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PubMed1982

Intraocular fibre growth of grafted locus coeruleus neurons: sensory denervation counteracts alterations induced by thyroid hormone deficiency.

Immature central noradrenaline neurons from the nucleus locus coeruleus were grafted to surgically thyroidectomized adult rats. As previously reported, fibre production from locus coeruleus in the host iris is hampered by thyroid hormone deficiency. We wanted to investigate if sensory denervation of the target iris tissue, a procedure known to enhance fibre production from locus coeruleus neurons, would interact with and possibly reverse the morphological signs of thyroid hormone deficiency. We found that a sensory denervation of the host iris reversed all morphological signs of the endocrine manipulation. Thus the number of axons found in bundles increased 30-fold and the density of accumulations intermingled with the fluorescent nerve plexus fell by half. Furthermore, the distribution of fibres in the host iris changed, spreading to more than double the surface area of the control thyroidectomized group. In all these respects the fibre growth of locus coeruleus in the sensorily denervated group mimicked what has been reported before in similarly denervated animals with intact endocrine status. These results show that the hampered nerve fibre growth induced by a thyroid hormone deficiency can be counteracted by a specific sensory denervation of the target tissue restituting the endocrine imbalance.

Animals↗

PubMed1986

Mechanisms of epileptic brain damage: evidence for a protective role of the noradrenergic locus coeruleus system in the rat.

This study explores the possibility that the noradrenergic locus coeruleus system influences epileptic brain damage. Bilateral 6-hydroxydopamine lesions of the locus coeruleus projection to the forebrain were found to aggravate neuronal necrosis in the neocortex following 60 min of flurothyl-induced status epilepticus. We propose that the activation of the inhibitory locus coeruleus system during status epilepticus counteracts a deleterious neuronal hyperexcitation, probably induced by excessive release of excitatory amino acids, thereby limiting neuronal necrosis.

Adrenergic Fibers↗

PubMed1993

Electrophysiological changes accompanying DSP-4 lesions of rat locus coeruleus neurons.

The electrophysiological characteristics of intracellularly recorded locus coeruleus (LC) neurons in brain stem slices from DSP-4 treated animals have been compared to those from untreated controls. LC neurons from DSP-4 treated animals had action potentials and Ca2+ spikes (elicited in the presence of TTX) of significantly reduced duration compared to controls. These observations suggest that chemical axotomy with DSP-4 reduces Ca2+ conductance in neurons of the locus coeruleus.

Action Potentials↗

PubMed2000

Differential regulation of neuropeptide Y mRNA expression in the arcuate nucleus and locus coeruleus by stress and antidepressants.

In rats, circulating corticosterone and insulin are involved in regulation of the hypothalamic neuropeptide Y (NPY) system, which in turn, is involved in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Since the HPA axis and stress responsivity is altered in diseases such as depression, we investigated interactions between the effects of stress and antidepressant drug treatment on arcuate nucleus and locus coeruleus NPY mRNA expressions using in-situ hybridization histochemistry. After acute (2 h) and repeated immobilization (2 h daily, for 14 days), plasma concentrations of corticosterone increased, and those of insulin decreased. The expression of NPY mRNA was significantly increased in the arcuate nucleus, but was unchanged in the locus coeruleus following acute and repeated immobilization. Adrenalectomized rats with systemic corticosterone replacement (ADX+CORT), whose corticosterone concentration was maintained at approximately 50-100 ng/ml during repeated stress, showed a decrease in plasma insulin and an increase in arcuate nucleus NPY mRNA similar to that observed in sham rats, suggesting that changes in NPY mRNA levels are more closely tied to circulating insulin than to circulating corticosterone. In contrast, locus coeruleus NPY mRNA expressions in ADX+CORT rats were significantly higher than those in sham rats after repeated stress. Desmethylimipramine (DMI) treatment for 24 days did not affect basal plasma concentrations of corticosterone or insulin, or arcuate nucleus NPY mRNA expressions, but significantly decreased basal levels of locus coeruleus NPY mRNA compared to saline-treated rats. After repeated immobilization (2 h daily, for 4 days), DMI significantly reduced the stress-induced rise in locus coeruleus NPY mRNA levels, but potentiated the stress-induced rise in arcuate nucleus NPY mRNA expression. These results demonstrate that: (1) the increase in arcuate nucleus NPY mRNA expressions in stressed rats closely follows the decrease in plasma concentrations of insulin; (2) increases in NPY mRNA expressions occur in the absence of changes in plasma corticosterone; and (3) desipramine treatment potentiated the effect of stress on arcuate nucleus NPY mRNA expressions, but blocked the repeated stress-induced increase in locus coeruleus NPY mRNA expressions. Thus, NPY mRNA expression in the arcuate nucleus and the locus coeruleus is sensitive to the effects of stress and to the antidepressant drug desipramine, but the arcuate nucleus NPY system is regulated by different mechanisms than the locus coeruleus NPY system. The results provide further evidence for the importance of circulating insulin in the regulation of the arcuate nucleus NPY system.

