Locus Ceruleus Cells Research Articles

Degeneration of the Locus Ceruleus Noradrenergic Neurons in the Stress‐induced Depression of Rats

We produced a model of depression in rats which have been exposed to 2-weeks forced walking stress. Electron microscopic observation on the locus ceruleus (LC) cells of the model rats disclosed low dense areas, destroyed membranes, aggregation of intracellular organs, and increased microglia. Density of LC axon terminals in the frontal cortex stained with dopamine beta-hydroxylase antiserum and percentage of LC cells stained with horseradish peroxidase or activated by electrical stimulation antidromically were low in the model. These indices increased in the model treated with imipramine. These findings suggest that the LC noradrenergic neurons degenerate in depression, but regenerate in remission.

Mu-Opioid receptors: Ligand-dependent activation of potassium conductance, desensitization, and internalization.

micro-Opioid receptor (MOR) desensitization and endocytosis have been implicated in tolerance and dependence to opioids. The efficiency of each process is known to be agonist dependent; however, it is not known what determines the relative efficiency of various agonists at either process. In the present study, homologous MOR desensitization in locus ceruleus (LC) neurons and MOR internalization in HEK293 cells were examined using a series of agonists. The results show that the rank order of this series of agonists was different when comparing the magnitude of hyperpolarization and the ability to cause desensitization in LC neurons. Endocytosis of MOR was also examined in HEK293 cells using the same agonists. The relative ability to cause endocytosis in HEK293 cells correlated with the degree of desensitization in LC cells. This strong correlation suggests that the two processes are closely linked. The results also suggest that agonist efficacy is not necessarily a predictor of the ability to cause MOR desensitization or endocytosis. Identification and characterization of the biophysical properties of agonists that favor desensitization and internalization of receptors will lead to a better understanding of opioid signaling.

μ-Opioid Receptors: Ligand-Dependent Activation of Potassium Conductance, Desensitization, and Internalization

μ-Opioid receptor (MOR) desensitization and endocytosis have been implicated in tolerance and dependence to opioids. The efficiency of each process is known to be agonist dependent; however, it is not known what determines the relative efficiency of various agonists at either process. In the present study, homologous MOR desensitization in locus ceruleus (LC) neurons and MOR internalization in HEK293 cells were examined using a series of agonists. The results show that the rank order of this series of agonists was different when comparing the magnitude of hyperpolarization and the ability to cause desensitization in LC neurons. Endocytosis of MOR was also examined in HEK293 cells using the same agonists. The relative ability to cause endocytosis in HEK293 cells correlated with the degree of desensitization in LC cells. This strong correlation suggests that the two processes are closely linked. The results also suggest that agonist efficacy is not necessarily a predictor of the ability to cause MOR desensitization or endocytosis. Identification and characterization of the biophysical properties of agonists that favor desensitization and internalization of receptors will lead to a better understanding of opioid signaling.

State-Related Activity, Reactivity of Locus Ceruleus Neurons in Behaving Monkeys

Publisher Summary This chapter summarizes several studies revealing tonic activity of neurons of the brain noradrenergic nucleus locus ceruleus (LC). LC is correlated with changing degree of alertness, while at the same time, LC cells respond phasically to behaviorally significant stimuli. The results support the hypothesis that the LC-norepinephrine system regulates states of alertness and significantly enhances the brain's ability to react adaptively to environmental stimuli. LC neurons have been recorded extracellularly from four cynomolgus monkeys performing a visual discrimination task. LC neurons exhibit relatively little activity during low-vigilance behaviors such as grooming or food consumption, while LC tonic activity typically accelerates during exploratory activity. These changes in LC discharge have been consistently inversely correlated with attentiveness to the task. Task performance has been best during moderate LC neuronal activity, whereas high LC tonic activity has been associated with behavioral hype activity and poor task performance. The amplitude of LC responses to both targets and distractor stimuli showed remarkable, albeit converse, modulation with different alertness states. These results show that a close relationship exists between attentiveness, LC tonic and phasical activities, and performance of a vigilance task. Phasic excitatory responsiveness of LC neurons may produce a transient, stimulus-oriented increase of attentiveness. In addition to the role proposed for restoring alertness, LC plays important role for memorizing dream content. A role for LC in memory is also consistent with tonic and phasic LC activity observed within the alert state. The specific stimuli that activate LC neurons and increase alertness are also the events most likely to be remembered. This speculation links attention and memory via functions hypothesized for the LC.

Central respiratory control of A5 and A6 pontine noradrenergic neurons.

