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PubMedDate not supplied

Lesion of locus coeruleus: the effect on pethidine and pentazocine analgesia.

Analgesic activity of pethidine and pentazocine in the locus coeruleus lesioned rats was evaluated. Bilateral destruction of locus coeruleus resulted in a marked decrease in noradrenaline content in forebrain but did not change significantly the levels of dopamine. Lesioned animals showed a marked decrease of predrug pain threshold. However, pethidine increased more effectively the nociceptive threshold in lesioned rats. The effect observed after pentazocine was generally similar but the maximal increase in pain threshold in lesioned animals did not differ significantly from the values observed in sham lesioned rats. The action of both analgesics was markedly prolonged after the lesion of the locus coeruleus.

Analgesics↗
PubMed1978

The cerebellar projection from locus coeruleus as studied with retrograde transport of horseradish peroxidase in the cat.

The cerebellar afferent projection from locus coeruleus has been studied in the cat by means of retrograde axonal transport of horseradish peroxidase. Labelled cells are present bilaterally in locus coeruleus only following injections in the cerebellar vermis (especially its anterior and posterior parts), the ventral paraflocculus and the flocculus. The labelled cells are restricted to the caudal half of the nucleus. A few labelled cells are also present in locus coeruleus following injections in the fastigial nucleus, and in nucleus interpositus anterior. The findings are discussed in relation to other studies on the efferent and afferent connections of the locus coeruleus.

Animals↗
PubMed1975

Histochemical characterization of a neocortical projection of the nucleus locus coeruleus in the squirrel monkey.

Histochemical evidence is presented for a catecholamine-containing projection from the nucleus locus coeruleus to the neocortex in the squirrel monkey. The innervation of superior temporal gyrus has been examined in particular. Glyoxylic acid-induced fluorescence shows an extensive arborization of fine, catecholamine-containing fibers with prominent varicosities in all layers of the neocortex. The nucleus locus coeruleus is identified as a source of these fibers by both ortho- and retrograde axonal tracing techniques. After injection of horseradish peroxidase into the neocortex, labelled cell bodies are localized throughout the major portions of the locus coeruleus. Conversely, after microinjection into the nucleus locus coeruleus, tritiated proline is transported into the neocortex where it appears within fibers similar in distribution to those revealed by fluorescence histochemistry. Both transport techniques indicate that cortical projections of the locus coerculeus originate from both ipsilateral and contralateral nuclei.

Animals↗
PubMed1979

Loss of nerve cell bodies in caudal locus coeruleus following treatment of neonates with 6-hydroxydopa.

The locus coeruleus is a well defined nucleus in cresylechtviolet preparations and the perikarya are easily distinguished. The coeruleus neurons are thought to be noradrenergic and during development can be selectively affected by the neurotoxin, 6-hydroxydopa (6-OHDOPA). In 6-month-old rats that were treated on day of birth with 6-OHDOPA (60 mg/kg, i.p.) there was a 32% loss of nerve cell bodies in the locus coeruleus. While it was apparent that loss of cell bodies occurred throughout the entire nucleus, the greatest loss of perikarya was from the caudal extent of the nucleus. It is known that sprouting of noradrenergic terminals occurs in the cerebellum of rats following treatment of newborns with 6-OHDOPA. That there are fewer cell bodies to contribute additional terminals further dramatizes this sprouting phenomenon.

Animals↗
PubMed1977

[Response of the locus coeruleus to asphyxia].

To ascertain the mechanisms of the locus coeruleus (LC) function the response of the locus coeruleus neurons to the experimental sharp asphyxia was investigated by the light and electron microscope techniques. Apart from the specific nervous effect (directly through the LC axons and through the stem reticular formation), LC produced humoral influence on the brain structures. There are two possible mechanisms by which catecholamines synthesized in the LC cells could reach the blood; 1) through the cell membrane and then through the basal membrane of the capillary bed and the cytoplasm of the endothelial cell; 2) by virtue of the glia cells.

Animals↗
PubMed1977

Ascending projections of the locus coeruleus in the rat. I. Axonal transport in central noradrenaline neurons.

