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PubMed1979

Serotonergic innervation of the locus coeruleus from the dorsal raphe and its action on responses to noxious stimuli.

The connexions between the dorsal raphe nucleus and the nucleus locus coeruleus were studied in urethane anaesthetized rats. 1. Cells in the locus coeruleus gave an excitatory response to a noxious stimulus, e.g. leg pinch. 2. This excitatory response was blocked by either a parenteral or an ionophoretic injection of morphine and recovered after an injection of naloxone. 3. Electrical stimulation in the region of the dorsal raphe blocked excitatory locus coeruleus responses to noxious stimuli. 4. While naloxone did not antagonize the effects of the dorsal raphe stimulation towards locus coeruleus activity, these effects were absent in rats pretreated with a serotonin synthesis inhibitor, PCPA or with 5,7-DHT which destroys serotonin-containing terminals, and were reduced by the serotonin antagonist methysergide. 5. A serotonin-containing inhibitory pathway between the dorsal raphe and the locus coeruleus is proposed to account for these results.

Action Potentials↗
PubMed1994

In vivo release of catecholamines in the locus coeruleus.

To investigate the release of endogenous dopamine, noradrenaline and adrenaline in the locus coeruleus, this brain area was superfused with artificial cerebrospinal fluid (CSF) through push-pull cannulae and the release of catecholamines was determined in the superfusate radioenzymatically. Collection of superfusates in time periods of 10 min revealed that release rates of the three catecholamines fluctuated, thus pointing to the existence of ultradian rhythms with following mean periods (minutes per cycle): noradrenaline 52 +/- 4, dopamine 37 +/- 2, adrenaline 36 +/- 2. The rhythm frequency of noradrenaline was significantly lower than the frequencies of dopamine and adrenaline. When the locus coeruleus was superfused with neuroactive drugs, superfusates were collected in time periods of 3 min. Superfusion with tetrodotoxin (1 mumol l-1) for 12 min elicited a prompt and sustained decrease (-70%) in the release rates of dopamine and adrenaline. The release rate of noradrenaline was also reduced, although to a lesser extent (-40%). Superfusion with veratridine (50 mumol l-1) led to an immediate and very pronounced enhancement in the release rates of dopamine, noradrenaline and adrenaline. The veratridine-induced increase in catecholamine outflow was decreased strongly by simultaneous superfusion with tetrodotoxin. The findings suggest that the release of endogenous catecholamines in the locus coeruleus fluctuates according to ultradian rhythms. Changes in the release on superfusion with veratridine and tetrodotoxin demonstrate the neuronal origin of the three catecholamines. The observed differences in the release characteristics between noradrenaline on the one hand and dopamine and adrenaline on the other might indicate that noradrenaline is partly released from somatodendritic sites of the noradrenergic cell bodies in the locus coeruleus.

Animals↗
PubMed1982

Electrophysiological properties of neurons contained in the locus coeruleus and mesencephalic nucleus of the trigeminal nerve in vitro.

Intracellular recordings were made from neurones contained in the locus coeruleus and mesencephalic nucleus of the trigeminal nerve (MNV), in tissue slices cut from guinea-pig pons and maintained in vitro. Locus coeruleus neurones were of -52.7 +/- 2.7 mV resting membrane potential; had an input resistance of 58.0 +/- 7.6 M omega and a membrane time constant of 7.3 +/- 1.0 ms. These neurones fired action potentials in response to depolarizing current pulses. Depolarizing synaptic potentials (DSPs) were recorded in locus coeruleus neurones in response to focal stimulation of the surface of the slice. MNV neurones were of -51.9 +/- 3.6 mV resting membrane potential; had an input resistance of 15.0 +/- 1.8 M omega and a membrane time constant of 1.35 +/- 0.16 ms. These neurones were also excitable but differed from locus coeruleus neurones in that they showed accommodation to depolarizing current pulses and time-dependent anomalous rectification with hyperpolarizing current pulses. In MNV neurones focal stimulation did not give rise to DSPs. Intracellular injection of Lucifer yellow revealed that the cell bodies of locus coeruleus neurones were small and multipolar whereas MNV neurones had larger, monopolar cell bodies.

Animals↗
PubMed1985

Locus coeruleus neurons in the neonatal rat: electrical activity and responses to sensory stimulation.

