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PubMedDate not supplied

[An electrographic analysis of the dynamic change in the functional state of the rat brain after destruction of the locus coeruleus].

Bilateral destruction of the Locus coeruleus in rats was carried out by means of 6-hydroxydopamine injections. Sham-operated animals served as control ones. Electrical activity was recorded in the region of the Locus coeruleus, the dorsal hippocampus, and in the caudatus-putamen complex. Beginning from the second week after surgery in experimental rats was observed a generalization of the theta-rhythm (7-9 Hz) in electrical activity of the Locus coeruleus, hippocampus and the caudatus-putamen complex during orienting-exploratory activity. At the same time such a rhythm was enhanced in animals with motor and orienting-exploratory agitation. In comparison to the sham-operated animals there were no changes in expression in the electrical activity of the subcortical structures of the rhythm of 5-6 Hz, accompanying immobilization state as well as that of 9-11 Hz, accompanying teeth chattering. The dynamics of changes of subcortical electrical activity of rats after the Locus coeruleus destruction may serve an index of the functional state of the animals under the conditions of noradrenergic deficiency. Changes of the brain electrical activity and behaviour of the animals revealed are considered to be a consequence of a relative enhancement of the central serotoninergic regulation of the subcortical structures being caused by a weakening of noradrenergic influences.

Animals↗

PubMed1983

The locus coeruleus: actions of psychoactive drugs.

The locus coeruleus is one of the most thoroughly investigated mammalian brain areas. Its fibers innervate large parts of the neuraxis, in particular, areas involved in cognitive functions such as the cortex and the hippocampus. A role of locus coeruleus has been proposed in such processes as memory, the control of vigilance, blood pressure and others. Results obtained in this and other laboratories demonstrate that the firing rate of locus coeruleus neurons is affected by a great number of psychoactive agents such as antidepressants, minor tranquillizers, neuroleptics, psychostimulants and certain psychogeriatric drugs. We have attempted to correlate the data obtained on the cell bodies of locus coeruleus with studies reporting effects on terminal areas and thereby gain an overall view of the action of the above mentioned drugs on this cell system. The activity of noradrenergic neurons in locus coeruleus is thought to correlate with the level of cortical vigilance. Special emphasis is placed on the finding that a number of drugs which exert a positive effect on cognitive functions in man and animals increase the firing rate of the rat locus coeruleus neurons.

Action Potentials↗

PubMed1995

Previous stress alters corticotropin-releasing factor neurotransmission in the locus coeruleus.

Spontaneous and stress-evoked discharge of locus coeruleus neurons were characterized in rats with a history of stress. Rats exposed to one or five daily 30-min sessions of footshock were anesthetized with halothane and surgically prepared for locus coeruleus single-unit recording immediately following the last session. Locus coeruleus spontaneous discharge rate and discharge evoked by sciatic nerve stimulation were comparable between acutely and repeatedly stressed rats and controls. In contrast, locus coeruleus activation produced by intracerebroventricular administration of corticotropin-releasing factor (3 micrograms) or by hypotensive challenge (which requires endogenous corticotropin-releasing factor release in the locus coeruleus) was greatly attenuated in acutely stressed rats. The corticotropin-releasing factor dose-response curve was shifted to the right in acutely stressed rats compared with controls. In repeatedly stressed rats, the effects of 3 micrograms corticotropin-releasing factor on locus coeruleus discharge were similarly diminished. Although the maximum effect produced by corticotropin-releasing factor was decreased in these rats, the dose-response curve was shifted to the left, indicative of sensitization. Hypotensive challenge, which was ineffective in acutely stressed rats, increased locus coeruleus discharge of repeatedly stressed rats by a similar magnitude as in matched controls. The return of locus coeruleus responsiveness to hypotension in repeatedly stressed rats may be related to the sensitization to corticotropin-releasing factor. Finally, the protocol of repeated stress did not alter the affinity or density of corticotropin-releasing factor receptors in either the frontal cortex or brainstem. Taken together, the results suggest that a history of stress alters corticotropin-releasing factor neurotransmission in the locus coeruleus at the postsynaptic level. However, these effects are not reflected by corticotropin-releasing factor binding kinetics in brainstem. Stress-induced changes in corticotropin-releasing factor neurotransmitter function in the locus coeruleus may play a role in certain symptoms of stress-related psychiatric disorders.

