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PubMed2003

Crucial role of TrkB ligands in the survival and phenotypic differentiation of developing locus coeruleus noradrenergic neurons.

The role of glial cell-line derived neurotrophic factor (GDNF) and neurotrophins in the development of locus coeruleus noradrenergic neurons was evaluated. We found that two neurotrophic factors previously reported to prevent the degeneration of lesioned adult central noradrenergic neurons, GDNF and neurotrophin 3 (NT3), do not play significant roles in the prenatal development of locus coeruleus noradrenergic neurons, as demonstrated by: (1) the lack of alterations in double Gdnf/Nt3 null mutant mice; and (2) the lack of survival-promoting effects of GDNF and/or NT3 in rat E13.5 primary cultures. In contrast, null mutant mice for TrkB, the tyrosine kinase receptor for brain-derived neurotrophic factor and neurotrophin 4, displayed a clear loss of locus coeruleus noradrenergic neurons. In accordance with this, treatment of rat E13.5 primary cultures with TrkB ligands prevented the early loss of noradrenergic neurons and maintained their survival for up to 6 days in vitro. Moreover, an additional 5-10-fold increase in the number of tyrosine hydroxylase positive noradrenergic neurons was detected after 12 hours in culture. This second effect of TrkB ligands involved neither proliferation nor survival, because the number of BrdU- or TUNEL-positive noradrenergic neurons did not change and the effect was elicited by delayed administration of either factor. Because TrkB ligands increased the number of tyrosine hydroxylase-positive cells expressing Phox2a, a paired homeodomain protein required for the development of locus coeruleus noradrenergic neurons, but did not affect the number of Phox2a-positive tyrosine hydroxylase-negative cells, our results suggest that the second effect of TrkB ligands may involve promoting or inducing a noradrenergic phenotype. In summary, our findings suggest that, unlike NT3 and GDNF, TrkB ligands are required and sufficient to promote the development of central noradrenergic neurons.

Animals↗

PubMedDate not supplied

Effect of hemilabyrinthectomy on monoamine metabolism in the medial vestibular nucleus, locus coeruleus, and other brainstem nuclei of albino and pigmented rats.

We compared in albino and pigmented rats the early effect of unilateral labyrinthectomy (UL) on the concentrations of monoamines (norepinephrine, dopamine, serotonin) and their respective metabolites--3-methoxy,4-hydroxyphenylglycol (MHPG), 3,4-dihydroxy-phenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5HIAA)--in medial vestibular nuclei (MVN), locus coeruleus, raphe dorsalis, and cochlear nuclei. The study was conducted 6 hours after UL in both strains, differing by the functional optokinetic responses of their central vestibular neurons and the time-course of their vestibular compensation. The results show that the monoaminergic changes are different in the two rat strains. In the MVN of albino rats, there was a bilateral increase of MHPG and an ipsilateral increase of dopamine suggesting activation of norepinephrine synthesis and metabolism, whereas no such changes were observed in the MVN of pigmented rats. On the other hand, the simultaneous increase of norepinephrine and DOPAC observed in the contralateral locus coeruleus of albino rats suggested enhanced norepinephrine synthesis, whereas in pigmented rats the decreased norepinephrine content found in the ipsilateral locus coeruleus might reflect an earlier strong stimulation of NE release. These biochemical results confirm the relevant role of locus coeruleus noradrenergic innervation in vestibular compensation and also point out the involvement of norepinephrine of the MVN in the early stages of this process. The different strain-related noradrenergic responses observed on the 6th hour suggest that the involvement of central norepinephrine, particularly from locus coeruleus innervation, may be more crucial and more sustained in the albino than in pigmented rats. No serotonin and 5HIAA changes were found in either brainstem nuclei of albino rats. In contrast, the increase of the ratio 5HIAA/5HT observed in raphe dorsalis, in ipsilateral locus coeruleus, and in both sides of MVN of pigmented rats suggested that UL induced an extended and enhanced utilization of 5HT in this strain.

Albinism↗

PubMed1997

GABA release in the locus coeruleus as a function of sleep/wake state.

GABA, glutamate, and glycine release in the locus coeruleus were measured as a function of sleep/wake state in the freely-behaving cat using the microdialysis technique. GABA release was found to increase during rapid-eye-movement sleep as compared to waking values. GABA release during slow-wave sleep was intermediate between that of waking states and rapid-eye-movement sleep. The concentration of glutamate and glycine in microdialysis samples was unchanged across sleep and wake states. Our findings are consistent with the hypothesis that GABAergic inhibition is responsible for the cessation of discharge in locus coeruleus neurons during REM sleep. The data suggest that a population of GABAergic neurons innervating the locus coeruleus are selectively active during rapid-eye-movement sleep.

