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The effects of neonatal X-irradiation on cerebellar cathecholamine levels in rats were studied at different postnatal intervals. Since synaptogenesis in the cerebellar cortex is basically a postnatal phenomenon, changes in noradrenaline (NA) and dopamine (DA) levels induced by X-rays on the cerebella (CE) of adult rats (60 days old) were also studied. With 200 rad at birth there was an increase in both NA (+ 75%) and DA (+ 40%) levels at day 30, with a return to control values by day 90. CE weight did not change with this dose. Both 500 and 700 rad given at birth induced a persistent increase in NA levels, even when studied at day 390 (+ 127%) and a long-term decrease in DA levels. A marked atrophy of CE was found, even at day 390 (a 61% decrease in weight). Histologic analysis showed that the cerebellar cortex lacked its interneurons (agranular cerebellar cortex) and that Purkinje cells were randomly arranged. Rats showed dystonia, fine tremor, posterior train ataxia and microcephalia. On the other hand, X-irradiation of adult rats did not change cerebellar catecholamine levels or produced cerebellar atrophy. These animals did not show motor deficits or microcephalia. Taken together, these results suggest that the long-term changes in cerebellar catecholamine levels induced by neonatal X-irradiation may be somehow related to the loss of cerebellar interneurons which develop early in the postnatal period, although a primary change(s) in the activity of noradrenergic neurons can not be excluded.

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When injected systemically to rodents, DSP4 inhibits the uptake of noradrenaline (NA) and depletes endogenous NA levels in the central nervous system and in the periphery. Pretreatment with the NA uptake blocker desipramine (DMI), with the NA precursor l-dopa or with the MAD inhibitor, pargyline, prevents the toxic effects of the compound. To investigate the mechanism of the NA depleting action of DSP4, the release of the neurotransmitter induced by nerve stimulation was studied "in vitro" in a tissue sensitive to the neurotoxic action of DSP4 such as the rat cerebral cortex previously loaded with tritiated NA. Incubation with 10 mumol/l DSP4 increased the spontaneous release of tritium from the cortex and produced a two-fold enhancement of tritium outflow during the stimulation of the cortical slices by exposure to K+ 20 mmol/l for 1 m. When the experiments were performed in a Ca++ free medium, DSP4 increased the spontaneous tritium outflow, but did not enhance the NA release by depolarization with K+. This latter effect could be due to the interaction with alpha-adrenoceptors since DSP4 did not potentiate the action of the alpha-antagonist yohimbine (1 mumol/l). DSP4, as did other uptake blockers, reduced the inhibitory effect of clonidine (0.1 mumol/l) on the NA release. Clonidine pretreatment "in vivo" (2 mg/kg), did not counteract the effect of DSP4 (25 mg/kg), suggesting that the enhanced release of NA induced by K+ does not play an important role in the depletion caused by DSP4. This is supported by the fact that DSP4 also enhanced the release of NA evoked by field stimulation of the rat vas deferens, a tissue resistant to the NA depleting action of the compound. The results indicate that the enhancement of the stimulation-induced release caused by DSP4, does not seem to play a triggering role in the NA depletion caused by the compound.

