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PubMed1978

Activation of an inhibitory noradrenergic pathway projecting from the locus coeruleus to the cingulate cortex of the rat.

Repetitive stimulation of the locus coeruleus evoked strong inhibition of the firing rate of about 50% of cells of the cingulate rat cortex. Forty per cent of the cells were not affected and 9% were excited by stimulation of the locus coeruleus. Pretreatment of the rats with reserpine and alpha-methyl-p-tyrosine drastically reduced the percentage of cells inhibited by locus coeruleus stimulation. The cells inhibited in response to stimulation of the locus coeruleus as well as those not inhibited were depressed by microiontophoretically applied norepinephrine. This inhibitory action of NE was observed in rats anesthetized either with urethane, chloral hydrate or with Nembutal. The transsynaptically elicited, as well as the norepinephrine elicited, depression of the cells' discharge rate was antagonized by the microiontophoretically applied beta-receptor blocking drug MJ 1999. These data suggest that the inhibitory action on cingulate cortical cells of locus coeruleus stimulation is mediated by the dorsal ascending noradrenergic pathway.

Adrenergic Fibers↗

PubMed1986

Efferent projections of nucleus locus coeruleus: topographic organization of cells of origin demonstrated by three-dimensional reconstruction.

The present study examines the spatial distribution within rat locus coeruleus of neurons projecting to particular brain regions. In order to accurately recreate, in digital and pictorial formats, the spatial distribution of neurons for the entire nucleus locus coeruleus, three-dimensional reconstructions were created which specified the location of each individual Nissl-stained locus coeruleus cell in each of five nuclei. Dynamic computerized displays were visually analyzed and statistically compared. The nuclei from different brains were found to be strikingly similar in density and distribution of cells. In order to determine whether the cells of origin for particular locus coeruleus projections were clustered within the nucleus, reconstructions were created of the distributions of cells labeled by injections of a retrograde tracer, horseradish peroxidase, into particular terminal regions. Groups consisting of animals with injections into the same target areas were visually and statistically compared. The cells of origin of most efferent projections were found to be spatially organized within locus coeruleus. Specifically, projections to both the dorsal and ventral hippocampus originated solely from the dorsal segment of the nucleus, while spinal cord projections originated from ventral-posterior locus coeruleus. Cells of origin of cerebral and cerebellar cortical efferents, as well as hypothalamic efferents, exhibited less clustering, although reliable differences in distribution were observed. The most striking example of clustered cells of origin was exhibited by the large norepinephrine-containing cells constituting the anterior pole of locus coeruleus which were labeled only by hypothalamic injections. This analysis of spatial organization within locus coeruleus is unique in its utilization of a defined control group, experimental groups consisting of strictly defined replications, accurate three-dimensional reconstruction, and statistical comparisons. The demonstrated spatial heterogeneity of locus coeruleus neurons with respect to efferent projections can now be compared to the spatial distributions of other cellular characteristics such as soma morphology, colocalized transmitters and physiological properties. Presumably, such spatial segregation reflects the operation of functionally important organizing principles within the nucleus.

Animals↗

PubMed1995

Afferent projections to the rat locus coeruleus demonstrated by retrograde and anterograde tracing with cholera-toxin B subunit and Phaseolus vulgaris leucoagglutinin.