Amino Acids↗

PubMed1981

[Effect of rhythmic stimulation of the locus coeruleus on spinal inhibition induced by activation of flexor reflex afferents in the cat].

Locus coeruleus rhythmic stimulation of 40/s frequency and 50-150 micro A current intensity diminished the inhibitory action from flexor reflex afferents on extensor monosynaptic reflexes in anaesthetized decerebellized cats. Such an effect appeared 600 ms after and reached maximum 1500-1700 ms after the locus coeruleus stimulation. The depression of inhibition was maintained during 2-3 s after cessation of the stimulation. No effect was observed when locus coeruleus was stimulated by a single stimulus or by a short high-frequency pulse train of the same current strength. An increase of the stimulation intensity evoked activation of neighbouring structures. The advantages of the rhythmic stimulation for revealing the influences of slow conducting pathways are discussed.

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↗

PubMed1992

Increase in galanin gene expression in locus coeruleus neurones of the rat following reserpine treatment.

Changes in galanin mRNA content in locus coeruleus neurones of the rat were studied after reserpine treatment (10 mg/kg s.c.) using an in situ hybridization technique and an alkaline phosphatase labelled oligodeoxynucleotide probe. An increase in galanin mRNA content in locus coeruleus neurones was detected as early as 3 h after reserpine treatment when compared to vehicle injected rats. A maximal increase in mRNA content was detected at 3 days after reserpine treatment. This transient increase in galanin mRNA content had subsided by post treatment day 20. The response of locus coeruleus neurones to the single reserpine injection was heterogeneous; cells in the dorsal portion of the nucleus exhibiting a greater response than ventrally located cells.

Animals↗

PubMed1993

[The functional role of monoaminergic and amino acid-ergic mechanisms of the locus coeruleus in anxiety from different aversive origins].

Dopamine and glutamine acid microinjection in the locus coeruleus of rats does not influence the alarm state in the test of "Threatening situation" avoidance, but weakens the state of alarm in the test of "illuminated site" avoidance. The local injection of GABA and noradrenaline mesatone effect imitators in this brain formation weakens the alarm state in the test of "threatening situation" avoidance but is not effective in the test of "illuminated site" avoidance. On the contrary, the chemical stimulation of locus coeruleus by serotonin influences the anxiolytic effect in two different experimentally modelled states of alarm. The participation of locus coeruleus and acidergic mechanisms in anxiety of diverse aversive genesis is discussed.

Animals↗

PubMed1987

Common alpha 2- and opiate effector mechanisms in the locus coeruleus: intracellular studies in brain slices.

Although alpha 2-adrenoceptor and opiate agonists act through separate receptors on neurons in the locus coeruleus (LC), there are several lines of evidence pointing to shared post-receptor effector mechanisms. Stimulation of either alpha 2- and opiate receptors causes a hyperpolarization of neurons in the locus coeruleus; this effect is due, at least partly, to an opening of a common set of K+ channels. Moreover, the alpha 2- and opiate receptor-induced hyperpolarizations are both reversed, at least partially, by membrane-permeable analogs of adenosine 3':5'-monophosphate (cAMP). These findings fit with biochemical models which propose that alpha 2- and opiate receptors have common actions through inhibiting adenylate cyclase through the inhibitory guanosine triphosphate (GTP) binding protein (Gi). As would be predicted by this model, pretreatment with pertussis toxin, an inactivator of Gi, blocks the hyperpolarizing effects of alpha 2- and opiate agonists in the locus coeruleus. These results suggest that the electrophysiological effects, mediated by these receptors, are transduced through Gi (or a closely related G protein). However, new evidence indicates that there may be both cAMP-dependent and cAMP-independent actions, mediated through G proteins. The opening of K+ channels by alpha 2- and opiate receptors appears to be independent of cAMP, whereas a cAMP-dependent inward current (IcAMP) would be affected by the inhibition of adenylate cyclase; these two G protein-mediated events work in concert to produce the alpha 2- and opiate hyperpolarization of neurons in the locus coeruleus.

8-Bromo Cyclic Adenosine Monophosphate↗

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↗

PubMed1980

Norepinephrine innervation of the cochlear nuclei by locus coeruleus neurons in the rat.