Adrenalectomy↗

PubMed1984

Fetal locus coeruleus transplanted into the transected spinal cord of the adult rat: some observations and implications.

The 16-day-old fetal locus coeruleus can survive and grow, when transplanted into the spinal cavity created by transection of the adult spinal cord. The implants usually break up into smaller cell groups which become lodged in the host spinal cord, mainly in the caudal region. There was a marked proliferation of the damaged coerulospinal noradrenergic fibers in the rostral, ventral horn region of the cord. A neurotrophic substance produced by the locus coeruleus implants is probably responsible for this effect. Evidence for vigorous axonal growth of noradrenergic fibers derived from the implants in the caudal region of the cord was obtained. In 2/12 cases, the surviving locus coeruleus did not grow into the host tissue. Neosympathetic innervation of the caudal region of the cord occurred both in cases in which the implants survived, or did not survive. The survival rate of the transected, implanted animals is greater than 90%. The success rate of fusion of the implant with the host tissue is 40%. Based on these results, and other reports published recently, it is concluded: (1) that the purely technical difficulties of transplantation and survival of the fetal locus coeruleus in the transected spinal cord of the young adult rat on a long-term basis can be successfully solved. (2) For optimum reinnervation, the transplant should be placed in the lumbar intumescence, and not in the spinal cavity created by transection. (3) The spinal cavity created by transection must be bridged by some other method. The use of fetal spinal cord tissue on fetal mesencephalic tissue may prove to be useful for this purpose. (4) Transection of the cord must be done sub-pially, in order to minimize retraction and compression of the cord. The damaged pia must be resutured. (5) A second fetal locus coeruleus implant should be placed adjacent to the exposed surface of the rostral region of the cord. The results are discussed both in the context of recent efforts to try to restore functional activity to the damaged spinal cord, and in terms of efforts to try to understand the problems involved in fostering the growth of fetal brain tissue in the damaged spinal cord of an adult host animal.

Animals↗

PubMed2003

Acute effect of simultaneous administration of tryptophan and ethanol on serotonin metabolites in the locus coeruleus in rats.

Using the microdialysis method, we investigated whether the levels of serotonin (5-hydroxytryptamine, 5-HT) and its metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTPL), in the locus coeruleus are influenced by tryptophan alone or simultaneous administration of tryptophan and ethanol. Tryptophan (50 mg/kg, i.p.) led to a significant increase in the levels of 5-HIAA, but not 5-HT in the locus coeruleus. However, ethanol (1.25 g/kg) had no effect on the levels of 5-HT and its metabolites. Combined administration of tryptophan and ethanol caused very marked increases in 5-HIAA and 5-HTPL levels in the locus coeruleus. A time lag in the increased 5-HIAA levels between tryptophan alone and tryptophan plus ethanol was observed. Moreover, 5-HIAA levels in the locus coeruleus induced by tryptophan were abolished by microinjection of 5,7-dihydroxytryptamine (150 microg/4 microl) into the dorsal raphe nucleus. Judging from the present results, the serotonergic afferents to the locus coeruleus may originate for about 20-30% from cell bodies located in the dorsal raphe nucleus. Teeth-chattering was significantly detected in the tryptophan plus ethanol-treated rats when compared with the tryptophan-treated rats, but not in the saline-treated controls. These results may suggest that the increased levels of 5-HIAA and 5-HTPL in the locus coeruleus induced by tryptophan are potentiated by ethanol, and that these levels are partly responsible for behavioral activation.

5,7-Dihydroxytryptamine↗

PubMed1980

Demonstration of projections from locus coeruleus to supraoptic nucleus by the HRP method with special reference to cell types in the rat.

Histochemical studies have been conducted on the distribution of labeled neurons in the rat pons at the level of the locus coeruleus after HRP injections into the supraoptic nucleus. In all the fifteen cases in which the supraoptic nucleus was found to be included in the injection site, labeled neurons were detected in the locus coeruleus whereas in the other nine cases in which the injection site was outside the supraoptic nucleus, labeled neurons were not detected in the locus coeruleus. Six cases having the injection site successfully localized within the supraoptic nucleus showed definitely a few labeled multipolar neurons only in the ipsilateral locus coeruleus. These findings demonstrate the presence of an efferent projection arising from the locus coeruleus to the ipsilateral supraoptic nucleus. It is suggested that mainly multipolar neurons in both divisions of this nucleus may contribute to this projection. There remains a possibility that the locus coeruleus may project to the supraoptic nucleus on the contralateral side.