The aim of this study was to examine the afferents to the rat locus coeruleus by means of retrograde and anterograde tracing experiments using cholera-toxin B subunit and phaseolus leucoagglutinin. To obtain reliable injections of cholera-toxin B in the locus coeruleus, electrophysiological recordings were made through glass micropipettes containing the tracer and the noradrenergic neurons of the locus coeruleus were identified by their characteristic discharge properties. After iontophoretic injections of cholera-toxin B into the nuclear core of the locus coeruleus, we observed a substantial number of retrogradely labeled cells in the lateral paragigantocellular nucleus and the dorsomedial rostral medulla (ventromedial prepositus hypoglossi and dorsal paragigantocellular nuclei) as previously described. We also saw a substantial number of retrogradely labeled neurons in (1) the preoptic area dorsal to the supraoptic nucleus, (2) areas of the posterior hypothalamus, (3) the Kölliker-Fuse nucleus, (4) mesencephalic reticular formation. Fewer labeled cells were also observed in other regions including the hypothalamic paraventricular nucleus, dorsal raphe nucleus, median raphe nucleus, dorsal part of the periaqueductal gray, the area of the noradrenergic A5 group, the lateral parabrachial nucleus and the caudoventrolateral reticular nucleus. No or only occasional cells were found in the cortex, the central nucleus of the amygdala, the lateral part of the bed nucleus of the stria terminalis, the vestibular nuclei, the nucleus of the solitary tract or the spinal cord, structures which were previously reported as inputs to the locus coeruleus. Control injections of cholera-toxin B were made in areas surrounding the locus coeruleus, including (1) Barrington's nucleus, (2) the mesencephalic trigeminal nucleus, (3) a previously undefined area immediately rostral to the locus coeruleus and medial to the mesencephalic trigeminal nucleus that we named the peri-mesencephalic trigeminal nucleus, and (4) the medial vestibular nucleus lateral to the caudal tip of the locus coeruleus. These injections yielded patterns of retrograde labeling that differed from one another and also from that obtained with cholera-toxin B injection sites in the locus coeruleus. These results indicate that the area surrounding the locus coeruleus is divided into individual nuclei with distinct afferents. These results were confirmed and extended with anterograde transport of cholera-toxin B or phaseolus leucoagglutinin. Injections of these tracers in the lateral paragigantocellular nucleus, preoptic area dorsal to the supraoptic nucleus, the ventrolateral part of the periaqueductal gray, the Kölliker-Fuse nucleus yielded a substantial to large number of labeled fibers in the nuclear core of the locus coeruleus.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗

PubMed1988

Locus coeruleus neurons in the rat containing neuropeptide Y, tyrosine hydroxylase or galanin and their efferent projections to the spinal cord, cerebral cortex and hypothalamus.

The efferent projections of locus coeruleus neurons which contain neuropeptide Y-, tyrosine hydroxylase- or galanin-like immunoreactivity were investigated using the indirect immunofluorescence technique combined with the retrograde transport of the fluorescent substance Fast Blue. Four groups of rats received injections of Fast Blue: (1) bilaterally into the mid-thoracic spinal cord (T6-T7); (2) unilaterally into the low cervical spinal cord (C4-C5); (3) unilaterally into the paraventricular, periventricular and dorsomedial hypothalamic nuclei; and (4) unilaterally into five sites in the cerebral cortex (frontal, cingulate and striate cortex). Efferent projections to the spinal cord, hypothalamus and cerebral cortex from neuropeptide Y-, tyrosine hydroxylase- and galanin-containing locus coeruleus cells were observed. A higher percentage of the peptidergic locus coeruleus neurons projected to the hypothalamus than to the spinal cord or cerebral cortex. The distribution and morphology of the neuropeptide Y- and galanin-containing neurons in the locus coeruleus were also investigated. Neuropeptide Y-like immunoreactivity and galanin-like immunoreactivity were found in small, medium and large multipolar neurons, as well as in fusiform locus coeruleus cells. The neuropeptide Y- and galanin-immunoreactive neurons were found throughout the locus coeruleus. In the caudal locus coeruleus, they were primarily located in the dorsal portion. Neuropeptide Y-like immunoreactivity and galanin-like immunoreactivity were only seen in a few tyrosine hydroxylase-positive neurons of the subcoeruleus group. The data show that the peptide-containing locus coeruleus neurons have efferent projections to the spinal cord, hypothalamus and cerebral cortex. The locus coeruleus may be divided into functional subdivisions dependent on the region of the locus coeruleus, the neurotransmitter/neuropeptide(s) contained within the neurons and their efferent projections.

Animals↗

PubMed1993

Differential effects of desipramine on direct- and sensory-evoked noradrenaline release in thalamic locus coeruleus terminals.