The cochlear nuclei (CN) contain a moderate concentration of norepinephrine (445 +/- 20 ng/g tissue) with dopamine levels (46 +/- 14 ng/g) that are low and within the precursor range expected for a norepinephrine (NE) terminal system. Lesion and horseradish peroxidase (HRP) experiments indicate that this innervation is bilateral and arises from fusiform and multipolar neurons in the locus coeruleus. Autoradiographic and fluorescence histochemical experiments demonstate that locus coeruleus fibers reach the ipsilateral ventral cochlear nuclei via a rostral pathway that projects from the rostral locus coeruleus laterally through the brain stem to the rostral tip of the ventral nuclei. This pathway is located dorsal to the motor and spinal trigeminal nuclei and ventral to the middle cerebellar peduncle. Descending coeruleo-cochlear fibers travel between the fourth ventricle and the vestibular nuclei to enter the acoustic striae. These fibers innervate both the dorsal and ventral nuclei. Contralateral locus fibers reach the CN by crossing in the pontine central gray at the rostral border of the fourth ventricle and by decussating with the fibers of the mesencephalic trigeminal nucleus ventral to the medial longitudinal fasciculus. The bilateral locus coeruleus innervation of the cochlear nuclei comprises a highly collateralized network of varicose axons which are not topographically organized. Unlike the cochlear nerve fibers in the CN which form specific projections, the locus coeruleus afferents to these sensory nuclei are diffuse and non-specific.

Animals↗

PubMed1987

Evidence that locus coeruleus is the site where clonidine and drugs acting at alpha 1- and alpha 2-adrenoceptors affect sleep and arousal mechanisms.

The behavioural and electrocortical (ECoG) effects of clonidine were studied after microinjection into the third cerebral ventricle, or microinfusion into some specific areas of the rat brain rich in noradrenaline-containing cell bodies (locus coeruleus) or into areas receiving noradrenergic terminals (dorsal hippocampus, amygdaloid complex, thalamus, frontal and sensimotor cortex). The ECoG effects were continuously analysed and quantified by means of a Berg-Fourier analyser as total power and as power in preselected bands of frequency. Clonidine (9.4 to 75 nmol) given into the third cerebral ventricle produced behavioural sedation and sleep and a dose-dependent increase in ECoG total voltage power as well as in the lower frequency bands. Much lower doses were required to produce similar behavioural and ECoG spectrum power effects after either unilateral or bilateral microinfusion of clonidine into the locus coeruleus. Doses of clonidine equimolar to those given into the third cerebral ventricle, were almost ineffective in inducing behavioural and ECoG sleep after their microinfusion into the dorsal hippocampus. In addition, a dose (0.56 nmol) of clonidine which, given into the locus coeruleus, produced marked behavioural sleep and ECoG synchronization, lacked effects when given into the ventral or anterior thalamus, into the amygdaloid complex or onto the frontal and sensimotor cortex. The behavioural and ECoG spectrum power effects of clonidine given into the third cerebral ventricle or into the locus coeruleus were prevented by antagonists of alpha 2-adrenoceptors but not by alpha 1-adrenoceptor antagonists. Intraventricular microinjection, or microinfusion into the locus coeruleus, of yohimbine, a selective alpha 2-adrenoceptor antagonist, produced behavioural arousal, increase in locomotor and exploratory activity, tachypnoea and ECoG desynchronization with a significant reduction in total voltage power. Similar stimulatory effects were also observed after microinjection of phentolamine into the same sites. No significant effects on behaviour and ECoG activity were evoked after intraventricular injection or microinfusion into the locus coeruleus of prazosin or methoxamine.

Adrenergic alpha-Antagonists↗

PubMed1992

In vivo catechol activity in the rat locus coeruleus following different nociceptive stimuli and naloxone.

The nucleus locus coeruleus (LC) has been implicated in the processing of spinal reflexes following noxious stimuli. It has been demonstrated that noxious stimuli activate LC neuronal firing, but little is known about the neurochemical changes that might occur following such activation. To determine the effects of different noxious stimuli on LC neuronal activity, anaesthetized rats were exposed to mechanical (tail pinch), thermal (55 degrees C water), and chemical (5% Formalin injected in the hind paw) stimuli; the catechol oxidation current (CA.OC), an index of noradrenergic neuronal activity, in the locus coeruleus was monitored using differential normal pulse voltammetry. In addition, the effect of the opioid antagonist naloxone on the CA.OC in the LC was examined. Exposure to both mechanical and chemical stimuli significantly increased CA.OC indicating an increase in LC noradrenergic neuronal activity, while the thermal stimulus had no effect. Treatment with naloxone (1 mg/kg i.v.) had no effect on CA.OC in the LC. The results show a differential responsiveness of LC noradrenergic neurons to different modes of noxious stimuli and fail to demonstrate a tonic opioid regulation of these neurons in the anaesthetized rat.