Newborn rats, 1-3 days of age, were anesthetized with urethane and single-unit activities were recorded extracellularly in the locus coeruleus. Ca. 35% of locus coeruleus neurons recorded were antidromically activated from stimulation of the frontal cortex. Although the majority of locus coeruleus neurons were not spontaneously active, non-noxious as well as noxious sensory stimuli such as touches to the skin, air puffs and tail pinches were very effective in exciting locus coeruleus neurons.

Animals↗
PubMed1999

ATP-sensitive and Ca2+-activated K+ channel activities in the rat locus coeruleus neurons during metabolic inhibition.

Locus coeruleus (LC) is the significant nucleus for consciousness and it is sensitive to metabolic inhibition. We investigated the effects of a metabolic inhibitor sodium cyanide (NaCN) on the rat dissociated LC neurons using nystatin-perforated patch recordings. Under voltage-clamp (VH=-40 mV), application of NaCN evoked outward currents composed of ATP-sensitive and Ca2+-dependent K+ channel currents (IKATP and IKCa2+). Onset of IKATP was faster than that of IKCa2+. Prolonged application of NaCN brought IKATP rundown but not IKCa2+ rundown. Okadaic acid prevented IKATP rundown, indicating that KATP channels are deactivated by dephosphorylation with protein phosphatase.

Adenosine Triphosphate↗
PubMed1985

Action of norepinephrine in the dentate gyrus. I. Stimulation of locus coeruleus.

The effect of stimulating locus coeruleus (LC) on the response of dentate gyrus granule cells to medial perforant pathway stimulation was studied in anesthetized rats. Field responses were recorded simultaneously at the mid-dendritic and granule cell levels. Two types of responses were recorded: those due to the synchronous firing of granule cell action potentials (population spikes) and those produced by excitatory synaptic activity (evoked synaptic potentials or ESPs). Stimulation of LC prior to stimulating the perforant pathway resulted in a decrease in the ESP (inward current) measured at the dendrites and, in most animals, an increase of the population spike measured at the granule cell level. Although LC stimulation decreased the ESP at the dendrites, the ESP at the granule cell body level (outward current) was not affected. The changes in granule cell responses following LC stimulation are discussed in relation to previous findings in freely moving rats.

Animals↗
PubMed1988

Behavior of monkeys during opiate withdrawal and locus coeruleus stimulation.

The noradrenergic nucleus locus coeruleus (LC) has been implicated in morphine withdrawal. The behavioral effects of opiate antagonist-precipitated morphine withdrawal in chair-restrained Macaca arctoides were therefore compared with LC electrical field stimulation. Both continuous LC stimulation and administration of low doses of naloxone to morphine pellet implanted monkeys produced a significant increase in the same group of behaviors reported previously to follow activation of the LC, without significant increases in general activity or distress behaviors. Signs of autonomic hyperactivity and distress were observed at high doses of naloxone, but not during LC stimulation. Monkeys which had not received morphine treatment did not specifically increased during low intensity LC stimulation is also selectively increased during naloxone-precipitated morphine withdrawal. These data are consistent with and suggest a behavioral consequence of the interactions of opioids with the LC reported at the molecular, intracellular, and cellular level.

Animals↗
PubMed1990

Autoradiographic localization of angiotensin II receptor binding sites on noradrenergic neurons of the locus coeruleus of the rat.

The locus coeruleus (LC) of the rat was lesioned by microinjection of selective neurotoxins into the brainstem. 6-Hydroxydopamine (6-OHDA), 3 micrograms/microliter, given unilaterally at two sites 0.6 mm apart on the rostro-caudal axis of the LC, was used to lesion catecholamine-containing neuronal elements. Ibotenic acid, 2.5 micrograms/0.5 microliters, administered similarly was used to lesion nerve cell bodies. Two weeks after administration of the neurotoxin, lesion efficacy was determined based on the norepinephrine content of the cerebral cortex ipsi- and contralateral to the lesion. 6-OHDA lesions of the LC caused a 46% reduction in ipsilateral cortical norepinephrine and a 60% reduction in specific 125I-[Sar1, Ile8]-angiotensin II (125I-SIAII) binding in the LC. Ibotenic acid lesions of the LC caused a 73% reduction in ipsilateral cortical norepinephrine and a 81% reduction in specific 125I-SIAII binding in the LC. These results indicate that AII receptor binding sites in the LC are localized on noradrenergic nerve cell bodies or their dendritic and axonal ramifications within the LC.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed2005

Hypothalamic projections to locus coeruleus neurons in rat brain.