Axonal transport of protein and metabolites of L-[3H(G)]3, 4-dihydroxyphenylalanine ([3H]DOPA) was studied in the central noradrenaline neurons of the pontine nucleus locus coeruleus and was correlated with regional alterations of noradrenaline content following destruction of the nucleus. Unilateral lesions of the locus coeruleus produce a partial depletion of noradrenaline in the ipsilateral hypothalamus and telencephalon, indicating that these neurons project widely to the ipsilateral forebrain. Twenty-four to 48 h following local injections of 50 micronCi [3H]proline, locus coeruleus neurons take up labeled material and transport it, presumably as protein, to ipsilateral structures in the midbrain, diencephalon and telencephalon including the neocortex. Similarly 8 h after injection of 25 micronCi [3H]DOPA into the locus coeruleus, transport of material including catecholamines occurs to ipsilateral diencephalon and telencephalon. Axonal transport of proteins to telencephalic structures is greatly diminished by selective lesions of catecholamine terminals with 6-hydroxydopamine (6-OHDA) and following destruction of the medial forebrain bundle. These results provide further support for the view that noradrenaline neurons of the locus coeruleus nucleus project widely within the neuraxis to ipsilateral structures of the brain stem, diencephalon and telencephalon, including all cortical areas. In addition, evidence is presented for a contralateral projection with a similar distribution. The rate of axonal transport of labeled protein and metabolites of [3H]DOPA including [3H]catecholamines in central noradrenaline neurons is estimated to be 3-4 mm/h and is accordingly similar to that reported for noradrenaline neurons of the peripheral sympathetic nervous system.

Adrenergic Fibers↗
PubMed1979

Functional reinnervation of rat hippocampus by locus coeruleus implants.

Transplants of the embryonic locus coeruleus (LC) region were implanted into the circuity of the hippocampal formation in adult rats in which the normal adrenergic afferents to the hippocampus had been removed. The growth of new adrenergic axons from the implant in the denervated hippocampus was followed for 1-14 months after surgery by means of fluorescence histochemistry, and the function of the implant-hippocampal connections was tested electrophysiologically after 2-3 months survival. In the successful cases the entire hippocampal formation was reinnervated from the LC implant within 3-6 months after operation, and the newly formed innervation still persisted unchanged by 14 months. The reinnervation was equally effective irrespective of the route by which the axons entered the hippocampus, i.e. along the lesioned fornix-fimbria or along a retrosplenial route. The pattern formed by the ingrowing LC axons mimicked to a large extent that of the normal LC afferents. Little growth was seen into denervated terminal fields of the commissural, septal or entorhinal afferents, pointing to a preference of the ingrowing LC fibers for the areas normally innervated by adrenergic afferents. In the electrophysiological experiments, stimulation of the LC implants caused (in 20 out of 29 cells monitored) an inhibition of the spontaneous activity of neurons in the host hippocampus. This inhibition had a relatively long latency and a long duration, similar to that observed after stimulation of the innate LC in the intact rat. As in the normal rat, the inhibitory responses were blocked by systemic or local application of the beta-adrenergic receptor blockers propranolol or sotalol. It is concluded that the adult rat brain is capable of carrying out all steps involved in correct functional reinnervation of a denervated region. Moreover, the implant-hippocampal preparation should be a highly suitable model system for functional studies of a central noradrenergic connection.

Adrenergic Fibers↗
PubMed1977

The effect of lesions in the locus coeruleus on the physiological responses of the cerebral blood vessels in cats.