Animals↗

PubMed1977

[Afferent pathway from locus coeruleus to the nucleus solitarius].

After the destruction of the nucleus tractas solitarii, just caudally to the writing pen by means of a stereotaxic instrument, the system of afferent fibres to the nucleus in question was investigated by the methods of Nauta and Fink--Heimer. The fibre terminals were revealed near locus coeruleus. Investigation of the locus coeruleus by Golgi method demonstrated that it usually has neurons of reticular type and transitional ones which resemble by their form the neurons specific for sensory formations. It is possible to conclude that locus coeruleus posesses connections of visceral origin which may play a part in the afferent influence of locus coeruleus on the brain cortex.

Animals↗

PubMed1996

Differential effects of the intraventricular administration of 6-hydroxydopamine on the induction of type II beta-tubulin and tyrosine hydroxylase mRNA in the locus coeruleus of the aging Fischer 344 rat.

Noradrenergic neurons of the locus coeruleus have been shown to respond to injury by increasing the synthesis of neurotransmitter (via the activation and induction of tyrosine hydroxylase, the rate-limiting catalyst in the production of catecholamines) and initiating compensatory axonal sprouting. However, this laboratory has recently described a significant deficit in the activation of tyrosine hydroxylase in the aged Fischer 344 rat, in contrast to the young and mature rat, following partial damage to cortical and hippocampal noradrenergic terminals induced by the neurotoxin 6-hydroxydopamine. To extend these observations, we measured changes in the relative levels of neuron-specific type II beta-tubulin and tyrosine hydroxylase mRNA in locus coeruleus neurons of 2, 12, and 24-month-old Fischer 344 rats following intraventricular infusions of 6-hydroxydopamine by using in situ hybridization histochemistry. These measures were used as markers of the responsiveness of these neurons to injury. 6-Hydroxydopamine treatment induced a persistent increase (at least 10 days) in the expression of type II beta-tubulin mRNA only in 2-month-old animals; this marker decreased in the 12 and 24-month-old animals. Relative levels of tyrosine hydroxylase mRNA increased in 2 and 12-month-old lesioned animals both 3 and 10 days post-treatment. In contrast, the induction of tyrosine hydroxylase mRNA in 24-month-old animals, seen three days post-treatment, was attenuated by 10 days. These data indicate that the capacity of locus coeruleus neurons to compensate for injury by either initiating a potential sprouting response or increasing their capacity to synthesize neurotransmitter is reduced in older animals.

Age Factors↗

PubMed1991

Synaptic potentials in locus coeruleus neurons in brain slices.

Neurons of the locus coeruleus (LC) fire action potentials spontaneously in vitro in the absence of any stimulation. This spontaneous activity is thought to arise from intrinsic membrane properties that include a balance between at least two ion conductances. One is a persistent inward sodium current that is active near the threshold for action potential generation. The second is a calcium-dependent potassium current that is activated following the entry of calcium during the action potential, is responsible for the after-hyperpolarization following the action potential, and decays over a period of 1-2 sec following the action potential. The spontaneous activity of LC neurons can be altered by both excitatory and inhibitory synaptic inputs. One excitatory input has been described that is mediated by glutamate receptors of both the non-NMDA and NMDA subtypes. Inhibitory synaptic potentials include those mediated by GABA (acting on GABAA-receptors), glycine (acting on a strychnine-sensitive receptor) and noradrenaline (acting on alpha 2-adrenoceptors). The presence of synaptic potentials mediated by these transmitters, studied in vitro, correlate with studies made in vivo and with histochemical identification of synaptic inputs to the locus coeruleus.

Action Potentials↗

PubMed1981

Cerebral blood flow and oxygen consumption in the rat brain after lesions of the noradrenergic locus coeruleus system.

The effect of lesions of the locus coeruleus neuron system on cerebral metabolic rate for oxygen (CMRO2) and blood flow (CBF) was evaluated in paralyzed and mechanically ventilated rats, using a 133xenon modification of the Kety-Schmidt inert gas technique. Bilateral electrothermic lesions of its ascending bundle caused no significant change in CBF or CMRO2. The 6-hydroxydopamine lesions did not influence the CBF and CMRO2 responses to hypercapnia and hypoxia. It is concluded that the locus coeruleus does not exert any resting tone on CBF and CMRO2 and that no influence on the CBF and CMRO2 responses to hypercapnia and hypoxia is mediated via its ascending projections.