Locus coeruleus (LC) neurons respond to autonomic and visceral stimuli and discharge in parallel with peripheral sympathetic nerves. The present study characterized the synaptic organization of hypothalamic afferents with catecholaminergic neurons in the LC using electron microscopy. Peroxidase labeling of axon terminals that were anterogradely labeled from the paraventricular nucleus (PVN) was combined with gold-silver labeling of tyrosine hydroxylase in the LC. Approximately 19% of the anterogradely labeled axon terminals formed synaptic specializations with tyrosine hydroxylase-immunoreactive dendrites in the LC. Retrograde transport from the LC combined with immunocytochemical detection of enkephalin and corticotropin-releasing factor (CRF) suggested that most of the LC-projecting PVN neurons (30%) were CRF immunoreactive and few (2%) were enkephalin immunoreactive. Finally, dual retrograde tracing from the LC and median eminence revealed that PVN neurons that project to the LC are a population distinct from that projecting to the median eminence. The present data suggest that a population of hypothalamic neurons is poised to directly modulate the activity of LC neurons and may integrate autonomic responses in brain by influencing LC neurons. Moreover, PVN neurons that use CRF as a neurohormone are distinct from those that use CRF as a neuromodulator to impact on the LC.

Animals↗
PubMed2001

Effects of chronic antidepressant drug administration and electroconvulsive shock on locus coeruleus electrophysiologic activity.

BACKGROUND: The locus coeruleus (LC) is the major noradrenergic cell body group in the brain. Although previous studies have examined changes in electrophysiologic activity of LC neurons produced by antidepressant drugs, only a small number have examined changes that occur with chronic drug administration, which is the therapeutically effective regimen, and only one group of investigators has assessed effects on activated (or "burst") firing of LC neurons under such treatment conditions. The present study assessed changes produced in rats by effective antidepressant treatments-several drugs given chronically (two tricyclic antidepressants, two selective serotonin reuptake inhibitors, and a monoamine oxidase inhibitor) as well as a series of electroconvulsive shocks (ECSs)-in single-unit electrophysiologic activity of LC neurons, measuring effects on spontaneous depolarization rate and also on sensory-evoked burst firing. METHODS: Drugs were administered via osmotic minipumps for either 14 or 30 days; ECSs were administered five times, with a 72-hour interval between each administration. Electrophysiologic recording of LC activity took place under halothane anesthesia on the last day of drug treatment or following a delay of 1 or 5 days after the final ECS. RESULTS: A common effect of all drugs tested and ECS treatment was to decrease LC spontaneous and sensory-evoked burst firing. CONCLUSIONS: The clinical efficacy of antidepressant medication and ECS may be mediated, in part, through reduction of LC neural activity. The findings reported here are consistent with recent indications that LC neurons are hyperactive in depressed individuals and with suggestions that some behavioral changes seen in depression can arise from consequences of rapidly depolarizing LC terminals, such as release of peptides.

Animals↗
PubMed1991

Afferent effects on locus coeruleus in opiate withdrawal.

The locus coeruleus (LC) has been hypothesized to play an important role in opiate withdrawal. This hypothesis is supported, in part, by the finding that LC neurons greatly increase their activity during antagonist-precipitated morphine withdrawal and that this increased activity correlates temporally with withdrawal behavior. However, this withdrawal-induced increase in unit activity is not seen in vitro in brain slices taken from morphine-dependent animals, indicating that afferents to the LC play an important role in the withdrawal-induced activation of these neurons. This chapter reviews data indicating: (1) the morphine-withdrawal-induced activation of LC neurons is mediated predominantly by non-N-methyl-D-aspartate (NMDA) excitatory amino acid pathways in the brain; (2) the activation of the LC during morphine withdrawal may be mediated, at least in part, by an excitatory amino acid projection from the nucleus paragigantocellularis. The role of other excitatory amino acid pathways in the withdrawal-induced activation of the LC remains to be determined; (3) intrinsic changes in the G-protein/cyclic AMP system of LC cells may play an important role in mediating the effects of afferent inputs to the LC during morphine withdrawal; (4) NMDA antagonists (unlike the alpha 2 agonist clonidine) attenuate the behavioral signs of morphine withdrawal without blocking the withdrawal-induced increase of LC unit activity. In addition, non-competitive NMDA antagonists like MK801 may not be useful to alleviate opiate-withdrawal symptoms in man because of their PCP-like side effects. However, competitive NMDA antagonists like LY274614 could be of great benefit for alleviating opiate-withdrawal withdrawal symptoms in man.

Afferent Pathways↗
PubMed2001

Role of nitric oxide in the stress-induced release of serotonin in the locus coeruleus.