The effects of desipramine on sensory-evoked (sciatic nerve stimulation) activation of locus coeruleus neurones were investigated in vivo by using treated carbon-fibre electrodes in conjunction with either differential normal pulse voltammetry or differential pulse amperometry. Firstly, the amplitude of the sensory-evoked increase in extracellular noradrenaline, monitored in thalamic locus coeruleus terminals, was not modified by desipramine (10 mg/kg), whereas that evoked by direct activation of locus coeruleus neurones was greatly increased: +143% for dorsal noradrenergic bundle stimulation and +761% for glutamate ejection in the locus coeruleus. Secondly, desipramine administered at the same dose significantly reduced (-48%) the activation of locus coeruleus neurones (monitored at the somato-dendritic level) evoked by prolonged sciatic nerve stimulation. Our results indicate that acute treatment with desipramine does not potentiate overall noradrenergic transmission by locus coeruleus neurones during sensory stimulation.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Locus coeruleus stimulation by corticotropin-releasing hormone suppresses in vitro cellular immune responses.

Previous studies have demonstrated that stressors alter cellular immune system function, and increase the activity of locus coeruleus neurons. Furthermore, stressors increase the release of corticotropin-releasing hormone (CRH) and locus coeruleus neurons are activated by CRH. Thus, the present study examined whether activation of the locus coeruleus by infusion of CRH modulates the function of blood and spleen lymphocytes assessed in vitro. CRH (100 ng) was administered into the region of the locus coeruleus in awake rats 1 hr before spleen and peripheral blood lymphocytes were collected for culture with nonspecific mitogens. Unilateral or bilateral microinfusion of CRH into the locus coeruleus produced a decrease in blood and spleen T-lymphocyte mitogenic responses to phytohemagglutinin, ConA, and an antibody to the T-lymphocyte antigen receptor. In contrast, infusion of saline into the locus coeruleus or CRH into the surrounding region of the dorsal pons did not alter spleen or blood lymphocyte responses. Plasma concentrations of adrenocorticotropic hormone, corticosterone, and IL-6 were increased by CRH infusion into the locus coeruleus. These results suggest that CRH-evoked activation of the locus coeruleus stimulates the hypophysial adrenal axis, possibly activates the sympathetic nervous system, and results in immunosuppression. Comparable changes in lymphocyte and hormone responses are produced by an aversive stimulus or a conditioned stressor, suggesting that activation of the locus coeruleus may be a component of stressor-induced immune alterations.

Adrenocorticotropic Hormone↗

PubMed1986

Dissociation of locus coeruleus activity and blood pressure. Effects of clonidine and corticotropin-releasing factor.

In order to determine whether pharmacologically-induced alterations in the spontaneous activity of neurons in the locus coeruleus are associated with changes in blood pressure, the activity of the locus coeruleus and blood pressure were recorded simultaneously in anesthetized rats after the administration of agents known to affect both of these parameters. Spontaneous activity of the locus coeruleus was decreased by intracerebroventricular (i.c.v.) administration of both clonidine and St 91, [2,(2,6-diethyl-phenylimino)imidazolidine chloride], a charged analogue of clonidine. However, only clonidine decreased the mean blood pressure after intracerebroventricular administration suggesting that either the receptors mediating decreases in the activity of the locus coeruleus are different to those mediating hypotension, or that St 91 does not distribute to sites involved in the control of blood pressure even after intracerebroventricular administration. Intravenous administration of clonidine, but not of St 91, decreased the activity of the locus coeruleus and produced a prolonged hypotension, thus suggesting a central mechanism for these effects. Both clonidine and St 91 administered intravenously, produced a brief initial period of hypertension which was not associated with consistent changes in the spontaneous activity of the locus coeruleus. Thus, noradrenergic agonists can decrease the activity of the locus coeruleus without affecting blood pressure, and increase blood pressure without affecting the activity of the locus coeruleus. The spontaneous activity of cells in the locus coeruleus was increased by 100% after the intracerebroventricular administration of corticotropin-releasing factor (CRF; 3.0 micrograms).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Membrane properties of rat locus coeruleus neurones.