Sympathetic nerve discharge (SND), phrenic nerve discharge (PND), and unit activity of locus ceruleus (LC) and of putative A5 noradrenergic cells were recorded in vagotomized rats anesthetized with urethan. SND was activated by stimulation of carotid chemoreceptors with hypoxia (N2 inhalation, 5-15 s or 12% O2 inhalation, 2-5 min) and displayed a prominent central respiratory modulation during the hypoxic challenge (postinspiratory pattern). LC cells were also activated by peripheral chemoreceptor stimulation. The discharge of most LC units (28 of 31) exhibited central respiratory modulation. 15 LC units had a postinspiratory pattern and 11 had an inspiratory one. Putative A5 cells were also excited by hypoxia and also displayed a clear central respiratory modulation (mostly postinspiratory pattern). These experiments indicate that 1) the firing rate of most pontine noradrenergic cells is increased by peripheral chemoreceptor stimulation, and 2) pontine noradrenergic neurons receive afferent information of a respiratory nature, possibly from their ventrolateral medullary inputs.

Locus ceruleus discharge characteristics of morphine-dependent rats: Effects of naltrexone

Spontaneous and sensory-evoked discharge was recorded from locus ceruleus (LC) neurons of halothane-anesthetized rats that were chronically administered morphine. LC spontaneous discharge rates of morphine-treated rats were comparable to those of rats chronically administered saline. Administration of 1.0 μg morphine (i.c.v.), a dose which completely inhibits LC discharge of morphine-naive rats, had no effect on LC spontaneous discharge of morphine-treated rats, demonstrating that opiate tolerance had developed. Naltrexone, 0.3 and 1.0 μg i.c.v., produced increases in LC spontaneous discharge rates that were 172 and 166% greater that baseline, respectively. Additionally, naltrexone disrupted LC discharge evoked by repeated sciatic nerve stimulation such that evoked discharge was decreased with respect to tonic discharge, and postactivation inhibition was attenuated. Naltrexone did not alter spontaneous or sensory-evoked LC discharge of rats chronically administered saline indicating that these neuronal effects are specific to opiate withdrawal. Pretreatment of rats with dexamethasone, or with an antagonists of corticotropin-releasing factor (CRF), a-helical CRF 9−41, did not attenuate the effects of naltrexone on LC discharge of morphine tolerant rats. The present study confirms other reports of LC activation associated with antagonist precipitated opiate withdrawal in vivo, and extends these observations by characterizing the disruptive effect of opiate withdrawal on the response of LC cells to phasically presented sensory stimuli, and demonstrating that the withdrawal response is not mediated by release of endogenous CRF.

Action of rilmenidine on locus ceruleus and dorsal raphe cells in vivo and in vitro

The effect of rilmenidine (S 3341) and clonidine on the firing rate of locus ceruleus (LC) and dorsal raphe (DR) cells was studied in vivo after systemic and microiontophoretic administration. The effect of the 2 drugs was also studied in vitro on brain slices containing LC cells. Rilmenidine and clonidine inhibited the firing of LC and DR neurons. Complementary experiments performed with yohimbine and prazosin demonstrated that the effect of LC is related to an agonistic action on α 2 somatodendritic receptors, whereas the effect observed on DR cells is indirect. On LC cells, clonidine is 30 to 60 times as potent as rilmenidine. These observations may be related to less sedative effects of rilmenidine than of clonidine.

Postnatal development of electrical activity in the locus ceruleus.

1. A method for adapting a standard stereotaxic frame for use with neonatal rats as young as postnatal day 1 (PD 1) was devised, and single-unit extracellular recordings were obtained from neurons in the locus ceruleus (LC) in urethan-anesthetized rats during different stages in development from PD 1 to PD 34. 2. The spontaneous firing pattern of neonatal LC neurons was characterized by long silent periods punctuated by brief epochs of sporadic firing. At PD 7-14, LC neurons exhibited periodic occurrences of irregular firing that lasted for 20-30 s. By PD 20, the pattern and rate of spontaneous activity were virtually indistinguishable from that of adults. 3. Conditioning stimulation of the dorsal noradrenergic bundle (DNB), given 10-200 ms prior to a test stimulus to the DNB, markedly reduced the amplitude of the antidromic action potentials to the test stimulus and sometimes resulted in spike decomposition. This refractoriness of the soma-dendritic membrane of LC cells was significantly attenuated with development and approached adult levels after PD 18. 4. Antidromic responses elicited by DNB stimulation were followed by a phase of inhibition or inhibition-excitation. Postactivation excitation was most prominent in cells that were not spontaneously active, and decreased steadily throughout development, probably because of the steady increase in spontaneous firing rate seen during maturation. 5. Although the conduction velocity of LC axons increased steadily from birth through PD 26, conduction time remained unchanged. 6. Neonatal LC neurons were equally sensitive to noxious and nonnoxious somatosensory stimuli. As development proceeded, LC neurons became less sensitive to innocuous somatosensory stimuli such as air puffs and tactile stimuli while simultaneously becoming more sensitive to noxious stimuli. Auditory and visual stimuli became effective for the first time at PD 14 and PD 12, respectively. 7. These results indicate that the electrical activity of LC neurons in the developing brain is intimately related to input from peripheral sensory sources. Therefore, the influence of the LC on the developing brain may occur predominantly through sensory input.