Serotonergic mechanisms within the locus coeruleus (LC) are thought to be important in various functions including the stress response. In this study we investigated a possible role of nitric oxide (NO) as an intermediary messenger in the regulation of the serotonin (5-HT) neurotransmission within the LC. Using the push-pull superfusion technique coupled with HPLC and electrochemical detection, the in vivo release of 5-HT was determined in time periods of 10 min in the LC of freely moving rats. Superfusion with three different NO donors, SIN-1 (linsidomine), S-nitroso-N-penicillamine (SNAP) or 3-(2-hydroxy-2-nitroso-1-propylhydrazino)-1-propanamine (PAPANO) increased 5-HT release in the LC. Superfusion with the precursor of NO, L-arginine, for 1 h led to a sustained increase in 5-HT release. On the other hand, the NOS inhibitor N-methyl-L-arginine methyl ester (L-NAME) did not significantly change the release of 5-HT. Infusion of N-methyl-D-aspartate (NMDA) or kainic acid, as well as exposure of rats to noise stress or tail pinch increased the release of 5-HT in the LC. Superfusion with L-NAME prevented the increase in 5-HT outflow by all these procedures, while the inactive isomer D-NAME had no effect. Taken together, the results of this study suggest that the release of 5-HT in the LC is facilitated by NO. Under resting conditions inhibition of NOS does not appear to substantially influence the release of 5-HT in the LC. However, there seems to be a facilitatory nitrergic influence on serotonergic responses evoked by excitatory amino acid receptor stimulation or various stress stimuli.

Animals↗
PubMed1994

Absolute number and size of pigmented locus coeruleus neurons in young and aged individuals.

Significant loss of noradrenergic neurons of the locus coeruleus in aging and Alzheimer's disease has been reported. The interpretation of these analyses, however, is problematic because of the model- and assumption-based nature of conventional sampling and estimation techniques. In the present study, unbiased stereological methods were used to estimate the total number and mean cell volume of pigmented neurons of the locus coeruleus in the brains of young and aged nondemented persons. No side-to-side differences are seen, and there is no change in pigmented cell number or size in the locus coeruleus of nondemented older persons as compared with that of young individuals. In light of previous studies that show severe locus coeruleus cell loss in Alzheimer's disease, these data support further critical investigations into the possible protective role of noradrenaline in normal cognitive functions and emphasize the importance of avoiding methodological bias in quantitative neuroanatomical studies.

Adult↗
PubMed1995

Inhibition of catecholamine (noradrenaline, dopamine) release in the locus coeruleus and the hypothalamus by baroreceptor activation: identification of the involved baroreceptors.

We have previously shown that experimentally induced blood pressure changes modify the release rates of catecholamines in the hypothalamus and the locus coeruleus. The aim of the present investigation was to identify the peripheral baroreceptors and the centripetal pathways responsible for the changes of catecholamine release in these brain areas. In anaesthetized cats, push-pull cannulae were bilaterally inserted into the locus coeruleus and the posterior hypothalamus. The two brain areas were superfused simultaneously with artificial cerebrospinal fluid. Baroreceptor activation by phenylephrine-induced blood pressure elevation decreased the release rate of noradrenaline in the locus coeruleus and the release rates of noradrenaline and dopamine in the posterior hypothalamus. Similar effects were elicited by electrical stimulation of the central trunk of the transected vagus and aortic depressor nerves (vagus-ADN). Transection of the nerves abolished the effect of phenylephrine on the release of noradrenaline in the locus coeruleus. Nerve transections attenuated slightly the decreased release of noradrenaline elicited by phenylephrine in the posterior hypothalamus, while the reduced dopamine release rate was not influenced. The selective stimulation of baroreceptors in the carotid sinus by an inflatable catheter did not influence the release of catecholamines in the locus coeruleus, while release rates of noradrenaline and dopamine in the posterior hypothalamus were decreased. The simultaneous superfusion of locus coeruleus and hypothalamus revealed that, in both areas, noradrenaline release is inhibited by baroreceptor activation. Noradrenergic neurons of the posterior hypothalamus are inhibited by baroreceptor impulses conducted by the carotid sinus nerve and vagus-ADN, while the noradrenergic neurons of the locus coeruleus seem to respond to impulses transmitted by vagus-ADN.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

alpha(2)-Adrenoceptor involvement in the in vitro inhibitory effect of citalopram on a subpopulation of rat locus coeruleus neurons.