Intracellular recordings were made from neurones in the locus coeruleus contained within a slice cut from rat pons and maintained in vitro. Most neurones fired action potentials spontaneously at frequencies of between 1 and 5 Hz; this did not arise from spontaneous synaptic input but appeared to result from endogenous properties of the membrane conductances. Under voltage clamp at potentials near threshold for action potential generation (-55 mV) there was a persistent inward calcium current. This current became less with membrane hyperpolarization and was abolished at about -70 mV. Two potassium currents were observed. The first had properties similar to that generally described as the "fast" potassium current (IK,A); it flowed transiently (for about 200 ms) when the membrane potential passed from about -65 to -45 mV, and was blocked by 4-aminopyridine. The second was a calcium-activated potassium current (IK,Ca); it flowed for several seconds following a burst of calcium action potentials. Spontaneous and evoked action potentials had both tetrodotoxin-sensitive and tetrodotoxin-resistant components. The latter was apparently due to calcium entry. The potential changes occurring during the spontaneous firing of locus coeruleus neurones could be reconstructed qualitatively from the ionic conductances observed. The membrane properties of the locus coeruleus neurones were remarkably uniform; however, about 5% of cells impaled within the region of the locus coeruleus were electrophysiologically distinct. These atypical cells had short duration action potentials, did not fire spontaneously and had large spontaneous depolarizing synaptic potentials.

Action Potentials↗

PubMed1997

GABA in locus coeruleus regulates spontaneous rapid eye movement sleep by acting on GABAA receptors in freely moving rats.

The aminergic neurons in the locus coeruleus are known to cease firing during rapid eye movement sleep. Since electrical stimulation of locus coeruleus reduced, while carbachol stimulation increased rapid eye movement sleep and gamma-aminobutyric acid (GABA) neurons as well as terminals are present in the locus coeruleus, we hypothesized that GABA may be involved for cessation of locus coeruleus neuronal firing during rapid eye movement sleep. Under surgical anaesthesia male Wistar rats (250-300 g) with bilateral guide cannulae targeting locus coeruleus were prepared for chronic sleep-wakefulness recording. Electroencephalogram (EEG), electrooculogram (EOG), electromyogram (EMG) were recorded in normal, after 250 nl saline and after picrotoxin (250 ng in 250 nl) injection bilaterally into the locus coeruleus. The results showed that mean duration per episode of rapid eye movement sleep was significantly reduced, although its frequency of generation/h was not significantly affected. This study suggests that GABA in locus coeruleus is involved in tonic regulation of rapid eye movement sleep and the action is mediated through GABAA receptor.

Animals↗

PubMed1986

Efferent projections of nucleus locus coeruleus: morphologic subpopulations have different efferent targets.

This study quantitatively addresses the hypothesis that there is a systematic relationship between the morphologic characteristics of locus neurons and the particular target regions they innervate. Following horseradish peroxidase injections into selected terminal fields, locus coeruleus cell bodies are heavily labeled by retrograde transport so that somata size and shape, and in many cases primary dendritic pattern can be observed. This allows the classification of neurons as one of six cell types: large multipolar cells within ventral locus coeruleus, large multipolar cells in the anterior pole of locus coeruleus, fusiform cells in dorsal LC, posterior pole cells, medium-sized multipolar cells (termed core cells in this report), and small round cells. It was found that while core cells contribute to the innervation of all terminal fields examined, other cell types project to more restricted sets of targets. The contributions of each type to selected efferents are presented in detail. In particular, fusiform cells project to hippocampus and cortex, large multipolar cells in ventral locus coeruleus project to spinal cord and cerebellum, and small round cells in central and anterior locus coeruleus, as well as large multipolar cells in anterior locus coeruleus, project to hypothalamus. These results, in conjunction with those described in the preceding report, indicate that locus coeruleus is intrinsically organized with respect to efferent projections with much more specificity than has previously been evident. This high degree of organization is consistent with other recent demonstrations of functional specificity exhibited by locus coeruleus neurons.

Animals↗

PubMed1993

In vivo noradrenaline release evoked in the anteroventral thalamic nucleus by locus coeruleus activation: an electrochemical study.