Animals↗

PubMed1978

The locus coeruleus noradrenergic system--evidence against a role in attention, habituation, anxiety and motor activity.

Lesions of the locus coeruleus system were induced by combined stereotaxic injections of 6-OH-dopamine to the ascending fibres and just lateral to the locus coeruleus itself, to deplete the noradrenaline content of both the cerebral and cerebellar cortices. A group of rats with cortical noradrenaline concentrations of less than 30 ng/g were compared with a group with lesser destruction of the system (mean noradrenaline concentration 71 +/- 44 ng/g) and with controls (mean noradrenaline 347 +/- 58 ng/g). Lesioned rats showed normal motor activity and exploration (assessed with a holeboard) and showed normal habituation of these behaviours. The lesioned rats gave no evidence of increased susceptibility to distracting auditory stimuli whilst licking for water, and the groups did not differ in their rate of habituation to these stimuli, or in dishabituation. In a social interaction test, lesioned animals showed a decrease in social contacts in an unfamiliar situation (interpreted as a response to anxiety) of similar magnitude to that seen in the control group. In this test, lesioned animals engaged in more 'aggressive' behaviour (boxing and wrestling) than did the controls. These findings are incompatible with hypotheses that the locus coeruleus system is an integral part of the physiological mechanisms which control gross motor behaviour, attention, habituation or anxiety. Together with previous findings with the benzodiazepines, the results with the social interaction test make it unlikely that the benzodiazepines exert their anxiolytic effects by inhibiting the locus coeruleus system.

Acoustic Stimulation↗

PubMed1980

[Fluorescence histochemical and neurohistological investigations on the locus coeruleus of the rat (author's transl)].

The Locus coeruleus (LC) of the adult rat was investigated by means of fluorescence histochemical and rapid GOLGI impregantion technique. The majority of LC neurons displayed, as a result of application of the FALCK-HILLARP-technique and the LOREN-technique, resp, the well-known fluorescence typical of catecholamine neurons. There was lack of fluorescence within a minor portion of cells. Fluorescence histochemically, serotoninergic afferents could be shown to go up to noradrenaline-containing neurons in some cases. In the GOLGI material, 3 types of neurons could be distinguished: Polygonal neurons exhibiting somatic spines, fusiform neurons, and small-sized spine-less neurons. Based on morphological features, the polygonal neuron type is considered to represent the monoamine-containing neurons of the Locus coeruleus. It appears uncertain at present to attribute the fusiform and small spineless neuron types in a functional manner. functional implications inherent that morphological heterogeneity have been discussed.

Animals↗

PubMed1991

Locus coeruleus stimulation exerts different influences on the dynamic changes of cerebral pial and intraparenchymal vessels.

The present experimental study was undertaken to investigate the effects of locus coeruleus stimulation on the dynamic changes of intraparenchymal vessels and pial vessels. Twelve cats were anaesthetized with alpha-chloralose and urethane. For stimulation of the locus coeruleus, a concentric stainless-steel needle electrode was inserted stereotaxically. During the stimulation, volumetric changes of the intraparenchymal vessels were monitored by a photoelectric method for estimating the cerebral blood volume (CBV) (6 cats), and the diameters of pial arteries were measured continuously using a video camera system (6 cats). The CBV followed a decreasing course during the stimulation of the locus coeruleus. The decrease in CBV from the control value (6.3 vol%) was 0.14 +/- 0.04 vol% at 80 s (p less than 0.05), 0.15 +/- 0.05 vol% at 100 s (p less than 0.05), and 0.15 +/- 0.03 vol% at 120 s (p less than 0.01). After cessation of the stimulation, CBV showed a gradual recovery. On the other hand, the diameters of the pial arteries did not change during or after the stimulation of the locus coeruleus. The above results suggest that the locus coeruleus has a vasoconstrictive effect on the intraparenchymal vessels, although it exerts no apparent influence on the pial arteries.

Animals↗

PubMed1994

Actions of a long-acting somatostatin analog SMS201-995 (sandostatin) on rat locus coeruleus neurons.