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When injected systemically to rodents, DSP4 inhibits the uptake of noradrenaline (NA) and depletes endogenous NA levels in the central nervous system and in the periphery. Pretreatment with the NA uptake blocker desipramine (DMI), with the NA precursor l-dopa or with the MAD inhibitor, pargyline, prevents the toxic effects of the compound. To investigate the mechanism of the NA depleting action of DSP4, the release of the neurotransmitter induced by nerve stimulation was studied [quot ]in vitro[quot ] in a tissue sensitive to the neurotoxic action of DSP4 such as the rat cerebral cortex previously loaded with tritiated NA. Incubation with 10 mumol/l DSP4 increased the spontaneous release of tritium from the cortex and produced a two-fold enhancement of tritium outflow during the stimulation of the cortical slices by exposure to K+ 20 mmol/l for 1 m. When the experiments were performed in a Ca++ free medium, DSP4 increased the spontaneous tritium outflow, but did not enhance the NA release by depolarization with K+. This latter effect could be due to the interaction with alpha-adrenoceptors since DSP4 did not potentiate the action of the alpha-antagonist yohimbine (1 mumol/l). DSP4, as did other uptake blockers, reduced the inhibitory effect of clonidine (0.1 mumol/l) on the NA release. Clonidine pretreatment [quot ]in vivo[quot ] (2 mg/kg), did not counteract the effect of DSP4 (25 mg/kg), suggesting that the enhanced release of NA induced by K+ does not play an important role in the depletion caused by DSP4. This is supported by the fact that DSP4 also enhanced the release of NA evoked by field stimulation of the rat vas deferens, a tissue resistant to the NA depleting action of the compound. The results indicate that the enhancement of the stimulation-induced release caused by DSP4, does not seem to play a triggering role in the NA depletion caused by the compound.

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The aziridinium derivative of the compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (az-DSP4) depletes endogenous noradrenaline stores and exerts neurotoxic actions on noradrenergic neurons. These effects are persistent in the central nervous system and transient in the periphery. To determine if transmitter release plays a role in the noradrenaline depletion caused by az-DSP4, the action of the compound was studied in isolated and spontaneously beating rat atria. 1. az-DSP4 enhanced atrial beating rate when present in the incubation medium at concentrations ranging from 10(-7) M to 10(-4) M but at 10(-3) M decreased that rate below basal levels. 2. Preincubation of atria for 30 min with the noradrenaline uptake blocker desimipramine (DMI, 10(-6) M) or with the beta-blocker propranolol (10(-7) M), abolished the positive chronotropic action of az-DSP4. 3. The rate-accelerating effect of az-DSP4 could be prevented by pretreating the rats with reserpine (5 mg/kg i.p. 24 h) or enhanced by pargyline pretreatment (100 mg/kg i.p. 18 h). 4. az-DSP4 stimulated the spontaneous efflux of tritium from the isolated atria previously labeled with 3H-noradrenaline (4 X 10(-7) M), an increase that was mainly accounted for by DOPEG. 5. COMT and MAO activities in atria homogenates were inhibited by az-DSP4 in a concentration-dependent manner. However, MAO inhibition did not result in a change of the metabolic pattern as could be expected. 6. The results obtained indicate that az-DSP4 enhances the rate of spontaneous beating of isolated rat atria.(ABSTRACT TRUNCATED AT 250 WORDS)

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The alkylating compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4) injected to rodents blocks norepinephrine (NE) uptake and reduces endogenous NE levels in the central nervous system and in the periphery. To investigate the processes leading to these alterations, rat cortical slices were incubated in the presence of DSP4. Cortical NE was depleted by 40% after incubation of slices in 10(-5) M DSP4 for 60 min and this was blocked by desipramine. The spontaneous outflow of radioactivity from cortical slices labeled previously with [3H]NE was enhanced markedly both during exposure to DSP4 and during the subsequent washings, suggesting that NE depletion could be due to this stimulation of NE release. The radioactivity released by DSP4 was accounted for mainly by NE and its deaminated metabolite 3,4-dihydroxyphenylglycol. The enhanced release, independent of external Ca++, apparently originated from the vesicular pool as it was absent after reserpine pretreatment. Activities of the enzymes related to NE synthesis were not altered by DSP4 in vitro and only monoamine oxidase activity was inhibited at high concentrations. Thus, the depletion of endogenous NE produced by DSP4 is probably due to a persistent enhancement of its release from the vesicular pool. Fixation of DSP4 to the NE transport system is necessary but not sufficient to produce the acute NE depletion and the characteristic long-term actions of the compound.