The effects of cerebral blood flow (CBF) of lesions placed stereotactically in or near the locus coeruleus were studied in 15 lightly anesthetized cats; 5 control cats in which the electrode was placed but no lesion created, and 10 experimental cats in which a lesion was created. The response of CBF to changes in Paco2 and in mean arterial blood pressure was determined by 133Xe-washout studies 10 days after the stereotactic procedures. The sites of the lesions were studied histologically, and their effects on catecholamine concentrations in the paraventricular hypothalamic nucleus, anterior ventral nucleus of the thalamus, and parietal cortex were determined by radio-chemical assay. Control animals and those with lesions near, but not in, the locus coeruleus had normal Paco2--CBF response curves and normal catecholamine concentrations in the areas of biopsy. Bilateral destruction of the locus coeruleus was confirmed in 3 animals on histological examination and in these animals there were decreased levels of catecholamines in the areas of assay, higher resting CBFs at normocapnia, and significantly abnormal CBF--Paco2 response curves. The autoregulatory response to changes in perfusion pressure was preserved. Thus, noradrenergic neurons originating in the locus coeruleus may contribute to the control of intraparenchymal cerebral vessels and disturbance of this control may be important in the pathology of cerebral ischemia.

Animals↗
PubMed1978

Effects of catecholamine depleting drugs and d-amphetamine on self-stimulation of the substantia nigra and locus coeruleus.

6-Hydroxydopamine treatments which preferentially depleted either norepinephrine or dopamine were used to define the importance of these transmitter systems in the behavioral alterations produced by catecholamine synthesis inhibitors and d-amphetamine on self-stimulation of the locus coeruleus and substantia nigra. After chronic reduction of brain dopamine, an acute depression of self-stimulation of both the locus coeruleus and substantia nigra occurred. Preferential depletion of norepinephrine with 6-hydroxydopamine did not result in a significant decrease in self-stimulation of locus coeruleus or substantia nigra. However, a dose of alpha-methyltyrosine wihch had no effect in control rats or in rats with brain norepinephrine depleted caused a significant reduction in responding at both electrode placements in animals depleted of brain dopamine. Administration of U-14,624 affected neither substantia nigra nor locus coeruleus self-stimulation, even though it produced an additional 70% depletion of norepinephrine. When d-amphetamine sulfate was given to 6-hydroxydopamine-treated rats, the facilitation of self-stimulation produced by this compound was significantly attenuated in rats with prior depletion of brain dopamine. Depletion of brain norepinephrine did not affect the actions of d-amphetamine on self-stimulation. In other experiments, the actions of d-amphetamine to increase self-stimulation of animals pretreated with reserpine was found to be antagonized by alpha-methyltyrosine but not by U-14,624. Results suggest that drugs can alter self-stimulation of a site in brain anatomically associated with noradrenergic neural pathways and self-stimulation of a site primarily associated with dopaminergic pathways in a similar manner. These data also provided evidence for the involvement of dopamine fibers in the pharmacological actions of d-amphetamine, reserpine and alpha-methyltyrosine.

Animals↗
PubMed1977

Behavioral effects of neuroleptics, apomorphine and amphetamine after bilateral lesion of the locus coeruleus in rats.

Bilateral lesions of the locus coeruleus (LC) markedly increased susceptibility to the cateleptogenic effects of neuroleptics. The apomorphine-induced stereotypy was enhanced in rats with lesioned LC whilst amphetamine stereotypy was only slightly increased. No changes in locomotor activity have been observed in LC-lesioned rats treated with apomorphine and amphetamine. This data indicates that lesions of the LC produce decreased activity of dopaminergic brain neurons as well as supersensitivity of dopaminergic receptors.

Animals↗
PubMed1975

Biochemical mapping of the noradrenergic projection from the locus coeruleus. A model for studies of brain neuronal pathways.

Mapping of the noradrenergic projection from neurons in the rat locus coeruleus has been examined by combining a sensitive radioisotopic assay for catecholamines with a microdissection technique to remove multiple separate brain nuclei. The effect of a unilateral locus coeruleus lesion on norepinephrine concentration in 19 brain regions ipsilateral and contralateral to the lesion was determined. Evidence for ipsilateral and bilateral innervation to specific regions is presented, and many regions appear to receive combined innervation from other noradrenergic loci, in addition to that from the locus coeruleus. Fluorescence rating was correlated with biochemical measurement of amine content with these techniques and proportionality was observed over a narrow range. With this proportionality taken into consideration, mapping results obtained by biochemical and fluorescence methods are compared.