The anteroventral thalamic nucleus is innervated by noradrenergic terminals exclusively originating in the locus coeruleus, a densely packed cell group located in the dorsotegmental part of the pons. In urethane-anaesthetized rats, electrical stimulations of locus coeruleus axons (dorsal noradrenergic bundle; 14 Hz, 20 s) evoked a rapid increase in the signal (catechol oxidation current) measured within the anteroventral thalamic nucleus by the use of carbon fibre electrodes combined with electrochemistry. This effect was reproducible and immediately reversible. Evoked changes in this current were found to be due to oxidation of noradrenaline released from terminals. The amplitude of the evoked noradrenaline release varied non-linearly with the frequency of stimulation. We investigated the influence of locus coeruleus activation on noradrenaline release measured in the anteroventral thalamic nucleus every second by means of differential pulse amperometry: (i) chemical activation of locus coeruleus by local injection of glutamate (0.2-0.8 nmol) immediately and consistently evoked noradrenaline release in a dose-dependent manner; and (ii) peripheral stimulation of the sciatic nerve (20 s)--known to enhance the firing rate of locus coeruleus neurons-evoked a noradrenaline release similar to that produced by a stimulation of the dorsal noradrenergic bundle at 8-10 Hz. Pharmacological and kinetic characteristics of the noradrenaline release were the same for central or peripheral stimulation of locus coeruleus neurons. Our results indicate that in vivo electrochemistry, because of its sensitivity and its high space and time resolution, is well suited for studies of evoked noradrenaline release from locus coeruleus terminals. This approach allowed us to describe the characteristics of central noradrenaline release evoked by central and peripheral stimulations of short duration. In particular, we observed a very close relationship between impulse flow and evoked noradrenaline release.

Animals↗

PubMed1984

Influence of ACTH on tyrosine hydroxylase activity in the locus coeruleus of mouse brain.

Tyrosine hydroxylase activity in noradrenergic neurons of the locus coeruleus was found to rise in bilaterally adrenalectomized adult mice, with maximum increase of the enzyme activity (52% above control) occurring 7 days after the surgery. No such increase of tyrosine hydroxylase activity was found in dopaminergic neurons of the substantia nigra. The increase of enzyme activity in the locus coeruleus following adrenalectomy was totally prevented by corticosterone replacement. Moreover, the adrenalectomy effect was abolished by hypophysectomy, indicating the involvement of the pituitary rather than the adrenocortical function. Chronic administration of ACTH (20 IU/kg, i.p., daily) resulted in an increase of tyrosine hydroxylase activity in the locus coeruleus, with a time course and magnitude similar to those found after adrenalectomy. Additionally, the effects of four ACTH analogs were determined. ACTH 1-24 and ACTH 4-10 were as effective as the whole ACTH molecule, whereas ACTH 4-10,7-D-Phe and ACTH 11-24 were ineffective. The effect of ACTH 4-10, a peptide fragment with no adrenocorticotrophic activity, further indicates that glucocorticoids are not involved. From these data, it appears that tyrosine hydroxylase in the locus coeruleus neurons is under the regulatory influence of pituitary ACTH. It remains to be determined whether the hormone can be transported from its pituitary origin to the locus coeruleus and exerts a direct action on the noradrenergic neurons. Regardless of the mechanism, the response of the noradrenergic neurons to pituitary activity may be an important component in physiological adaptation of the central nervous system to chronic stress.

Adrenal Glands↗

PubMed1992

Collateralized projections from neurons in the rostral medulla to the nucleus locus coeruleus, the nucleus of the solitary tract and the periaqueductal gray.

We have examined collateral projections of locus coeruleus afferent neurons in the rostral medulla to the caudal nucleus of the solitary tract or to the periaqueductal gray using double retrograde labeling techniques in the rat. The present findings confirm previously reported connections to the locus coeruleus, the nucleus of the solitary tract and the lateral periaqueductal gray from the nucleus paragigantocellularis in the rostral ventral medulla. Our results also reveal previously unreported projections from the rostral dorsomedial medulla (in a similar region as locus coeruleus-projecting neurons) to the lateral periaqueductal gray. Following retrograde tracer injections into the nucleus of the solitary tract and the locus coeruleus, doubly labeled neurons were seen in both the nucleus paragigantocellularis and in the rostral dorsomedial medulla. Cell counts revealed that approximately 25% of locus coeruleus-projecting neurons in the nucleus paragigantocellularis, and 12% in the dorsomedial medulla, also innervate the caudal nucleus of the solitary tract. In contrast, no doubly labeled neurons within the rostral ventral medulla were found following injections into the lateral periaqueductal gray and the locus coeruleus, although singly labeled neurons for the two tracers were interdigitated in some regions. Following these injections, numerous neurons were also retrogradely labeled in the dorsomedial medulla in the region of the medial prepositus hypoglossi and the perifascicular reticular formation. A small percentage of locus coeruleus afferents in the dorsal medulla (approximately 10%) also projected to the lateral periaqueductal gray. These results indicate that neurons in both the ventrolateral and dorsomedial rostral medulla frequently send collaterals to both the locus coeruleus and the caudal nucleus of the solitary tract. A small number of neurons in the dorsomedial medulla project to both the locus coeruleus and the lateral periaqueductal gray, but separate populations of neurons project to the locus coeruleus and the lateral periaqueductal gray from the ventrolateral medulla. These results functionally link the locus coeruleus and the nucleus of the solitary tract by virtue of common afferents, and support other studies indicating the importance of central autonomic circuitry in the afferent control of locus coeruleus neurons.