Animals↗

PubMed2001

GABAergic neurons in prepositus hypoglossi regulate REM sleep by its action on locus coeruleus in freely moving rats.

GABA in locus coeruleus modulates REM sleep. Apart from the presence of interneurons, locus coeruleus also receives GABAergic inputs from prepositus hypoglossi in the medulla, where the presence of REM-ON-like neurons have been reported. Therefore, it was hypothesized that GABAergic projections from prepositus hypoglossi to locus coeruleus may modulate REM sleep. The experiments were conducted on chronic rats prepared for recording EEG, EOG, and EMG in freely moving conditions. Bipolar stimulating electrodes were implanted in prepositus hypoglossi bilaterally, while chemitrodes were implanted bilaterally in locus coeruleus. The prepositus hypoglossi were bilaterally stimulated (3 Hz, 250 microsec, 100 microA) for 8 h in the presence and absence of picrotoxin (0.25 microg/250 nl) microinjection bilaterally in locus coeruleus, followed by poststimulation recording for 4 h. It was observed that stimulation of prepositus hypoglossi alone significantly increased REM sleep primarily by increasing the REM sleep duration per episode. However, when it was stimulated in the presence of picrotoxin in LC, REM sleep decreased, predominantly due to decreased REM sleep duration per episode. The results of this study suggest that GABAergic inputs from prepositus hypoglossi act on locus coeruleus and regulate REM sleep, possibly by inhibition of REM-OFF neurons.

Animals↗

PubMed1984

Intraocular grafting of cultured brain tissue: growth, vascularization and neuron survival in locus coeruleus and cortex cerebri.

Locus coeruleus and cortex cerebri from embryonic (ED 17) and newborn rats were kept 4 days in tissue culture under conditions maintaining organotypic features and then transplanted to the anterior chamber of the eye of adult rats. Vascularization from the host iris was delayed in pre-cultured grafts as compared to directly grafted material. In spite of this, several morphological parameters developed normally. Thus, pre-cultured grafts grew considerably in oculo. Falck-Hillarp histochemistry showed that grafts of cortex cerebri received an adrenergic innervation from the host iris and that locus coeruleus grafts contained central adrenergic neurons capable of innervating a sympathetically denervated host iris. The successful combination of tissue culture and intraocular transplantation should permit the selective advantages of both techniques to be applied to the same tissue pieces, generating new information unobtainable by either method alone.

Animals↗

PubMed1995

Opioid inhibition in locus coeruleus.

1. Inhibition of locus coeruleus (LC) neurons by opioids is mediated by hyperpolarization associated with an increase in potassium conductance. However, opioids caused an outward current even at potentials more negative than the potassium equilibrium potential in the majority of LC neurons recorded in brain slices cut in the horizontal plane. 2. Whole cell and intracellular recording were made from LC neurons in the slice preparation and currents were measured with a switch clamp amplifier. 3. Local application of [Met]5enkephalin (ME) by iontophoresis resulted in two different effects depending on the site of application. Iontophoresis of ME close to the cell caused an outward current that reversed polarity near the potassium equilibrium potential. Whereas application at a distance > 200 microns resulted in an outward current that did not reverse polarity even at strongly negative potentials. 4. When potassium conductances were blocked with internal Cs and/or external Ba, the opioid current was reduced to < 15% of control. 5. Low sodium solutions were used to reduce sodium-dependent conductances. These solutions hyperpolarized LC neurons themselves, decreased outward currents caused by ME, and shifted the reversal potential of the ME induced current to less negative values. 6. Electrotonic coupling of LC neurons in neonatal animals is thought to synchronize spontaneous activity. In this study, synchronous activity in cells from adult animals also was observed, suggesting that electrotonic coupling in the LC persists into adulthood. 7. Carbenoxolone, an agent thought to block electrotonic coupling, had no effect on the action potential, spontaneous activity, or the resting conductance but blocked electrotonic coupling between LC neurons in neonates, blocked synchronous activity in LC neurons from adult animals, and shifted the reversal potential of the opioid current to the potassium equilibrium potential. 8. All results are consistent with the hypothesis that LC cells are electrotonically coupled. Such electrotonic coupling at the level of the nucleus locus coeruleus would mediate synchronous regulation of noradrenaline in widespread areas of the brain.

