braell, W. A., and Rothman, J. E. (1985) J. Biol. Chem 260, 10057-10062) suggested that the uncoating ATPase had two sites for bound nucleotide, one specific for ATP and one binding both ATP and ATP analogues but not ADP. In contrast, we found that enzyme with bound ADP did not bind further adenosine 5'-(beta,gamma-imino)triphosphate or dATP, nor did more than one ATP molecule bind per enzyme even in 200 microM free ATP. These results strongly suggest that the enzyme has only one binding site for nucleotide. During steady-state ATP hydrolysis, 85% of the bound nucleotide at this site was determined to be ATP and 15% ADP; this is consistent with the rate of ADP release determined in the exchange experiments noted above, where ADP release was found to be six times faster than the overall rate of ATP hydrolysis.
Ethological procedures were employed to examine the differences in behaviour between oestrous and dioestrous control mice, and to investigate the changes to behavioural responsiveness in oestrous and dioestrous mice induced by treatment with the anxiolytic compounds, chlordiazepoxide (CDP, 21.5 mg/l), buspirone (12.8 mg/l) and the 5-HT3 receptor antagonist, BRL 46470 (40 micrograms/l). Compounds were given in drinking fluid for 6-8 days prior to behavioural observations (average daily intake: CDP--5 mg/kg; buspirone--2.5 mg/kg; BRL 46470--10 micrograms/kg). Behaviour of the females was examined in the "approach-avoidance" situation of 5 min encounters with an unfamiliar male in a neutral cage. Oestrous controls spent more time in social investigation, sniffing of the substrate and scanning than dioestrous controls and spent less time in digging and exploration. Each of the anxiolytic compounds, CDP, buspirone and BRL 46470, significantly raised the duration of social investigation both in oestrous and dioestrous females. Each of these compounds also increased the duration of "digging" by oestrous females, and duration of the social element "investigate" in dioestrous females. Effects on the occurrence of other individual elements within each behavioural category depended on the anxiolytic compound administered and the stage of the ovarian cycle at the time of testing. There were few significant differences between the behaviour of the male partners in each group. It is concluded that in this paradigm both oestrous and dioestrous females are sensitive to the enhancement of social investigation by anxiolytic compounds and that the use of female mice in this test situation may provide a potentially useful method in drug screening.
The effects of ritanserin on the behaviour of adult male CD1 mice were examined after acute intraperitoneal injection (0.1, 0.3 and 0.6 mg/kg) and after administration for 12-15 days in the drinking fluid at 1.6 mg/l (0.32 mg/kg daily) and 3.1 mg/l (0.7 mg/kg daily). The behaviour of each mouse was examined by ethological procedures during 5 min social encounters with an untreated partner in an aversive situation, an unfamiliar neutral cage, and in a familiar situation, the animal's home cage. Behaviour also was monitored for 5 min in the light-dark box. In the acute studies, behavioural observations commenced at 30 min after injection. In the home cage, ritanserin significantly increased social investigation during social encounters and reduced exploratory activity at all doses tested, after both acute and subchronic administration. In the neutral cage, acutely administered ritanserin increased social investigation and reduced non-social activity at all dose levels. Effects were maximal at 0.3 mg/kg, and at this dose it also increased aggression. In the neutral cage after subchronic administration, ritanserin at both dose levels increased aggression, digging and investigation of the substrate and occurrence of the social act, "attend", while reducing the time spent in non-social exploration. Ritanserin did not affect behaviour in the light-dark box. The significance of these findings relative to the anxiolytic and antidepressant effects of ritanserin is discussed.