The aim of the present study was to investigate the modulation of locus coeruleus neurons by the selective serotonin (5-HT) reuptake inhibitor citalopram using single-unit extracellular recordings in rat brain slices. Citalopram inhibited the activity of a subpopulation of locus coeruleus neurons; thus 10 microM citalopram inhibited neurons by 53+/-17% (5 out of 15 cells), whereas the inhibition due to 100 microM was 64+/-4% (32 out of 42 cells). This effect was partially reversed (47+/-11%) by the alpha(2)-adrenoceptor antagonist idazoxan (10 microM), whereas it was unaffected by antagonists for 5-HT(1A), 5-HT(2,) and 5-HT(3) receptors, and mu opioid receptors. 5-HT (50 or 200 microM), the 5-HT(1A) receptor agonist 8-OH-DPAT (+/-)-8-hydroxy-2-(DI-n-propyl-amino) tetralin hydrobromide, 10 microM) and the 5-HT(2) receptor agonist DOI ([+/-]-2,5-dimetoxy-4-iodoamphetamine) hydrochloride, 10 or 30 microM) also inhibited a subpopulation of locus coeruleus cells. In addition, citalopram but not 5-HT, enhanced by 1.7 fold the inhibitory effect of noradrenaline. Long-term treatment with citalopram (20 mg/kg/day) did not modify the effect of noradrenaline and bromoxidine. Taken together, our results indicate that citalopram exerts an inhibitory effect on locus coeruleus noradrenergic neurons. alpha(2)-adrenoceptor activation may underlie this effect as a result of elevated levels of noradrenaline in the synaptic cleft.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Mediation of micturition reflex by central norepinephrine from the locus coeruleus in the cat.

We examined whether norepinephrine originating in the locus coeruleus mediates the micturition reflex in anesthetized cats. 6-Hydroxydopamine, a catecholamine neurotoxin, injected bilaterally into the locus coeruleus markedly decreased catecholamine fluorescence in the lesioned area and induced urinary retention after 72 to 84 hr. At this time, there was no or only slight contraction of the urinary bladder induced by its distension, while the contraction was noted before the treatment. However, phenylephrine, an alpha 1-receptor agonist, applied intrathecally in 6-hydroxydopamine-treated animals induced moderate bladder contraction. In sham-operated animals, the bladder contraction on its distension was inhibited by intrathecally applied prazosin, an alpha 1-receptor antagonist. Thus, in the micturition reflex, norepinephrine derived from the locus coeruleus acts on the alpha 1-adrenergic receptors in the sacral cord, and induces urinary bladder contraction via activation of the sacral parasympathetic preganglionic neurons.

Animals↗
PubMed1990

Tyrosine hydroxylase and galanin mRNA levels in locus coeruleus neurons are increased following reserpine administration.

The neuropeptide galanin coexists in 80-90% of the norepinephrine-containing neurons in the locus coeruleus. In situ hybridization histochemistry was used to examine the effects of reserpine treatment or swim stress on tyrosine hydroxylase and galanin mRNA concentrations in locus coeruleus neurons. Reserpine administration significantly increased tyrosine hydroxylase and galanin mRNA levels in the locus coeruleus. The reserpine-induced increase in tyrosine hydroxylase mRNA was significantly correlated with the reserpine-induced increase in galanin mRNA. Three consecutive days of swim stress did not significantly alter either tyrosine hydroxylase or galanin mRNA concentrations in the locus coeruleus. These data suggest that both tyrosine hydroxylase and galanin gene expression in locus coeruleus neurons may be regulated by a reserpine-sensitive mechanism.

Animals↗
PubMed1988

Diminished sympathetic excitation of locus coeruleus noradrenergic neurons in the conscious mature spontaneously hypertensive rat.

We undertook a study to determine whether the activation of the nucleus locus coeruleus might be responsible for the sympathetic hyperactivity in the spontaneously hypertensive rat (SHR). Conscious mature SHR showed increased arterial pressure and plasma catecholamines with electrical stimulation of the locus coeruleus. However, SHR showed smaller increases in arterial pressure and plasma noradrenaline than Wistar-Kyoto rats (WKY). The spontaneous unit discharge in locus coeruleus neurons responded reciprocally to peripherally induced changes in arterial pressure and blood volume. However, the unit discharge in the SHR locus coeruleus is less responsive than that in WKY. Therefore, the locus coeruleus in mature SHR does not seem to be involved in the hyperactivity of the sympathetic nervous system. However, this may not be the case in young SHR.

Animals↗