Animals↗

PubMed2000

Role of locus coeruleus in foot shock-evoked Fos expression in rat brain.

The robust activation of locus coeruleus neurons in response to a variety of stressors, in conjunction with the widespread outputs of the locus coeruleus, suggest that the locus coeruleus may be important in mediating responses to stress. Previous studies in rats have demonstrated that exposure to foot shock elicits Fos expression, a marker of neuronal activation, in the locus coeruleus and other brain sites. In order to evaluate the involvement of the locus coeruleus in foot shock-induced activation of other brain sites, shock-induced Fos expression was examined in the locus coeruleus and other brain areas known to be activated by foot shock, following direct inhibition of the locus coeruleus by local infusion of muscimol, a GABA agonist, prior to foot shock. Control rats received infusions of artificial cerebrospinal fluid into the locus coeruleus or muscimol into areas outside of locus coeruleus. Rats infused with artificial cerebrospinal fluid and then exposed to foot shock had significant increases in Fos expression in several brain areas, including locus coeruleus, nucleus O, several subdivisions of the hypothalamus, subnuclei of amygdala, bed nucleus of the stria terminalis and cingulate cortex. Inhibition of the locus coeruleus prior to foot shock significantly inhibited Fos expression in the locus coeruleus, nucleus O, some subdivisions of the hypothalamus including the magnocellular and medial parvicellular paraventricular hypothalamic nucleus, subnuclei of amygdala, and cingulate cortex. In contrast, inhibition of the locus coeruleus did not affect shock-induced Fos expression in other areas, including certain subdivisions of the hypothalamus and bed nucleus of the stria terminalis. We suggest that foot shock may activate multiple pathways, with activation of certain discrete nuclei requiring input from the locus coeruleus and activation of others occurring independently of locus coeruleus input.

Animals↗

PubMed1987

Alterations in responsiveness of noradrenergic neurons of the locus coeruleus in deoxycorticosterone acetate (DOCA)-salt hypertensive rats.

Locus coeruleus may have a function in central blood pressure regulation and possibly in the pathogenesis of hypertension. In keeping with this notion, we have recently shown that deoxycorticosterone acetate (DOCA)-salt hypertensive rats demonstrate a greater increase in blood pressure induced by locus coeruleus stimulation than control animals. In an attempt to elucidate the underlying mechanisms leading to this alteration in responsiveness of the locus coeruleus, the sensitivity of noradrenergic neurons of the locus coeruleus to the transmitter candidates, epinephrine and glutamate, was investigated in DOCA-prehypertensive (3 days post-DOCA), DOCA chronic hypertensive (6-8 weeks post-DOCA) and control rats using conventional microiontophoretic and single cell recording techniques. Iontophoretically applied epinephrine produced a current-dependent decrease in spontaneous firing rate of all noradrenergic neurons in both DOCA-treated and control rats. Locus coeruleus neurons of DOCA-treated rats at 3 days and 6-8 weeks were less sensitive to epinephrine than those of control rats and the magnitude of the depression in spontaneous firing rate was less. By contrast, iontophoretic applications of glutamate produced an increase in activity of all noradrenergic locus coeruleus neurons. However, there was minimal difference in glutamate sensitivity between neurons of DOCA and control rats. Since the changes in epinephrine sensitivity are apparent not only in the chronic stage but also in the prehypertensive stage, our findings suggest a potential role of the adrenergic input to the locus coeruleus in the pathogenesis of DOCA-hypertension.

Animals↗

PubMed1987

Effect of locus coeruleus and periventricular gray substance lesions on suprachiasmatic damage-induced persistent estrous.

To assess the relation between the suprachiasmatic nucleus and the locus coeruleus, persistent estrous was induced in female rats by damage of the suprachiasmatic nucleus followed with electrolytic damage of the locus coeruleus. Locus coeruleus lesions resulted in a transient loss of persistent estrous indicated by sustained diestrous aspect of the vaginal smears. There was a direct correlation between duration of estrous loss and the amount of locus coeruleus damage. Simultaneous damage to the periventricular gray substance, adjacent to the locus coeruleus, prevented the suppression effects of locus coeruleus damage upon persistent estrous. These results suggest a physiological role of the locus coeruleus and periventricular gray substance in the modulation of the neuroendocrine control of ovarian function due to suprachiasmatic nucleus activity.