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The systemic injection of newborn rats of the mitotic inhibitor vinblastine sulfate (0.25 microgram/s.c. 48 h after birth), produces marked and persistent changes in peripheral sympathetic neurons. Approximately half the neuronal population of the superior cervical ganglia was destroyed already at 16 days of age and this was accompanied by a partial but persistent depletion of noradrenaline (NA) from peripheral organs receiving a rich sympathetic nerve supply such as the heart, salivary glands and spleen. After the systemic injection of vinblastine to newborn rats, the content of NA in several brain regions remained unaltered at 45-60 days of age. To overcome the obstacle that the blood-brain barrier could represent to vinblastine penetration into the brain, the compound was injected directly into the brain of rat pups at 2 days of age (0.25-1.0 microgram). When these animals were killed 45-60 days later, no changes were found in the concentration of NA in the cerebral cortex, the spinal cord or the cerebellum but NA levels were increased in the brain stem. Besides producing a partial but persistent peripheral sympathectomy, vinblastine injected either systemically or intracerebrally to newborn rats, provides a useful tool for the analysis of similarities and differences between the ontogenesis of central and peripheral NA neurons.

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Bilateral electrical stimulation of the preganglionic fibers to the superior cervical ganglia of the rat markedly reduces the number of osmiophilic dense cores present in the nerve vesicles of the sympathetic fibers in the pineal gland. These cores owe their density to the presence of noradrenaline and serotonin in the vesicles. When sympathetic nerves of the pineal organ are exposed immediately after stimulation for a brief period to the false neurotransmitter 5-hydroxydopamine, either in vitro or in vivo, dense precipitates reappear in the electron-lucent vesicles. On the basis of these observations, it is concluded that the vesicles remaining in the nerves after releasing their neurotransmitter content have the capacity to take up and store monoamines. This provides a morphological correlate for the recent biochemical evidence suggesting that the vesicles in sympathetic nerves are reused after neurotransmitter release.

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Antiserum to nerve growth factor (anti-NGF) given intraventricularly to newborn rats systemically injected with 6-hydroxydopa (6-OH-DOPA), did not prevent the long-term increase of brain stem noradrenaline produced by 6-OH-DOPA when given alone. Since the anti-NGF was biologically active and penetrated into the brain parenchyma, the role played by NGF in the outgrowth of central noradrenergic neurons, responsible for the elevation of brain stem noradrenaline, does not seem to be important.

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The pharmacological actions of the compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) are compatible with a specific neurotoxic effect on both peripheral and central noradrenergic neurons. The systemic injection of DSP-4 to adult rats transiently alters sympathetic neurons in the periphery but in the central nervous system the compound determines a marked and prolonged reduction of noradrenaline (NA) levels in all brain regions studied. When DSP-4 was injected systemically to rats at birth in doses ranging from 6.25 to 100 micrograms/g, no changes were found in peripheral sympathetic neurons 40 days later. On the contrary, in the same conditions and in relation to the dose injected, there were marked and persistent changes in the levels of NA in different regions of the brain. In the cerebral cortex and the spinal cord, the neonatal injection of SDP-4 produced a marked and long-lasting depletion of NA levels, similar to that observed after injection of the compound to adult rats. These changes were accompanied by a moderate increase in brain stem NA and a marked elevation of the amine in the cerebellum. These changes, different from the depletion observed in both regions when the compound was given to adult rats, are however similar to those observed after the neonatal injection of the neurotoxic compounds 6-hydroxydopamine or its precursor amino acid, 6-hydroxydopa. This indicates that probably central noradrenergic neurons respond in the same manner after different chemical injuries. DSP-4 crosses the placental barrier because when it was given to pregnant rats at the end of gestation, long-term changes were found in brain NA levels in their offspring, similar to those produced by the neonatal administration of the compound. This new neurotoxic compound provides a very useful tool for the study of noradrenergic neurons both in adult animals and during ontogenesis.

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