Animals↗
PubMed1979

Distribution of hypertrophied locus coeruleus projection to adult cerebellum after neonatal 6-hydroxydopamine.

Following treatment as neonates with a high subcutaneous dose of 6-hydroxydopamine (6-OHDA), the projections of the locus coeruleus were mapped in the brains of adult rats. This was done using the technique of unilateral lesions in the nucleus followed by simultaneous determinations of norepinephrine (NE) levels, dopamine-beta-hydroxylase (DBH) activity and synaptosomal [3H]NE uptake in various terminal areas. In particular the cerebellum was subdivided into 3 areas in order to assess any changes from normal in the distribution of the hypertrophied noradrenergic projections here. In vehicle-control rats the lesions resulted in an 80--85% loss of NE in the parietal cortex ipsilateral to the lesion and a 15--20% loss contralaterally. In the control cerebellum the locus coeruleus projection, based upon changes in all 3 markers, is distributed 2/3 ipsilaterally and 1/3 contralaterally with the same pattern present in all 3 subregions. The neonatal 6-OHDA treatment resulted in virtually complete loss of noradrenergic terminals in the cerebral cortex. Following neonatal 6-OHDA treatment cerebellar levels of NE, DBH and [3H]NE uptake increased by between 20--60%, with the smallest increases occurring in [3H]NE uptake. In these rats the locus coeruleus accounted for at least 75--80% of the cerebellar noradrenergic parameters. Unlike control rats however, the lesions in these rats produced only ipsilateral decreases in NE and DBH. On the other hand changes in [3H]NE uptake indicated a normal 2/3 ipsilateral, 1/3 contralateral pattern. It is suggested that two separable events occur in the noradrenergic projection to the cerebellum. The first is the regeneration of an increased number of nerve terminals, or sprouting, and the second is a build-up of synaptic vesicles, or collateral accumulation. The sprouting, judging from the [3H]NE uptake data, occurs with apparently normal distribution, but the accumulation of NE and DBH is confined predominantly to the ipsilaterally projecting axon terminals. This may be the consequence of collateral accumulation resulting from the degeneration of the largely ipsilateral coeruleocortical projection.

Animals↗
PubMed1976

Evidence that self-stimulation of the region of the locus coeruleus in rats does not depend upon noradrenergic projections to telencephalon.

Rats with intracranial self-stimulation (ICSS) electrodes in the locus coeruleus and adjacent pontine tegmental structures received stereotaxically placed bilateral injections of 6-hydroxydopamine (4 mug/2 mul) into the mesencephalic trajectory of the dorsal tegmental noradrenergic bundle. The consequent depletions of norepinephrine in the cerebral cortices and hippocampi (96.7%) did not result in significant changes in ICSS. Thus, diencephalic and telencephalic noradrenergic projections of the locus coeruleus do not appear to be critical for the occurrence of ICSS from that nucleus or its surrounding region. Nor do these projections appear to be crucially involved in the enhancement of this ICSS by D-amphetamine. Rats in this study showed two-fold increases in responding following injections of D-amphetamine sulfate (0.5 mg/kg) both before and after the lesions of the dorsal tegmental bundle. These results suggest that the ascending projections of the locus coeruleus are not critically involved in ICSS of the dorsal pontine tegmentum.

Animals↗
PubMed1978

Atonia after carbachol microinjections near the locus coeruleus in cats.

The effect of microinjections of carbachol into the dorsolateral pontine tegmentum on the behaviour of cats is investigated. Injections of small amounts (50 and 500ng) of carbachol into the pontine reticular formation induced muscular atonia in otherwise awake animals. The atonia is not due to cholinergic stimulation of the noradrenergic cells of the locus coeruleus or the dorsolateral pons, since the most effective sites were situated ventrally to the locus coeruleus and alpha- and beta-adrenergic blocking agents did not affect the antonia. The results are discussed in view of the postulated role of the locus coeruleus in paradoxical sleep.

Animals↗
PubMed1978

The relationship of the locus coeruleus to the amygdala in the cat.