Animals↗

PubMed2003

Novel objects in a holeboard probe the role of the locus coeruleus in curiosity: support for two modes of attention in the rat.

Idazoxan, an alpha 2 adrenoceptor antagonist (2 mg/kg), enhanced novel object investigation in a holeboard in rats as previously reported (V. Devauges & S. J. Sara, 1990). Two weeks of 10 min/day in 37 degrees C water increased dopamine-beta-hydroxylase staining density in the locus coeruleus but did not enhance novel object investigation. In contrast to idazoxan, however, the warm water treatment increased rearing, center entries, and activity, a pattern previously described during tonic infusion of norepinephrine into the hippocampus. Correlations among dopamine-beta-hydroxylase measures and behavior reinforced these tonic norepinephrine/behavior associations. The behavioral effects across the idazoxan and warm water experiments support G. Aston-Jones et al.'s (1999) 2 modes of attention hypothesis for locus coeruleus function: Phasic locus coeruleus activity promotes focused attention; tonic locus coeruleus activity promotes scanning attention.

Animals↗

PubMed1996

Pharmacological characterization of P2 purinoceptor types in rat locus coeruleus neurons.

The frequency of spontaneous action potentials of locus coeruleus neurons was recorded extracellularly in pontine slices of the rat brain. The adenosine 5'-triphosphate (ATP) analogues alpha,beta-methylene ATP (alpha,beta-meATP) and 2-methylthio ATP increased the firing rate with a similar potency, while uridine 5'-triphosphate (UTP) was inactive. Diadenosine 5'-pentaphosphate (Ap5A), diadenosine 5'-tetraphosphate (Ap4A) and diadenosine 5'-triphosphate (Ap3A) all facilitated the firing. When equimolar concentrations were compared, Ap5A had the largest effect followed by Ap4A and Ap3A. Suramin markedly inhibited responses to alpha,beta-meATP and 2-methylthio ATP; the effect of Ap4A was only slightly depressed by suramin. Pyridoxalphosphate-6-azophenyl-2,4-disulfonic acid (PPADS) strongly antagonized alpha, beta-meATP, but failed to alter the effects of 2-methylthio ATP and Ap4A. Reactive blue 2 weakly antagonized alpha,beta-meATP and did not interfere with 2-methylthio ATP and Ap4A. Moreover, suramin depressed responses to (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA), but not to substance P. PPADS failed to affect the AMPA- and NMDA-induced increases in firing. Hence, locus coeruleus neurons may possess receptors for adenosine nucleotides (P2X and P2Y purinoceptors) and dinucleotides (P2D purinoceptors); receptors for uridine nucleotides (P2U purinoceptors or pyrimidinoceptors) are probably absent.

Adenosine↗

PubMed1993

Dye-coupling among neurons of the rat locus coeruleus during postnatal development.

Simultaneous recordings from pairs of locus coeruleus neurons in neonatal rat brain slices previously demonstrated synchronous, subthreshold oscillations of membrane potential (rats < 24 days old) and electronic-coupling between 40% of pairs of neurons from rats less than 10 days old. In the present study, slices from 1-21 day-old rats were stained with avidin-HRP-diaminobenzidine only if a single neuron per slice was impaled for longer than 10 min using an electrode containing biocytin. In slices from rats less than one week old, multiple stained neurons (3.8 +/- 0.6 neurons/slice) were observed in 10 of 11 slices. Apparent contacts between stained neurons were observed at varying distances along dendrites. In rats older than one week significantly fewer multiple stained neurons were observed (three of 20 slices). The proportion of neurons displaying spontaneous subthreshold oscillations of membrane potential decreased with age, and the frequencies of subthreshold oscillations of membrane potential and entrained action potentials increased with age. The presence of multiple stained neurons was not correlated with the occurrence of subthreshold oscillations, cell input resistance, or the number of coupled neurons predicted from the shape of electronic potentials. In recordings from neurons displaying subthreshold oscillations, input resistance was lower and the number of coupled neurons predicted from electrotonic potentials was greater than in those without oscillations. These results suggest that low resistance pathways are common between locus coeruleus neurons in brain slices from rats younger than about one week old, consistent with previous electrotonic-coupling studies.(ABSTRACT TRUNCATED AT 250 WORDS)

3,3'-Diaminobenzidine↗

PubMed1992

Serotonin-norepinephrine interactions: a voltammetric study on the effect of serotonin receptor stimulation followed in the N. raphe dorsalis and the Locus coeruleus of the rat.

