Degeneration Of Nerve Terminals Research Articles

Chemically induced degeneration of indoleamine-containing nerve terminals in rat brain

Chemically induced degeneration of indoleamine-containing nerve terminals in rat brain

Degeneration of sympathetic nerves in vitro and development of smooth muscle supersensitivity to noradrenaline.

1. The sequence of events involved in degeneration of sympathetic nerve terminals has been studied in vitro in the expansor secundariorum muscle of the chicken.2. The muscle underwent a degeneration contraction due to abrupt release of noradrenaline stores from the nerves about 18 hr after isolation. The tension reached its peak within 6 hr at about 44% of the maximum tension developed to added noradrenaline.3. Responses to nerve stimulation were transiently potentiated by 35% on average just before the onset of the degeneration contraction and then failed abruptly.4. Degeneration release of noradrenaline was Ca(2+)-dependent. Development of the degeneration contraction was delayed by temporary withdrawal of Ca(2+) from the medium and was accelerated by a twofold increase in Ca(2+) concentration when applied at a critical period close to the onset.5. Neither continuous nerve stimulation nor alterations in the length of the nerve stump influenced the course of the degeneration contraction in vitro.6. When the muscle was left in situ after denervation, the degeneration contraction occurred between 2 and 3 days later depending on the length of the distal portion of nerve. Cutting the nerve supply 5 cm closer to the muscle in vivo hastened the loss of transmission and the onset of the degeneration contraction by 24-48 hr.7. Supersensitivity to noradrenaline occurred soon after the degeneration contraction but the full development of a sevenfold supersensitivity to noradrenaline, equivalent to that produced by cocaine, took up to 48 hr. No further increase in sensitivity to noradrenaline could be detected in vitro after chronic denervation in vivo for up to 30 days.8. It is concluded that the degeneration contraction and failure of transmission was precipitated by an abrupt increase in the Ca(2+) permeability of the axon causing discharge of transmitter from vesicles. This was probably the result of depletion of essential factors normally transported somatofugally in the axon at 1-2 mm/hr. The supersensitivity to noradrenaline that develops subsequently appears to be due to a loss of the uptake mechanism of the nerve terminals.

Changes in continuously recorded intracranial pressure of conscious rabbits at different time-periods after superior cervical sympathectomy.

AbstractThe intracranial pressure, measured as the ventricular fluid pressure (VFP), was recorded continuously during about 2 days via a cannula inserted into the left lateral ventricle of the brain of conscious rabbits. The effect of bilateral removal of the superior cervical ganglia on the VFP was studied at various time‐periods after operation, and the results were compared with those from unoperated control animals. The pressure changes attributed to the sympathectomy are referred to as the net VFP. The operation ultimately caused a disappearance of noradrenaline from intracranial sympathetic nerves. The net VFP was not affected during an 8‐hr period of the recording starting 5–8 hrs after sympathectomy. During the following 35 hrs it was reduced by approximately 25 mm physiological saline followed by a return to initial or somewhat higher levels. Four days after sympathectomy the net VFP was significantly increased throughout the recording period. Two weeks after the operation the pressure had returned to the same, or even lower level compared with the non‐sympathectomized control animals. The variations in the net VFP at different time‐periods after sympathectomy are considered to reflect mainly changes in the intracranial vascular bed due to the leakage and disappearance of the noradrenaline transmitter from the degenerating nerve terminals followed by denervation supersensitivity. The results are discussed in terms of a sympathetic influence on the intracranial pressure mediated through the volume of the intracranial vascular bed, and/or the cerebrospinal fluid production in the choroid plexuses.

Neurochemistry of reward and punishment: Some implications for the etiology of schizophrenia

Publisher Summary This chapter discusses some implications for the etiology of schizophrenia. Genetic studies provide indirect support for the idea that an impairment of noradrenergic function may be involved in schizophrenia. Several lines of biochemical evidence suggest that 6-hydroxydopamine is the aberrant metabolite that causes schizophrenia. This compound is an autoxidation product and metabolite of dopamine and its formation can occur to a significant extent in the intact animal. 6-Hydroxydopamine induces a specific degeneration of peripheral sympathetic nerve terminals with a marked and long-lasting depletion of norepinephrine. It is found that when injected intraventricularly into the rat brain, 6-hydroxydopamine similarly causes a prolonged or permanent depletion of brain catecholamines. Only catecholamine-containing neurons are affected, and brain norepinephrine is more severely depleted than dopamine. Electron microscopic evidence reveals that norepinephrine nerve terminals in the brain degenerate and eventually disappear after repeated doses of 6-hydroxydopamine. Single doses of 6-hydroxydopamine of 200 μg or less, however, may decrease brain norepinephrine without apparent ultrastructural damage. It is found that despite the profound damage to central noradrenergic neurons, rats treated with 6-hydroxydopamine are reported to be grossly indistinguishable from controls except for a slight decrease in body weight and a lack of self-grooming.