Animals↗

PubMed1986

Effect of locus coeruleus and periventricular gray substance lesions on bright light-induced persistent estrous.

To assess the relation between the suprachiasmatic nucleus and the locus coeruleus, persistent estrous was induced in female rats by exposure to constant bright light followed with electrolytic damage of the locus coeruleus. Locus coeruleus lesions resulted in a transient loss of persistent estrous indicated by sustained diestrous aspect of the vaginal smears. There was a direct correlation between duration of estrous loss and the amount of locus coeruleus damage. Simultaneous damage to the periventricular gray substance adjacent to the locus coeruleus prevented the suppression effects of locus coeruleus damage upon persistent estrous. These results suggest a physiological role of the locus coeruleus and periventricular gray substance in the modulation of the neuroendocrine control of ovarian function due to suprachiasmatic nucleus activity.

Animals↗

PubMedDate not supplied

Raphe projections to the locus coeruleus in the rat.

Afferent projections to the locus coeruleus from the various raphe nuclei, particularly of the midbrain (nuclei raphe dorsalis and medianus) and pons (nuclei raphe pontis and magnus), have been studied in the rat by retrograde transport methods using horseradish peroxidase (HRP). The locus coeruleus, in both its dorsomedial and ventrolateral divisions, and in its various anterior-posterior components, were injected with 0.05 microliters of horseradish peroxidase following which various structures of the brainstem, particularly the raphe nuclei, were examined for HRP reactive cells. It was found that injections in most components of the locus coeruleus were associated with HRP positive cells in varying degrees of density in the nuclei raphe dorsalis, medianus, pontis, and magnus, with considerably sparser labelling in the anterior aspects of the medullary raphe nuclei pallidus and obscurus. Labelled cells were also seen in the nuclei of the solitary tract, contralateral locus coeruleus. lateral reticular areas of the pons and midbrain, nuclei pontis oralis and caudalis, vestibular nuclei, mesencephalic nucleus of the trigeminal nerve, fastigial nuclei of cerebellum and medial parabrachial nuclei. These data, showing widespread innervation of the locus coeruleus from all raphe nuclei, as well as many other brainstem areas, in the rat support the general view of heavy innervation of the locus coeruleus from both extra-raphe and raphe nulcei. These latter raphe projections, probably serotonergic in nature, provide anatomical support for the various experiments indicating considerable regulation of locus coeruleus activities, such as phasic events of REM sleep, among other, by widespread projections from most raphe nuclei was well as several other regions of the brainstem.

Afferent Pathways↗

PubMed1993

Effects of locus coeruleus inactivation on electroencephalographic activity in neocortex and hippocampus.