Animals↗

PubMed1979

Regional topography within noradrenergic locus coeruleus as revealed by retrograde transport of horseradish peroxidase.

A hitherto unsuspected degree of regional topographic organization in the noradrenergic nucleus, locus coeruleus, was revealed by the use of retrograde transport of horseradish peroxidase (HRP) from terminal areas receiving noradrenergic innervation. HRP was injected into hippocampus, hypothalamus, thalamus, caudate-putamen, septum, amygdala-piriform cortex, cerebellum and cortex. Successful transport was obtained from all areas, including the caudate-putamen and cerebral cortex. The pattern of HRP positive cells in the ipsilateral locus coeruleus was markedly different depending on the location of the HRP injection. Thus, hippocampal injections labeled cells in the dorsal locus coeruleus but not at all in the ventral tip. Injections of HRP into caudate-putamen or cerebellum labeled the ventral tip along with the rest of the dorsal portion. HRP injections into the septum labeled cells only in the dorsal half of the dorsal locus coeruleus. There thus exists a three tier division of locus coeruleus into the ventral one third, dorsal one third and intermediate one third. A further division was seen in the anterior-posterior plane with HRP injections into the thalamus labeling the posterior pole of locus very intensely but with little transport to more anterior levels; conversely HRP injection into the hypothalamus resulted in intense labeling only in the anterior pole of locus coeruleus. Amygdala-piriform cortex HRP injections revealed a further pattern with very intensely reactive cells scattered sparsely throughout the nucleus. Cortical HRP injections yielded weaker labeling also in occasional, scattered cells. All HRP transport to locus coeruleus was shown to be noradrenergic by degeneration with 6-hydroxydopamine and due to terminal, rather than fiber of passage, uptake by control injection into the dorsal NA bundle. It is concluded that the locus coeruleus is not an homogenous nucleus with respect to the origin of the noradrenergic projections to sundry forebrain, spinal and cerebellar areas but is comprised of distinct subdivisions of noradrenergic neurons.

Amygdala↗

PubMed1995

Effects of pretreatment with corticotropin-releasing factor on the electrophysiological responsivity of the locus coeruleus to subsequent corticotropin-releasing factor challenge.