Studies on norepinephrine-containing afferents to Purkinje cells of rat cerebellum. I. Localization of the fibers and their synapses

After freeze-drying and exposure to formaldehyde vapors, catecholamine-containing axons are found in the Purkinje cell and molecular layers of the cerebella of normal rats. The fluorescent fibers are absent after acute reserpine treatment or chronic treatment with 6-hydroxydopamine; the latter treatment occasionally leaves a few dystrophic fluorescent axons in the deeper folia of the cerebellum. A similar distribution of reactive fibers was seen by light microscopic autoradiography after intracisternal injection of [ 3H]norepinephrine. With electron microscopy after the same treatment, autoradiographic grains were localized largely to fine unmyelinated axons and to small axons making synaptic contact both with the surface of major Purkinje dendrites and with small dendritic spines. Particularly intense labeling was found over a few large preterminal axons containing large granular vesicles. After intracisternal injection of 6-hydroxydopamine, which completely removes all detectable cerebellar norepinephrine, degenerating nerve terminals were again found to contact larger dendritic trunks and spines. The dystrophic structures also contained large numbers of large granular vesicles. Small granular vesicles were also found in terminals making axo-dendritic synapses in the molecular layer when the tissue was fixed after intracisternal injection of 5-hydroxydopamine. These combined studies indicate that certain cerebellar nerve terminals will take up [ 3H]norepinephrine and both 5- and 6-hydroxydopamine. Each of the cytochemical methods indicates that the endogenous norepinephrine is contained within axons which synapse with Purkinje cell dendrites and dendritic spines.

Studies on norepinephrine-containing afferents to Purkinje cells of rat cerebellum. III. Evidence for mediation of norepinephrine effects by cyclic 3′, 5′-adenosine monophosphate

The relationship between cerebellar adenyl cyclase and norepinephrine (NE) receptivity of cerebellar Purkinje cells was explored by recording their spontaneous discharge during microiontophoretic application of various substances. The depression in firing rate of single Purkinje cells produced by NE was usually mimicked by adenosine 3′5′-monophosphate (cyclic AMP). The synthetic dibutyryl derivative of cyclic AMP, however, was no more potent than the parent compound. Two other adenine nucleotides, adenosine triphosphate (ATP) and 5′-AMP generally accelerated discharge rate or had no effect. The excitatory effects of the nucleotides may be related to chelation of divalent cations, since EDTA and citrate were universally found to accelerate unit firing while calcium ions always slowed or blocked spontaneous activity. Further evidence for a link between the effects of NE and cyclic AMP was seen with the administration of the methyl xanthines, which inhibit the enzymatic breakdown of cyclic AMP by phosphodiesterase. Theophylline and aminophylline, whether parenterally or iontophoretically administered, markedly potentiated the depressant effects of both NE and cyclic AMP on Purkinje cells. Methyl xanthines usually transformed the infrequent speeding effects of cyclic AMP to those of slowing, or brought about an inhibitory response in cells previously non-responsive to cyclic AMP. Furthermore, iontophoresis of prostaglandins E 1 and E 2 (but not F 1α, F 2α, linoleic or linolenic acids), and of nocotinate, reported to reduce cyclic AMP levels in peripheral neuro-effector systems, also block the action of iontophoretically applied NE in rat cerebellum. To determine if the locus of the action of the various iontophoretically applied substances was exerted presynaptically on the proposed adrenergic terminals on Purkinje cells, 6-hydroxydopamine (6-HODA) treated animals were studied. Under these conditions the effects of all the drugs and their interactions appeared identical to those of normal cerebella, in spite of biochemical and histochemical evidence for complete degeneration of adrenergic nerve terminals. These studies provide indirect evidence for mediation of NE effects by cyclic AMP in a living single cell system. Thus, they parallel in vitro studies with cerebellar slices which show an increase in cyclic AMP levels with NE, as well as histamine. Taken with the histochemical data for norepinephrine nerves terminating on Purkinje cells, the findings point to a possible transsynaptic modulation of adenyl cyclase activity.