The effects of inhibition of locus coeruleus neuronal discharge activity on cortical and hippocampal electroencephalographic activity were examined in halothane-anesthetized rats. A combined recording/infusion probe was used to place 35-150-nl infusions of the alpha 2-noradrenergic agonist, clonidine (1 ng/nl) which inhibits locus coeruleus neuronal discharge activity, immediately adjacent to the locus coeruleus. The recording electrode allowed verification and quantification of the electrophysiological effects of these infusions. Simultaneously, electroencephalographic activity was recorded from sites in frontal neocortex and dorsal hippocampus and subjected to power spectrum analyses. Neither cortical nor hippocampal electroencephalographic activity was substantially affected following unilateral locus coeruleus inactivation. In contrast, bilateral clonidine infusions that completely suppressed locus coeruleus neuronal discharge activity in both hemispheres altered cortical and hippocampal electroencephalographic status. The cortical response to bilateral LC inhibition was characterized by a shift from low-amplitude, high-frequency to large-amplitude, slow-wave activity. Additionally, theta-dominated activity in the hippocampus was replaced with mixed frequency activity. The onset of these changes in forebrain electroencephalographic activity was coincident with the complete bilateral inhibition of locus coeruleus neuronal discharge activity. The resumption of pre-infusion electroencephalographic patterns closely followed recovery of locus coeruleus neuronal activity or could be induced with systemic administration of the alpha 2-noradrenergic antagonist, idazoxan. Clonidine infusions placed 800-1200 microns from the locus coeruleus were less effective at inducing a complete suppression of locus coeruleus activity. These infusions either did not completely inhibit locus coeruleus discharge (35 nl infusions), or did so with a longer latency to complete locus coeruleus inhibition and a shorter duration of inhibition (150 nl infusions). Changes in forebrain electroencephalographic activity occurred only following the complete bilateral suppression of locus coeruleus neuronal discharge activity. These electroencephalographic responses closely followed or coincided with the onset of complete bilateral locus coeruleus inhibition and persisted throughout the period during which bilateral LC neuronal discharge activity was completely absent (60-240 min). Recovery of electroencephalographic patterns was coincident with the reappearance of locus coeruleus discharge activity. These results suggest that the clonidine-induced changes in forebrain electroencephalographic activity were dependent on the complete bilateral suppression of locus coeruleus discharge activity, and that under the present experimental conditions the locus coeruleus/noradrenergic system exerts a potent and tonic activating influence on forebrain electroencephalographic state. These results support the hypothesis that this system may be an important modulator of behavioral state and/or state-dependent processes.

Adrenergic alpha-Antagonists↗

PubMed1980

Monoaminergic presynaptic axons and dendrites in rat locus coeruleus seen in reconstructions of serial sections.

Locus coeruleus was studied in rats pretreated with intraventricularly administered 5-hydroxydopamine 1/2 to 3 hours prior to conventional aldehydeosmium fixation. Presynaptic profiles in locus coeruleus neuropil were classified according to the characteristics of their vesicle populations and other features, as in our previous report. Similar categories of endings were observed, and the sites of postsynaptic innervation were identical to those described previously, that is, a majority of synapses were made with dendrites between 0.5 and 2.5 micrometers in cross-sectional diameter, a significant proportion was seen ending onto somatic and dendritic spines, with a relative paucity of synapses made with spine-free membrane of somata and large dendritic trunks. There were no significant differences between different morphological categories of afferent terminals and their spatial distribution onto various postsynaptic targets on locus coeruleus neurons. In addition to various membrane-bound compartments of the cytoplasm, three categories of synaptic endings were labelled by the synaptic marker, while all others were unlabelled. One of these was identified previously as containing small, rounded synaptic vesicles and an unusually large number of large, dense core vesicles. The synaptic vesicles were lightly labelled with scattered, small, eccentrically placed opaque cores inside the synaptic vesicles, apparently randomly distributed throughout the terminal. This terminal is thought to be serotonergic. A second category of labelled synapse has been previously identified as that derived from small, unmyelinated axons having clusters of pleomorphic synaptic vesicles in which the vesicles are heavily labelled by 5-hydroxydopamine. These are believed to represent catecholaminergic synaptic endings derived from recurrent collaterals as well as extrinsic catecholaminergic innervation of locus coeruleus. A final category of heavily labelled profile was identified as presynaptic dendrites, which, along with recurrent catecholaminergic axon collaterals, probably play an important part in the intrinsic regulation of nucleus locus coeruleus. When 59 labelled synapses were examined in adjacent serial sections, every vesicle-containing profile was associated with a synaptic contact having characteristic membrane specializations. A similar result was obtained when 132 other unlabelled terminals of different categories were examined in serial sections.

Animals↗

PubMed1978

Locus coeruleus fibre growth in oculo induced by trigeminotomy.

Locus coeruleus from fetal donors was homologously grafted to the anterior eye chambers of adult rats whose eyes were sympathetically denervated. After intraocular maturation, outgrowth of noradrenaline-containing fibres from the locus coeruleus neurons on the host iris was studied by Falck--Hillarp fluorescence histochemistry. In control animals locus coeruleus grafts produce a halo of noradrenaline-containing nerve fibres around the graft, covering approximately one third of the surface of the host iris. Sensory denervation of host eyes carrying maturated locus coeruleus grafts was produced by intracranial lesions of the trigeminal nerve. Such lesions induced a rapid growth response in the grafted locus coeruleus neurons, leading within three weeks to complete innervation of the host iris. It was concluded that removal of non-sympathetic, non-parasympathetic nerve fibres on the host iris elicits a strong fibre-growth response in the grafted locus coeruleus.