Quinpirole (0.25, 0.5 and 1.0 mg/kg) was administered by intraperitoneal injection to pair-housed adult DBA/2 mice. Controls received injections of physiological saline. Effects on behaviour during 5 min social encounters with untreated partners were examined by ethological procedures, commencing at 30 min after injection. Behaviour was examined in an aversive and less aversive situation, an unfamiliar neutral cage and the home cage. Behavioural effects were then assessed in a two-compartment black and white test box. Quinpirole dose-dependently increased the frequency and duration of flight, including the specific element "retreat". At 0.5 mg/kg, the element, "freeze", was also increased during encounters in the neutral cage. Immobility (a flaccid sitting posture) and sniffing of the substrate were increased by quinpirole to a similar extent at all dose levels, while non-social activity and social investigation were reduced. The significance of the effects of quinpirole in the home cage and neutral cage were qualitatively similar; the only quantitative differences were a greater enhancement of the duration of immobility and the frequency of substrate sniffing in the home cage. In the light-dark box, quinpirole reduced the number of transitions between light and dark compartments and decreased line crossings and scans/unit time in the light compartment, although it increased the amount of time in the light compartment into which mice had been originally placed. The induction of immobility and decrease of several active behavioural responses may arise from a D2 autoreceptor inhibition of locomotor activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of buspirone (1, 5 and 10 mg/kg, i.p.) on the behaviour of adult male CD1 mice have been compared with those of chlordiazepoxide (1, 4 and 8 mg/kg, i.p.). Commencing at 30 min after injection, the behaviour of each mouse was examined by ethological procedures during 5 min social encounters with an untreated partner in the animal's home cage and in the more aversive situation of an unfamiliar neutral cage. In both test environments, buspirone at 1 and 5 mg/kg and chlordiazepoxide (CDP) at 1 and 4 mg/kg increased social investigation and some of its constituent elements, while decreasing non-social activity and the element, "explore" (and for CDP, of "scanning" also). In both test environments, the increase of social investigation by buspirone and CDP was less marked at 10 and 8 mg/kg, respectively. For CDP, although not for buspirone, this effect was related to dose-dependent increases of immobility coupled with reductions of exploratory non-social activity and scanning below those occurring at the intermediate dose level. Buspirone at 5 mg/kg increased social investigation to a greater extent in the home cage (P < 0.01) than in the unfamiliar neutral cage (P < 0.05), whereas CDP was approximately equipotent in the two test situations. In the neutral cage, buspirone at all dose levels showed an additional effect of increasing the time spent by the mice in digging, whereas chlordiazepoxide dose-dependently increased aggression. These results indicate anxiolytic activity by both compounds after acute administration, and identify certain differences in the profile of their other effects on social behaviour.
GABAA-receptors in the brain display a striking structural heterogeneity, which is based on a multiplicity of diverse subunits. The allocation of GABAA-receptor subtypes to identified neurons is essential for an analysis of the functional significance of receptor heterogeneity. Among GABA-receptive neurons, well-characterized examples include the serotonergic and GABAergic neurons in the raphe nuclei. The GABAA-receptor subtypes expressed in these two types of neurons were analysed using antisera which recognize selectively the alpha 1- and alpha 3-subunits, and their co-localization with serotonin and glutamate decarboxylase was assessed by confocal laser microscopy in double and triple immunofluorescence staining in the rat. The vast majority of serotonergic neurons express strong alpha 3-subunit-immunoreactivity, but are devoid of alpha 1-subunit staining. In contrast, both the alpha 1- and alpha 3-subunit-immunoreactivities are present in glutamate decarboxylase-positive neurons. Thus, serotonergic and GABAergic neurons selectively express distinct patterns of alpha subunits, suggesting that they possess distinct subtypes of GABAA-receptors. The occurrence of neuron-specific GABAA-receptor subtypes may open new possibilities for the targeting of drugs with selective therapeutic actions.
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Brucellosis in mice results in a distinct immunosuppression which may be abrogated by immunomodulators, such as levamisole, bestatin, interleukin-2 (IL-2) and Polyporus umbellatus. The data presented here provide evidence that immunosuppression in addition to infection of target tissues and allergic reactions (including types 3 and 4) contributes to the pathogenesis of brucellosis. The present study also provides some basic data regarding the value of this animal model, and criteria for observing the effect of therapy on chronic brucellosis.
