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Notes: Summary 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is an agent which produces a parkinsonian syndrome in man. To explore the use of MPTP in a rodent model of parkinsonism, male albino mice (NMRI) were given MPTP (50 mg/kg, s.c.) twice with a 6–8 h interval. Up to 10 weeks after injection, mice were killed and high-pressure liquid chromatography was used to assay dopamine (DA) and noradrenaline (NA) concentrations in various regions of the CNS. At 4 and 10 weeks after injection, DA levels were significantly reduced in occipital cortex (-40%), hippocampus (-30%), and striatum (-60%). NA levels were reduced by 60–80% in frontal and occipital cortex, hippocampus, and cerebellum. Neither DA nor NA concentration was reduced in spinal cord. Dopaminergic denervation was also suggested by electrophysiological data which showed that treatment with MPTP increased the spontaneous discharge rate of caudate neurons and decreased the potency of locally administered phencyclidine, an indirect DA agonist. However, denervation was evidently not complete enough to produce postsynaptic receptor supersensitivity, as MPTP treatment did not increase the potency of locally applied DA, and it did not increase 3H-spiperone binding in striatal membrane preparations. These results suggest that MPTP causes regionally selective and long-term reductions of catecholamine transmission in the CNS of the mouse.

Notes: Summary Possible neurotoxic actions of intracerebral injections of ibotenic acid, a conformationally restricted analogue of glutamic acid, have been evaluated in rat brain and compared with those of kainic acid. Light microscopical analysis revealed that ibotenic acid produced a marked disappearance of nerve cells in all areas studied, namely striatum, the hippocampal formation, substantia nigra and piriform cortex. Lesions in areas distant to the injection site were not seen. Axons of passage and nerve terminals of extrinsic origin did not seem to be damaged, since, e.g., no apparent degeneration of the dopaminergic terminals in the neostriatum was observed except for a small area surrounding the cannula. In the neostriatum, enkephalin immunoreactive neuronal cell bodies as well as nerve terminals disappeared after injection of ibotenic acid into this nucleus. After injection into the substantia nigra tyrosine hydroxylase immunoreactive cell bodies in the zona compacta disappeared, whereas no certain effect could be seen on the enkephalin immunoreactive nerve fibers. In vitro experiments, conducted with striatal synaptosomal and membrane preparations, showed that ibotenic acid differed from kainic acid by being devoid of a significant inhibitory effect on high affinity glutamate uptake and by having a low affinity for 3H-kainic acid binding sites. Furthermore, ibotenic acid did not interfere with the binding of a number of radioligands for other transmitter receptors. As compared to kainic acid, ibotenic acid has the advantage of being less toxic to the animals and of producing more discrete lesions, possibly due to faster metabolism and/or other fundamental biochemical differences. Because of these special features, ibotenic acid seems to represent a valuable new tool in the morphological and functional analysis of central neuronal systems.

Notes: Summary Groups of male rats were treated for a period of 14 days with imipramine (10Μmol/kg) given twice daily. Separate groups of rats received a single dose treatment using the same dose and experimental design as for the repeated treatment. Employing the avidin-biotin immunoperoxidase technique for immunohistochemistry 5-hydroxytryptamine (5-HT)-, substance P (SP)- and thyrotropin releasing hormone (TRH)-like immunoreactivities (IRs) were visualized in consecutive coronal sections of the brain stem and of the spinal cord. The IRs were studied by means of morphometric and microdensitometric procedures using automatic image analysis on profiles representing nerve terminal networks of the ventral horn of the cervical and lumbar enlargements of the spinal cord as well as their coexistence (5-HT/SP and 5-HT/TRH). With the same technique 5-HT IR was measured in the 5-HT nerve cell groups of the medulla oblongata (B 1, B 2, B 3) and of the nucleus raphe dorsalis (B 7) of the midbrain. In addition 5-HT and 5-hydroxyindolacetic acid (5-HIAA) levels were measured in the ventral and dorsal horns of the cervical and lumbar enlargements of the spinal cord using high performance liquid chromatography (HPLC). In the same parts of the spinal cord SP IR was studied by means of radioimmunoassay (RIA). The microdensitometric studies showed that chronic, but not acute, imipramine treatment selectively increased SP IR in the 5-HT/SP/TRH costoring nerve terminals of the medial part of the ventral horn in both the cervical and the lumbar enlargements. Furthermore, quantitative analysis of the entity of coexistence in the 5-HT nerve terminal networks of these areas showed that all the 5-HT nerve terminals contained SP and TRH IRs and that this phenomenon remained after acute and chronic imipramine treatment. The microdensitometric studies on the 5-HT nerve cell groups of the medulla oblongata and of the nucleus raphe dorsalis demonstrated that chronic, but not acute, imipramine treatment selectively increased 5-HT IR in the nerve cell bodies of the lateral part of group B 3 as evaluated from the median grey values. Acute, but not chronic, imipramine treatment significantly increased the field area of 5-HT IR of nerve cell bodies in group B 7, reflecting an increase in the mean profile area of the 5-HT IR nerve cell body profiles. Instead, the mean profile area of 5-HT IR cell bodies of group B 1 was acutely reduced by imipramine. The biochemical studies demonstrated that chronic imipramine treatment selectively reduced 5-HT utilization in the ventral horn of the spinal cord and selectively increased SP IR in the dorsal horn of the lumbar enlargement. In view of these observations it is suggested that chronic imipramine treatment specifically increases SP IR in the 5-HT/SP/TRH costoring nerve terminals of the ventral horn probably related to reduced SP release and reduced 5-HT utilization in these terminals. The results obtained in group B 7 may be explained by a regulation by the3H-imipramine raphe binding sites of fast axonal transport, an influence which may have therapeutic consequences. This mechanism may also be responsible for the increase in 5-HT IR seen upon chronic imipramine treatment in the lateral part of the 5-HT nerve cell body group B 3. Such an effect may lead to a metabolic down-regulation of group B 7, having a possible role for the antidepressant activity of imipramine. The reduction of the mean profile area of 5-HT IR cell bodies of group B 1 seen in the acute treatment can possibly be caused by, noradrenaline (NA) uptake inhibition in inhibitory NA terminals innervating the B 1 group. These results also illustrate the heterogeneities in the responses of the 5-HT nerve cell groups to antidepressant treatment. The ability of chronic imipramine treatment to increase SP IR in the dorsal horn of the lumbar enlargement may reflect the existence of a monoamine-SP interaction in the substantia gelatinosa due to the NA and/or 5-HT uptake blocking activity of imipramine. The existence of such an interaction may help to explain the antinociceptive effect of chronic imipramine treatment.