The actions of sandostatin involving rat locus coeruleus (LC) neurons were examined using an intracellular recording in a brain slice preparation. Bath application of sandostatin (5-100nM) reversibly decreased the firing rate of all neurons tested in a dose-dependent manner. Sandostatin was 9.5 times more potent than somatostatin in light of an inhibition of the spontaneous firing rate. In addition to the inhibition of spontaneous firing, larger concentrations of sandostatin (30-100nM) also hyperpolarized the neurons of the locus coeruleus and simultaneously caused a reduction in input resistance. At the highest concentration (100nM) applied, sandostatin produced complete inhibition of firing of all neurons tested (n = 49); the inhibition was associated with a 11.6mV hyperpolarization (range 2.2-26.4 mV, n = 49) and a 21.8% reduction in input resistance (range 2.6-55.2%, n = 39). The voltage-current relationship of the resting cell revealed an inward-going rectification that became enhanced after the perfusion of sandostatin (100nM) for 5 min. The reversal potential for the sandostatin-induced hyperpolarization was -111 +/- 1 mV (n = 10), which is approximately the potassium equilibrium potential. This hyperpolarization was blocked by both caesium chloride and barium chloride. Our results also showed that sandostatin displayed an antagonistic action on mu opiate receptors. Both the somatostatin-agonistic and opiate-antagonistic activities of sandostatin were conclusively found to be stronger than those of somatostatin; in addition, the inhibitory actions of sandostatin on LC neurons were due to an opening of the inward-going rectification potassium channels.

Animals↗

PubMed1992

Disease-specific patterns of locus coeruleus cell loss.

Computer visualization techniques were used to map and to quantitatively reconstruct the entire locus coeruleus, including the nucleus subcoeruleus, to compare the topographic patterns of cell loss in postmortem brains from patients with Parkinson's disease, Alzheimer's disease, and Down syndrome. There was comparable cell loss in all three diseases (approximately 60%) compared with aged normal subjects, and there was a significant loss of nucleus subcoeruleus cells specifically in patients with Parkinson's disease (63%). There was a significant positive correlation between the magnitude of locus coeruleus cell loss and the duration of Alzheimer's disease, but no such correlation was found for Parkinson's disease. In patients with Parkinson's disease, there was comparable cell loss throughout the rostral-caudal extent of the nucleus; however, in patients with Alzheimer's disease and Down syndrome, the greatest cell loss always occurred within the rostral portion of the nucleus, with a relative sparing of caudal cells. These data are consistent with the hypothesis that cell loss in Parkinson's disease is the result of a pathological process that attacks the catecholaminergic cells of the locus coeruleus and the subcoeruleus in general; in Alzheimer's disease and Down syndrome, however, the pathological process only affects the rostral, cortical-projecting locus coeruleus cells and spares the caudal, noncortical-projecting cells.

Aged↗

PubMed1992

[Inhibitory effects of Hachimijiogan on micturition reflex via the locus coeruleus].

Pharmacological studies were undertaken to elucidate the role of Hachimijiogan in the micturition reflex via the locus coeruleus, using alpha-chloralose-anesthetized cats. Rhythmic contractions of the urinary bladder induced by continuous infusion of saline into the bladder were dose-dependently inhibited by intravenous injection of Hachimijiogan (10, 30 and 90 mg/kg), as well as flavoxate hydrochloride (1 and 3 mg/kg). In contrast, contraction of the urinary bladder elicited by electrical stimulation of the locus coeruleus was significantly suppressed by intravenous injection of flavoxate, but not affected by that of Hachimijiogan. These results suggest that Hachimijiogan acts on the afferent pathway from the urinary bladder to the locus coeruleus, thereby inhibiting the micturition reflex, while it has no effects on the efferent pathway from the locus coeruleus to the urinary bladder.

Animals↗

PubMed1994

Agonist binding to alpha 2-adrenoceptors is elevated in the locus coeruleus from victims of suicide.

The binding of an agonist, p-[125I]iodoclonidine, and an antagonist, [3H]yohimbine, to alpha 2-adrenoceptors was measured autoradiographically in the locus coeruleus from 10 pairs of antidepressant-free victims of suicide and age-matched controls. Agonist binding to alpha 2-adrenoceptors was significantly greater in the locus coeruleus from victims of suicide compared with control subjects. In contrast, antagonist binding to alpha 2-adrenoceptors in the locus coeruleus did not differ significantly between control and suicide subjects. HPLC analysis of norepinephrine in tissue sections of the locus coeruleus did not reveal any differences between control subjects and suicide victims, suggesting that differences in agonist binding are not a result of differences in retention of the endogenous agonist norepinephrine in tissue sections. The increase in agonist binding to alpha 2-adrenoceptors in the locus coeruleus of victims of suicide links an altered expression of the high-affinity state of autoinhibitory alpha 2-adrenoceptors with suicide.

Adult↗