Further observations on the enlargement of synaptic vesicles in degenerating optic nerve terminals of the avian tectum

The terminal degeneration of retino-tectal fibers was investigated electron microscopically in the pigeon. Continuing the research of Cuénod and coworkers, the effects of various technical procedures upon the configuration of synaptic vesicles during the initial phases of Wallerian degeneration were studied. The presence of large vesicles in the degenerating nerve terminals was shown to be independent of the method of fixation: paraformaldehyde, glutaraldehyde and acrolein with subseunt osmication gave essentially similar results to those obtained with osmic acid fixation alone. Larger vesicles were also observed in the freeze-etched preparations of the degenerating optic nerve terminals: there was no essential difference between aldehyde-fixed and unfixed specimens with respect to the enlarged size of vesicles. Enlarged vesicles of degenerating endings turned out to be ZIO (zinc iodide-osmium tetroxide)-positive. In 2 cases, we succeeded to obtain selective vesicle staining in degenerated boutons by slightly modifying the ZIO technique.

Time course of the effects of 6-hydroxydopamine on catecholamine-containing neurones in rat hypothalamus and striatum.

1. The effects of intraventricular injection of 6-hydroxydopamine (6-OHDA) on tyrosine hydroxylase activity, uptake of (3)H-noradrenaline and endogenous catecholamine concentration in rat hypothalamus and striatum were investigated at various times after the injection of 6-OHDA.2. In the hypothalamus after the injection of 250 mug of 6-OHDA there was a rapid decrease in tyrosine hydroxylase activity, (3)H-noradrenaline uptake and noradrenaline content, which was essentially complete within 2 hours.3. In the striatum after this dose of 6-OHDA there was a much slower reduction in tyrosine hydroxylase activity and (3)H-noradrenaline uptake during the first 48 h after drug injection. For the first 24 h the dopamine concentration in this brain area was increased significantly above control values, but had fallen below control values by 48 hours.4. After the injection of a smaller dose of 6-OHDA (25 mug) the only detectable change in the striatum was a rapid increase in the dopamine concentration. In the hypothalamus this dose induced a rapid depletion of noradrenaline, not accompanied initially by any significant reduction in tyrosine hydroxylase activity.5. These results are consistent with the hypothesis that 6-OHDA causes a rapid degeneration of catecholamine-containing nerve terminals in the central nervous system (CNS). These degenerative changes, indicated by the loss of tyrosine hydroxylase and noradrenaline uptake sites, did not appear to be preceded by an initial displacement of endogenous catecholamines by 6-OHDA, except possibly at early times after the administration of small doses of the drug.

Effects of 6-hydroxydopamine on CNS catecholamines, spontaneous motor activity and amphetamine induced hyperactivity in rats.

THE compound 6-hydroxydopamine (6-OHDA) produces a long-lasting depletion of brain noradrenaline (NA) and dopamine (DA) when injected into the lateral ventricle of the rat brain1. This treatment also results in a reduction in the activities of the catecholamine biosynthetic enzymes, tyrosine hydroxylase and DOPA decarboxylase, in the hypothalamus and corpus striatum. In addition there is a marked reduction in the rate of uptake of 3H-NA into tissue slices from these regions1. These findings are consistent with the evidence from morphological studies2,3 which suggest that the compound causes an acute degeneration of adrenergic nerve terminals in the sympathetic nervous system when admioistered systemically. The effects of 6-OHDA in the CNS are restricted to NA and DA containing neurones, and there is no recovery for periods of up to 142 days after treatment1. The doses of 6-OHDA injected into the brain are not sufficiently large to have any effects on the peripheral sympathetic nervous system2.

Lesions of central norepinephrine terminals with 6-OH-dopamine: biochemistry and fine structure.

Intracisternal injections of 6-hydroxydopamine produce rapid and long-lasting depletion of brain catecholamines without effects on serotonin concentrations. Depletion of norepinephrine is greatest in areas containing only nerve terminals and axons and least in areas containing monoamine cell bodies. The norepinephrine loss is accompanied by electron microscopic evidence of nerve terminal degeneration and decreased turnover. Dopamine loss is less marked and is not accompanied by degeneration or alteration of turnover rate.