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The antidepressant drug, fluoxetine (FLX), a selective serotonin reuptake inhibitor, was administered to Syrian hamsters, and its acute and chronic effects on EEG sleep and hypothalamic temperature were recorded. Acute fluoxetine treatment at doses of 5, 10, 20 and 40 mg/kg decreased REM sleep and hypothalamic temperature in a dose-dependent manner. It increased NREM sleep, and, at doses of 20 and 40 mg/kg, it increased wakefulness. At 40 mg/kg, it decreased motor activity. During chronic treatment, tolerance developed to FLX's REM sleep-inhibiting effects, but tolerance did not develop to FLX's hypothalamic temperature-decreasing effects. Chronic FLX treatment produced circadian phase-dependent decreases in temperature beyond those that were observed during acute treatment. The apparent dissociation during chronic treatment between FLX's temperature-lowering effects and its REM-decreasing effects might be related to long-term changes in 5HT receptor function or FLX pharmacokinetics.
Adult male CD1 mice received the 5-HT3 receptor antagonist, BRL 46470A, by intraperitoneal injection at three dose levels (2.5 mg/kg, 25 and 2.5 micrograms/kg). Controls were injected with physiological saline. At 30 min after injection, the behaviour of each mouse was examined by ethological procedures, when encountering an untreated partner for 5 min in its home cage and for 5 min in the more aversive situation of an unfamiliar neutral cage. The behaviour of each mouse also was monitored for 5 min in a two compartment light-dark box. At all doses tested, BRL 46470A increased the time spent in the light compartment of the light-dark box. At the smallest dose (2.5 micrograms/kg), the number of transitions between light and dark compartments was increased and there also was an increase (per unit time) in the numbers of squares crossed and number of scans in the light compartment. At all doses tested, BRL 46470A increased social investigation and reduced non-social exploratory activity in both the home cage and the unfamiliar neutral cage. In both test situations, increase of social investigation was maximum at 25 micrograms/kg, and at this dose, aggressive behaviour was also enhanced. In the neutral cage, digging in the sawdust by drug-treated mice showed a progressive dose-related increase. These results indicate potent anxiolytic-like activity by BRL 46470A and also demonstrate increased reactivity to unfamiliar environmental stimuli, such as novel sawdust. The significance of these findings is discussed.
The effects of dl-propranolol on the behaviour of adult male CD1 mice were examined after acute intraperitoneal injection (1.5 and 6 mg/kg) and after administration for 10-13 days in the drinking fluid at 12.4 mg/l (1.9 mg/kg daily) and 24.9 mg/l (4.6 mg/kg daily). The behaviour of each mouse was examined by ethological procedures during 5 min social encounters with an untreated partner in an aversive and a less aversive situation, an unfamiliar neutral cage and the animals' home cage. The behaviour of each mouse also was monitored for 5 min in the light-dark box. In the acute studies, behavioural observations commenced at 30 min after the injection. In the light-dark box, propranolol, after acute administration, increased the number of transitions between the light and dark compartments and increased scanning in the light area but propranolol had no significant effect after subchronic administration. In the home cage, propranolol significantly increased social investigation during social encounters and reduced exploratory activity at all doses tested, after both acute and subchronic administration. In the neutral cage, propranolol, after acute administration, increased digging of the sawdust and decreased exploratory activity at both dose levels, while at the largest dose it also increased social investigation. In the neutral cage, propranolol, given by subchronic administration, increased aggressive behaviour as well as social investigation and digging of the sawdust at both dose levels, while reducing non-social exploratory activity. The largest dose of propranolol also increased investigation of the substrate. These results indicate that propranolol increased reactivity to normal environmental and social stimuli, in addition to its anxiolytic profile of behavioural effects.(ABSTRACT TRUNCATED AT 250 WORDS)