In vivo voltammetry with carbon fibre electrodes was used to study the effect of the serotoninergic (5-HT) neuronal system on the noradrenergic (NE) system in the Locus coeruleus of the rat. The voltammetric DOPAC signal in the Locus coeruleus, used as a measure of NE neuronal activity, was increased after systemic application of the 5-HT1B agonist CGS-12066B, the 5-HT2 antagonist ritanserin, and, to a lesser extent, by ipsapirone, a 5-HT1A agonist. The findings suggest that the NE neuronal system of the Locus coeruleus is stimulated by 5-HT1A and 5-HT1B receptor activation and inhibited by 5-HT2 receptors. Likewise the 5-HT releaser and uptake inhibitor fenfluramine increased the DOPAC level in the Locus coeruleus. In contrast to the 5-HT1 agonists, which reduced 5-hydroxyindoleacetic acid (5-HIAA) in the Nucleus raphe dorsalis, ritanserin increased the 5-HIAA signal in this nucleus. This finding could help to explain the action of ritanserin as sleep-modulating substance.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1975

Circling behaviour produced by unilateral lesions in the region of the locus coeruleus in rats.

Rats with unilateral lesions in the region of the locus coeruleus circled tightly to the opposite side when given apomorphine or amphetamine. This turning behaviour was transient and disappeared within some 30 days after surgery. It was seen most obviously in animals with severe unilateral destruction of the locus coeruleus, which caused on average a 55% reduction in the level of noradrenaline in the ipsilateral cerebral cortex. It was not marked in animals with partial unilateral lesions of the locus coeruleus, which caused only an average fall in cortical noradrenaline of 22%. It was not seen in sham operated animals or animals in which lesions were placed into adjacent structures such as the cerebellum above, superior cerebellar peduncle laterally, and brain stem ventrally. A clue to the mechanism of this phenomenon may lie in the observation that dopamine in the ipsilateral striatum was increased 5 days after operation, when circling occurred, but had returned to normal by 30 days when circling had ceased. It is suggested that the lesion causes a reduction in impulse traffic in the ipsilateral nigrostriatal pathway, and that circling is due to preferential stimulation of the ipsilateral striatal dopamine receptors by both drugs; apomorphine directly, amphetamine by release of endogenous dopamine.

Amphetamine↗

PubMed1995

Protein kinases in the locus coeruleus and periaqueductal gray matter are involved in the expression of opiate withdrawal.

The aim of this study was to evaluate the role played in the behavioral expression of morphine withdrawal syndrome by protein kinases in the locus coeruleus and the periaqueductal gray matter. Two different families of specific protein kinases have been investigated: serine/threonine and tyrosine kinases. Rats were implanted with cannulas into both the lateral ventricle and the locus coeruleus or the periaqueductal gray matter. Physical dependence was induced by chronic peripheral administration of morphine (from 7 to 30 mg/kg) and withdrawal syndrome was precipitated by injection of naloxone (2 micrograms) into the lateral ventricle. The administration of the serine/threonine kinase inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, H7 (1, 3, 10, and 30 nmol per side) into the locus coeruleus induced a strong attenuation of morphine withdrawal behavior. Signs related to the motor component of abstinence, such as jumping, rearing, and hyperactivity, were the most severely reduced. However, this effect was not dose-dependent, and the response was almost the same with all the doses used. A similar attenuation was observed after the injection of H7 (1, 3, and 10 nmol per side) into the periaqueductal gray matter, but in this case motor signs were less strongly reduced and a larger number of signs were modified, mainly when using the highest dose. The administration of the tyrosine kinase inhibitor 2-hydroxy-5-[N(2,5-dihydroxyphenyl)methyl]amino]-benzoic acid 3-phenylpropyl ester, KB23 (0.3, 1, and 3 nmol per side) into the locus coeruleus or the periaqueductal gray matter had no effect on the withdrawal syndrome behavior, except on teeth chattering. These results suggest that in the locus coeruleus and in the periaqueductal gray matter, serine/threonine kinases are implicated in the behavioral expression of morphine abstinence. In these brain structures, tyrosine kinases appear not to be involved.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