Animals↗

PubMed1998

Injection of corticotropin-releasing hormone into the locus coeruleus or foot shock increases neuronal Fos expression.

Previous research suggests that corticotropin-releasing hormone can act in the locus coeruleus to increase the firing of locus coeruleus neurons and elicit physiological responses resembling those associated with stress. The present study used immunocytochemical detection of Fos as a measure of neuronal activation to identify brain areas that were activated by bilateral injections of corticotropin-releasing hormone into the locus coeruleus of rats. Injection of corticotropin-releasing hormone into the locus coeruleus increased the expression of Fos in the locus coeruleus as compared with injection of vehicle into the locus coeruleus or injection of corticotropin-releasing hormone into neighbouring pontine sites. The pattern of Fos expression throughout the brain after injections of corticotropin-releasing hormone into the locus coeruleus was generally consistent with the anatomical organization of efferent projections arising from the locus coeruleus; increased Fos expression was observed in many brain areas including the ventral lateral septum, septohypothalamic nucleus, bed nucleus of the stria terminalis, the central amygdaloid nucleus, the dorsomedial nuclei of the hypothalamus, and the thalamic paraventricular and rhomboid nuclei. Foot shock also increased Fos expression in the locus coeruleus and the other brain regions that expressed Fos after corticotropin-releasing hormone injections into the locus coeruleus. A few brain regions, most notably the hypothalamic paraventricular nucleus, expressed Fos in response to foot shock but not corticotropin-releasing hormone. These results indicate that local injection of corticotropin-releasing hormone into the locus coeruleus stimulates the activity of the locus coeruleus neurons. However, the pattern of Fos expression throughout the brain evoked by injection of corticotropin-releasing hormone into the locus coeruleus does not fully replicate the effects of foot shock.

Animals↗

PubMed1987

Locus coeruleus neurons projecting to the forebrain and the spinal cord in the cat.

The intranuclear organization of the cat locus coeruleus neurons was investigated anatomo-physiologically. The locus coeruleus neurons project to the forebrain through the dorsal noradrenergic bundle and to the spinal cord. Horseradish peroxidase, a retrograde tracer, was pressure-injected into either the dorsal noradrenergic bundle or the ventrolateral funiculus of the high cervical cord (C1-C2). The cats (n = 12) were killed after a 2- or 3-day survival period. The frontal sections (100 micron) throughout the locus coeruleus were observed by light microscope after carrying out the diaminobenzidine reaction. The labeled locus coeruleus neurons were located predominantly in the rostral locus coeruleus proper and locus coeruleus alpha when horseradish peroxidase was injected into the dorsal noradrenergic bundle, whereas they were predominantly located in the caudal locus coeruleus alpha and subcoeruleus when horseradish peroxidase was injected into the spinal cord. In the electrophysiological experiments, cats (n = 30) were anesthetized with alpha-chloralose and two stimulating electrodes were placed stereotaxically in the dorsal noradrenergic bundle and the ipsilateral ventrolateral funiculus of the high cervical cord (C1-C2), respectively. Monophasic square-wave pulses (2.5 Hz, 100 microsecond duration, 800 microA) were delivered. A recording glass electrode, filled with 2 M NaCl saturated with Fast Green, was placed in the locus coeruleus. Neurons with different conduction velocities, which were evoked by the antidromic stimulation of the dorsal noradrenergic bundle and spinal cord, were verified in the locus coeruleus and the adjacent areas. The slow conductive neurons with a conduction velocity of less than 1 m/s had a slow firing rate (1.6 +/- 0.9/s). They were located predominantly in the rostral locus coeruleus proper and locus coeruleus alpha by the dorsal noradrenergic bundle stimulation. From the anatomical and electrophysiological experimental results, it was concluded that the conduction velocities of the horseradish peroxidase-labeled neurons observed in locus coeruleus proper and locus coeruleus alpha were mostly slow and less than 1 m/s. Most of the slow conductive neurons were considered to be noradrenergic. Neurons evoked antidromically by both the dorsal noradrenergic bundle and spinal cord stimulation were not observed.