Both acute central administration of exogenous, and stress-induced release of endogenous corticotropin-releasing factor result in electrophysiological activation of the noradrenergic neurons constituting the locus coeruleus. The present experiments were designed to examine whether single (1) or repeated (8) intracerebroventricular pretreatment with exogenous corticotropin-releasing factor would alter locus coeruleus electrophysiological responsivity to subsequent corticotropin-releasing factor challenge in rats. A single corticotropin-releasing factor (3 microg) pretreatment significantly attenuated challenge-induced locus coeruleus activation 24 and 72, but no 96 h later, while a single vehicle pretreatment had no significant effect on the response to subsequent challenge at any pretreatment-to-test interval. Repeated pretreatment with either corticotropin-releasing factor or vehicle completely attenuated locus coeruleus response to challenge 24 h after the final pretreatment. Seventy-two hours after the last vehicle pretreatment, challenge resulted in a significant increase in locus coeruleus activity, though the response was less than in naive controls. Challenge continued to produce no effect on locus coeruleus activity in repeated corticotropin-releasing factor-pretreated rats at this (72 h) time point. One week (168 h) after the cessation of repeated pretreatment, challenge resulted in a significant increase in locus coeruleus activity which was equal to that of naive controls in vehicle-pretreated rats, but reduced by comparison to controls in corticotropin-releasing factor-pretreated rats. Basal discharge rates of locus coeruleus neurons 24 h after the last repeated corticotropin-releasing factor pretreatment were significantly less than in naive controls. Thus, the failure of challenge to increase neuronal activity in these rats was not due to a "ceiling" effect caused by elevated tonic discharge rate. Repeated vehicle pretreatment produced a functional change similar to that produced by exogenous corticotropin-releasing factor administration. One hypothesis is that repeated vehicle pretreatment was stressful and caused the repeated release of endogenous corticotropin-releasing factor. This hypothesis was tested by determining whether locus coeruleus neurons remained responsive to challenge following repeated administration of a corticotropin-releasing factor antagonist. Thus, the effect if repeated pretreatment with the antagonist, [D-Phe, Nle, Calpha MeLeu]CRF was also examined. Challenge resulted ina significant increase in discharge rate 24 h after the final antagonist pretreatment, providing support for the hypothesis. Additionally, in rats repeatedly pretreated with vehicle, carbachol challenge induced an increase in locus coeruleus activity equal to that induced in naive controls. These results indicate that prior exposure to corticotropin-releasing factor, or the repeated mild stress of vehicle infusions, reduces locus coeruleus responsiveness to corticotropin-releasing factor, and reveal that the relationship between these two neurotransmitter systems is modifiable. This altered relationship may contribute to stress-related affective disorders in which both systems have been implicated.

Animals↗

PubMed1987

Release of serotonin in the locus coeruleus of normotensive and spontaneously hypertensive rats (SHR).

The aim of the present work was to clarify whether differences exist between the release of endogenous serotonin in the locus coeruleus of normotensive and hypertensive rats. The locus coeruleus was superfused with artificial cerebrospinal fluid (aCSF) through a push-pull cannula and serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were determined in the superfusate by HPLC combined with electrochemical detection. Compared with normotensive Wistar-Kyoto (WKY) rats, the basal release rate of serotonin in the locus coeruleus of spontaneously hypertensive rats (SHR) was increased more than twofold. Intravenous infusion of noradrenaline (4 microg/kg min) increased mean arterial blood pressure to the same extent in hypertensive and normotensive rats. The pressor response was associated with an increased serotonin release. In WKY rats, the release of serotonin in the locus coeruleus evoked by noradrenaline infusion was more pronounced than in SHR. In WKY rats, intravenous infusion of sodium nitroprusside (150 microg/kg min) led to a fall in blood pressure which was less pronounced and lasted shorter than in SHR. The depressor response was associated with decreased serotonin release. In WKY rats, the decrease in serotonin release evoked by sodium nitroprusside was more pronounced and lasted longer than in SHR. Neither noradrenaline nor sodium nitroprusside influenced the outflow of 5-HIAA. The sensory stimuli noise and tail pinch led to a slight rise in arterial blood pressure which was similar in WKY rats and SHR. These stimuli enhanced the release rate of serotonin and the outflow of 5-HIAA to the same extent in the locus coeruleus of normotensive and hypertensive rats. The findings suggest that the enhanced release of serotonin in the locus coeruleus of genetically hypertensive rats reflects a mechanism counteracting the disturbed blood pressure homeostasis. Stressors influence blood pressure and release of serotonin in the locus coeruleus of SHR and WKY rats to the same extent.

Animals↗

PubMed1995

Spatial and non-spatial learning in the rat following lesions to the nucleus locus coeruleus.

The present experiment examined the effects of unilateral or bilateral locus coeruleus lesions on general activity, acquisition of a non-monotonic serial pattern (14-0-3-7 food pellets, respectively), and response learning acquisition in a Greek cross version of the Morris water maze. Sham-operated control rats were capable of tracking the elements of the serial pattern while rats with a unilateral locus coeruleus lesion were moderately impaired, and those with bilateral locus coeruleus lesions were severely impaired. A similar pattern of working memory deficits emerged in an analysis of the response-learning data in the Greek cross. The results are discussed in terms of the current understanding of norepinephrine and the locus coeruleus in learning and memory processes.

Analysis of Variance↗