Adrenergic neuron blockers and transmitter release after sympathetic denervation studied in the conscious rat.

Abstract13 to 15 hrs after excision of the superior cervical ganglion the postdenervation ptosis in the rat is reversed for about 12 hrs due to release of transmitter from degenerating nerve terminals. This degeneration contraction has been studied in unanesthetized rats. A special apparatus with an image splitting eyepiece was constructed for the measurement of the palpebral aperture at a distance. The time course of the degeneration contraction was found to correlate well with that of postdenervation transmitter depletion earlier found by other workers using biochemical and histochemical methods. Earlier findings that postdenervation depletion is delayed by bretylium were fully confirmed. It was also found that the neuron‐blockers beta‐TM 10 (10–50 mg/kg), bethanidine (10–50 mg/kg) and BW 392C60 (10–75 mg/kg) caused much less delay than bretylium at 1 to 50 mg/kg. The delayed degeneration contraction has a normal appearance and magnitude. There is no correlation between the neurone blocking action of the drugs and their “delaying effect”.

Autonomic innervation of the car iris. An electron microscopic study.

An identification of individual adrenergic and cholinergic nerve terminals would appear to be possible at the ultrastructural level. It is submitted that there exists a significant dual innervation of the feline dilator muscle and to a lesser extent a dual innervation of the feline sphincter muscle. Selective degeneration experiments have been performed showing a rapid degeneration of the specific nerve terminals with sparing of the unaffected fibers.

Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. II. Neurologic, genetic, and electrophysiologic findings in various neuronal degenerations.

THE companion paper 1 on this topic considered the inherited hypertrophic neuropathies in which peroneal muscle weakness and atrophy is prominent. In those disorders, a symmetric neurogenic weakness and atrophy is an early and prominent feature, conduction velocities of peripheral nerves are markedly reduced, and histologic studies reveal abnormalities of Schwann cells and of myelinization. This paper considers cases of neuronal degeneration in which peroneal muscle weakness and atrophy is prominent. In this group of cases, conduction velocities of nerves are either normal or slightly low and nerve biopsies show no evidence of segmental demyelinization or hypertrophy of nerve. In some of these cases there is probably selective degeneration of anterior horn and dorsal root ganglion cells with degeneration of axons; in other cases the site of degeneration of the neuron is less well understood—a metabolic disorder of the neuron may be the cause of degeneration of nerve terminals

An electron microscopic study of selective, acute degeneration of sympathetic nerve terminals after administration of 6-hydroxydopamine.

Le traitement de chats par la 6-hydroxydopamine (6-HO-DA) provoque une degenerescence selective et reversible des terminaisons nerveuses adrenergiques postganglionaires. Les terminaisons nerveuses cholinergiques ne sont pas affectees par ce traitement.

Septal efferents in the cat

Four selected cases were studied following placement of 1–2 mm lesions in the septum of the cat. Degeneration of nerve fibers and terminals was observed in the olfactory peduncle, olfactory tubercle, gyrus rectus and overlying gyrus cinguli. Projections to posterior cortex occurred over the fornix longus and body of the fornix to the gyrus cinguli, subiculum and hippocampal gyrus. Other projections occurred downstream via three pathways. A dorsal route was traced over the stria medullaris to thalamic nuclei and midbrain. A central pathway coursed through the internal medullary lamina and zona incerta into the prerubral field. Ventrally, degeneration traveled over the diagonal band, medial forebrain bundle and ventral tegmental tract into the midbrain. The over-all degeneration preferential was to the anterior thalamic nuclei, lateral reticular nucleus of the thalamus and hippocampus. Differential projections evidenced by terminals occurred in the septum, anterior and other thalamic nuclei, hypothalamus and midbrain reticular nuclei. Degeneration was noted differentially within the columns of the fornix, diagonal band and medial forebrain bundle. These differential topographic projections of the septum are proposed as a possible structural basis for diverse effects reported in the literature concerning septum studies. The septum is considered as part of an accessory thalamus functioning within a larger system referred to as a “dynamic scale”. It is also implied that this functional concept could be true of other cerebral structures.