Action Potentials↗

PubMed1976

The roles of noradrenaline and dopamine in contraversive circling behaviour seen after unilateral electrolytic lesions of the locus coeruleus.

Unilateral electrolytic lesions of the locus coeruleus in rats result in spontaneous ipsiversive rotation, which is then replaced by contraversive rotation. One week after lesioning, when spontaneous turning ceases, apomorphine and d-amphetamine elicit contraversive circling behaviour, which was not affected by noradrenergic receptor blockade but was abolished by dopamine receptor blockade. The drug-induced contraversive circling response was also reproduced by piribedil but not clonidine. Combined unilateral electrolytic locus coeruleus and substantia nigra lesions on the same side resulted in apomorphine- and d-amphetamine-induced ipsilateral rotational behaviour which was indistinguishable from that seen with substantia nigra lesions alone. In rats with unilateral locus coeruleus lesions, the dose of intrastriatally injected apomorphine required to produce circling was less on the lesioned than the non-lesioned side. Direct injection of noradrenaline into one substantia nigra caused contraversive circling. Direct injection of phenoxybenzamine into one substantia nigra followed by apomorphine caused ipsiversive circling. The results suggest that the circling behaviour seen after unilateral locus coeruleus lesions depends on an asymmetry of striatal dopamine receptor activity and are consistent with a proposed coeruleus-nigral noradrenergic pathway, which enhances impulse flow in the dopaminergic nigrostriatal system.

Animals↗

PubMed1999

Dependence of serotonin release in the locus coeruleus on dorsal raphe neuronal activity.

The serotonergic innervation of the locus coeruleus paetly derives from the dorsal raphe nucleus (DRN). Using the push-pull superfusion technique, we investigated whether and to what extent the release of serotonin and the extracellular concentration of its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the locus coeruleus are influenced by the neuronal activity of the DRN. In anaesthetized rats, a push-pull cannula was inserted into the locus coeruleus, which was continuously superfused with artificial cerebrospinal fluid (aCSF). Serotonin and 5-HIAA levels in the superfusate were determined by HPLC combined with electrochemical detection. Electrical stimulation (5 Hz, 300 microA, 1 ms) of the DRN for 5 min, or its chemical stimulation by microinjection of glutamate (3.5 nmol, 50 nl), led to an increased release of serotonin in the locus coeruleus and to a slight (2 mmHg) decrease in blood pressure. Superfusion of the locus coeruleus with tetrodotoxin (1 microM) abolished the increase in the release rate of serotonin evoked by electrical stimulation of the DRN, while the slight fall in blood pressure was not influenced. Thermic lesion (75 degrees C, 1 min) of the DRN elicited a pronounced decline in serotonin release rate within the locus coeruleus, the maximum decrease being 52%. The decrease in the release of serotonin was associated with a long-lasting rise in blood pressure. Microinjection of the serotonin neurotoxin 5,7-dihydroxytryptamine (5 microg, 250 nl) into the DRN led to an initial increase in the serotonin release rate that coincided with a short-lasting fall in blood pressure. Subsequently, the release of serotonin was permanently reduced and was associated with hypertension. Microinjection of the 5-HT1A receptor agonist (+/-)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT; 7.5 nmol, 50 nl) into the DRN led to a long-lasting reduction of the release rate of serotonin in the locus coeruleus. Microinjection of 8-OH-DPAT into the DRN also slightly lowered blood pressure (3 mmHg). Neither stimulations nor lesion of the DRN, nor microinjection of 8-OH-DPAT into this raphe nucleus, altered the extracellular concentration of 5-HIAA. Judging from the present biochemical results it appears that the serotonergic afferents to the locus coeruleus originate to more than 50% from cell bodies located in the DRN. The neuronal serotonin release in the locus coeruleus is modulated by 5-HT1A receptors lying within the DRN. Changes in blood pressure and release of serotonin elicited by stimulating or lesioning the DRN point to the importance of serotonergic neurons extending between this raphe nucleus and the locus coeruleus in central cardiovascular control.

5,6-Dihydroxytryptamine↗