In eight cats a unilateral lesion was produced in the locus coeruleus using either a 20 degree or a 30 degree rostrocaudal parasagittal electrode approach. The animals were killed after a survival period of 10 days. Ascending locus coeruleus projections found in the five animals with the best area destruction went through the dorsal pontine tegmentum into the mesencephalic central tegmental tract, entered the thalamic centromedian--parafascicularis nuclear complex, and divided into dorsal and ventral fascicles. The dorsal fascicle spread into much of the rostral thalamus, while the ventral one passed to the lateral hypothalamus and zona incerta. The lateral hypothalamic fibres extended rostrally into the preoptic area. No degeneration was seen passing in or through the amygdaloid body or stria terminalis. Critical analysis of our own findings and those of other investigators forces the conclusion that apparent projections to the amygdaloid area are really fibres of passage to the pyriform cortex and septum.

Amygdala↗
PubMed1977

Effects of locus coeruleus lesions upon cerebral monoamine content, sleep-wakefulness states and the response to amphetamine in the cat.

The purpose of the present study was to investigate the effects of complete lesions of the noradrenaline locus coeruleus neurons upon wakefulness and paradoxical sleep. Radiofrequency lesions of the nucleus were performed in 8 chronically implanted cats which were continuously recorded with an EEG for 5 days prior to and 21 days following the lesions, when they were sacrificed. In 3 of these animals amphetamine (2 mg/kg) was administered on one control day and on the 10th day post-lesion. Following sacrifice, monoamine content was assayed in discrete brain regions, and the lesion was examined in Nissl-stained sections of the pons. (1) The majority (x 69%) of the locus coeruleus was bilaterally destroyed by the lesions which only minimally exceeded the boundaries of the nucleus within the dorsolateral pontine tegmentum. Noradrenaline was depleted by a mean of 85% in the paleo- and neocortex and by a mean of 60% in the thalamus and midbrain. (2) EEG activation reappeared within 12-48 h following the lesion and represented a normal percentage of recording time on the 3rd and subsequent days post-lesion. The behavioral arousal and long-lasting EEG activation produced by amphetamine was qualitatively and quantitatively the same pre- and post-lesion. (3) Despite alteration of certain components, paradoxical sleep reappeared within 48 h and recovered to normal amounts by the second week post-lesion. Muscle atonia was permanently absent in 7 animals. Ponto-geniculo-occipital (PGO) spiking was acutely redistributed across all states and chronically reduced in frequency (by a mean of 50%) within paradoxical sleep. These results indicate that the noradrenaline locus coeruleus neurons are not necessary for the tonic maintenance of EEG activation that occurs in normal wakefulness and in amphetamine-produced arousal. Furthermore, these neurons are not necessary for the occurrence of paradoxical sleep, although they may be involved in modulation of PGO spiking.

Animals↗
PubMed2025

A comparison of viral strategies and model systems to target norepinephrine neurons in the locus coeruleus reveals high variability in transgene expression patterns.

The locus coeruleus (LC) norepinephrine (NE) system is involved in a variety of physiological and pathophysiological processes. Refining our understanding of LC function largely relies on selective transgene expression in LC-NE neurons, allowing targeted manipulation and readout of noradrenergic neurons. Here, we performed a side-by-side comparison of the most commonly used strategies to genetically target the LC, including different cre driver lines and promoter-mediated transgene expression. We report differences between these strategies in terms of transgene expression efficacy and specificity. Parallelly, we found no behavioral alterations in cre-expressing mice of any mouse line compared to wild-type littermates. Finally, to further facilitate the investigation of LC-NE function, we created a suite of constructs, including a reporter protein, a calcium indicator, and a light-driven cation channel, whose expression is mediated by the previously described PRS×8 promoter. These constructs allow identification, monitoring, and manipulation of LC-NE activity either in wild-type mice, or in combination with tissue-specific manipulations of different cre driver lines. The results of our study are crucial for the interpretation of previous experiments using the respective targeting strategies, as well as for the design of future studies.

Animals↗