Dopamine (DA) in the dorsal and ventral striatum is associated with different aspects of locomotor activity control. The ventral striatum may form an interface between the limbic system and the extrapyramidal motor system. The distribution of dopaminergic fibers in this interface position was studied in detail with a method applying antibodies against DA. Furthermore, the ultrastructural morphology of the DA fibers was examined by means of immuno-electron microscopy. The results show that DA immunoreactivity is distributed over the ventral striatum in a highly compartmentalized fashion. In the dorsal striatum few compartments were found. The DA fibers in the ventral striatum establish mainly symmetric synaptic contacts, preferably with dendritic shafts and spines. The results are discussed in relation to previous data concerning the light and electron-microscopic identification of catecholaminergic fibers in the ventral and dorsal striatum.
The utility was explored of a new approach to detect retrospectively exposure to nerve agents by means of conversion of the inhibitor moiety bound to the active site of the enzyme BuChE in plasma with fluoride ions into a phosphofluoridate which is subsequently analyzed by means of gas chromatography (GC). This quantifies >or=0.01% inhibition of BuChE and identifies the structure of the inhibitor except for the original leaving group. A three-tiered approach was followed involving the five classical nerve agents GA, GB, GF, GD, and VX, as well as the active metabolite of parathion, i.e., paraoxon: in vivo experiments in rhesus monkeys after iv administration of a sign-free dose of agent and concomitant in vitro experiments in plasma of rhesus monkeys and humans should allow an assessment of in vivo retrospectivity in humans. A systematic investigation was performed in order to find a single set of reaction conditions which yields a maximum amount of phosphofluoridate for all nerve agents. Fluoride-induced reactivation at 25 degrees C at a final concentration of 250 mM KF during 15 min in a pH-range between 4 and 6 appears to be effective. The in vitro decrease with time in reactivatibility of inhibited BuChE in plasma from humans and rhesus monkeys was largely due to aging of the phosphyl moiety, except for VX where spontaneous reactivation was a major cause. The decrease followed first-order except for a biphasic course in the case of GF in human and rhesus monkey plasma as well as of GD in rhesus plasma. In vitro half-lifes in human plasma ranged between ca. 14 h for GB and ca. 63 h for GA. A comparison of the in vivo data from rhesus monkeys and the in vitro data is complicated by the observation that the in vivo decrease with time of fluoride-reactivated phosphofluoridate is biphasic for all nerve agents. The terminal in vivo phase pertains to a small fraction of the amount of initially regenerated phosphofluoridate but is responsible for a considerable degree of retrospectivity, ranging between 14 and 56 days for GF and GB, respectively. The new procedure can be used in a variety of practical applications, e.g., (i) biomonitoring in health surveillance at exposure levels that are several orders of magnitude lower than presently possible; (ii) diagnosis in case of alleged exposure to nerve agents in time of war or after terrorist attacks; (iii) in forensic cases against suspected terrorists that have handled organophosphate anticholinesterases; and (iv) in research applications such as investigations on lowest observable effect levels of exposure to nerve agents.
The occurrence of post-exercise proteinuria was investigated in intact and splenectomized dogs after treadmill running and swimming and compared to control experiments. Albumin and lysozyme were measured by radial diffusion. Urinary protein was analyzed by SDS-polyacrylamide gel electrophoresis. Swimming in the splenectomized dogs increased the albumin excretion in the first 30 min after exercise from 0.03 to 0.22 mg X min-1 and the lysozyme excretion in the same period from 0.11 to 0.75 micrograms X min-1. Swimming in intact dogs caused smaller increase in the lysozyme and albumin excretions during the exercise period itself as well as in the albumin excretion in the first 30 min after exercise. Running had no effect on urinary albumin or lysozyme but increased the low molecular weight protein fraction in the splenectomized dogs. Plasma lactate concentrations were higher during swimming in the splenectomized dogs than in the intact dogs. Possible mechanisms of post-exercise proteinuria are discussed.
A physiologically based model was developed which describes the in vivo toxicokinetics of the highly reactive nerve agent C(+/-)P(+/-)-soman at doses corresponding to 0.8-6 LD50 in the atropinized guinea pig. The model differentiates between the summated highly toxic C(+/-)P(-)-soman stereoisomers at supralethal doses and the individual nontoxic C(+/-)P(+)-isomers. Several toxicant-specific parameters for the soman stereoisomers were measured in guinea pig tissue homogenates. Cardiac output and blood flow distribution were measured in the atropinized, anesthetized, and artificially ventilated guinea pig. The model was validated by comparison of the time courses for the blood concentrations of the two pairs of stereoisomers in the guinea pig after i.v. bolus administration with the blood concentrations predicted by the model. The predictions put forward for the summated C(+/-)P(-)-isomers are in reasonable agreement with the experimental data obtained after doses corresponding to 2 and 6 LD50. In view of large differences in the rates of hydrolysis of the C(+/-)P(+)-isomers, these two isomers had to be differentiated for satisfactory modeling of both isomers. In order to model the toxicokinetics of C(+/-)P(-)-soman at a dose of 0.8 LD50, the almost instantaneous elimination of the C(+)P(-)-isomer at that dose had to be taken into account. The sensitivity of the predictions of the model to variations in the parameters has been studied with incremental sensitivity analysis. The results of this analysis indicate that extension to a model involving four individual stereoisomers is desirable in view of large differences in the biochemical characteristics of the two C(+/-)P(-)- and C(+/-)P(+)-isomers.
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