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PubMed1992

Ethanol attenuates the response of locus coeruleus neurons to excitatory amino acid agonists in vivo.

Recent in vitro electrophysiological studies have revealed that ethanol specifically reduces N-methyl-D-aspartate (NMDA)-activated ion currents, e.g. in hippocampal slices. In the present study, utilizing extracellular recording techniques, the effect of ethanol on excitatory amino acid induced excitability of rat locus coeruleus noradrenergic neurons was investigated in vivo. Administration of ethanol (2 g/kg, i.p.) significantly inhibited the excitation of the locus coeruleus neurons as produced by microiontophoretic application of glutamate, NMDA or quisqualate, but not that of kainate. In contrast, the locus coeruleus response to similarly applied acetylcholine was unaffected by the ethanol treatment. Although ethanol did not alter the basal firing rate of locus coeruleus neurons, the drug significantly changed the firing pattern of the neurons into a more regularized rhythm. It is proposed that the presently observed attenuation of glutamate excitation of locus coeruleus by ethanol may constitute part of the underlaying mechanism for ethanol intoxication in man.

Acetylcholine↗
PubMed2006

Systemic effect of cannabinoids on the spontaneous firing rate of locus coeruleus neurons in rats.

Previous reports have described modulation of noradrenergic activity by cannabinoid receptors. The aim of the present research was to examine the effect of two synthetic cannabinoid CB1/CB2 receptor agonists, R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)-methyl]pyrrolol-[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone (WIN 55212-2) and (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55940), on the spontaneous activity of locus coeruleus noradrenergic neurons by single-unit extracellular recordings in vivo and in vitro. In anaesthetized rats, intravenous administrations of WIN 55212-2 (31.3-500 microg/kg) or CP 55940 (31.3-500 microg/kg) increased the firing rate of locus coeruleus neurons in a dose-dependent manner. The stimulatory effect of WIN 55212-2 was blocked by pretreatment with the cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR 141716A; 2 mg/kg). Paradoxically, local administration of WIN 55212-2 (8.3-31.3 pmol) into the locus coeruleus and intracerebroventricular injections of WIN 55212-2 (10-20 microg) or CP 55940 (20-40 microg) failed to change the spontaneous firing rate of locus coeruleus neurons. Likewise, in rat brain slice preparations perfusion with WIN 55212-2 (10 microM) or CP 55940 (10-30 microM) did not specifically affect the spontaneous firing rate of locus coeruleus cells. Therefore, we conclude that synthetic cannabinoids increase the spontaneous firing activity of noradrenergic neurons in the rat locus coeruleus through cannabinoid CB1 receptors. This stimulation appears to be indirectly induced via a receptor mechanism probably located at the peripheral level.

Action Potentials↗
PubMed1984

Ultrastructural and histochemical evidence for differentiation of intraocular locus coeruleus grafts and invasion of the host iris by central neurites and glia.

Intraocular grafts of dorso-lateral pons, including the noradrenaline-containing cell group locus coeruleus, have been studied with ultrastructural and histochemical techniques. Also, the invasion of neuronal and glial constituents from the grafts into the iris of the host animal is described. In mature brain grafts, aggregates of locus coeruleus neurons were easily discernible with monoamine histofluorescence. These cells had an ultrastructural appearance very similar to that in situ. Numerous somatic spines were frequently associated with synaptic specializations, and monoamine-containing vesicles could be found scattered in the cytoplasm of the locus coeruleus cells. Large neurons of the nucleus tractus mesencephalici nervi trigemini were also found. These cells were neurofilament-immunoreactive just as in situ, and were ultrastructurally characterized by size, distribution of the granular endoplasmic reticulum and abundant large terminals in synaptic contact with their somata and processes. All grafts showed a vigorous astroglial proliferation, evidenced both with immunohistochemistry of glial fibrillary acidic protein and electron microscopy. The astroglial cells were more numerous, larger and with more processes than in adult in situ counterparts. At the attachment site of the brain stem grafts, the iris dilator plate was entirely changed ultrastructurally by a vigorous invasion of neuronal and astrocytic processes. The normal, loose connective tissue stroma of the iris was replaced by layers of almost exclusively central nerve fibres and astrocytes respectively. Monoamine histofluorescence demonstrated an extreme adrenergic hyperinnervation of the iris at the attachment site of the graft, compared to the normal sympathetic ground plexus, whereas neurofilament immunohistochemistry did not visualize any substantial ingrowth of such positive central nerve fibres. Immunohistochemistry of glial fibrillary acidic protein strongly supported the ultrastructural evaluation, showing profound astroglial invasion deep into the iris stroma. Electron microscopic identification of central nerve fibres in the iris showed numerous adrenergic locus coeruleus fibres with small dense-core vesicles. Also, bundles of thin, central, unmyelinated axons were found deep in the iris as well as occasional dendrites. Both large dense-cored and small clear vesicles were encountered in the iris fibres of brain graft origin. Axo-dendritic synaptic specializations formed by locus coeruleus-derived adrenergic fibres were found in the iris.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

The effects of benzodiazepine and non-benzodiazepine anxiolytics on locus coeruleus unit activity.

Two theories have been put forth concerning the anxiolytic actions of the anti-anxiety drugs. One theory maintains that these drugs decrease locus coeruleus output, and the other maintains that they facilitate gamma-aminobutyric acid (GABA) neurotransmission at benzodiazepine (BZ)-linked GABA receptors. The BZ-anxiolytic diazepam does decrease locus coeruleus neuronal impulse flow. However, this decrease is not due to effects on BZ-linked GABA receptors in the locus coeruleus. Furthermore, the non-BZ anxiolytic buspirone, its metabolite and its analog all slightly increase locus coeruleus neuronal impulse flow. This increase, in the case of the metabolite, appears to be due, in part, to blockade of alpha 2-adrenoceptors. Finally, buspirone, unlike diazepam, did not potentiate GABA inhibition at BZ-linked GABA receptor sites (i.e. cerebellar Purkinje cells). These data suggest that the non-BZ anxiolytic buspirone produces its anti-anxiety effects by unconventional mechanisms.

Action Potentials↗
PubMed1986

Electrophysiological effects of the enantiomers of 3-PPP on neurons in the locus coeruleus of the rat.

Extracellular single unit and microiontophoretic studies were carried out in rats, anesthetized with chloral hydrate, to investigate the actions of the enantiomers of the dopamine (DA) agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) on the firing rate of noradrenaline-containing neurons in the locus coeruleus (LC). Intravenously-administered (+)-3-PPP dose-dependently reduced firing of cells in the locus coeruleus with a 50% inhibition occurring after 2 mg/kg. This action was partially antagonized by the alpha 2-noradrenaline (NA) antagonist, yohimbine, but not by the DA antagonist haloperidol or the alpha 1-antagonist prazosin. Pretreatment with reserpine completely blocked the suppressant effect of (+)-3-PPP on firing rate. Iontophoretically-applied (+)-3-PPP did not influence the basal firing rate of cells in the locus coeruleus and failed to influence the inhibitory action of simultaneously-applied DA. Neither intravenously nor iontophoretically administered (-)-3-PPP influenced basal firing rate of neurones in the locus coeruleus. However, intravenously-administered drug weakly reversed the inhibitory action of the alpha 2-agonist clonidine (100 micrograms/kg) and iontophoretic ejection antagonized the inhibitory action of DA. These findings suggest that (-)-3-PPP possesses a weak antagonist action at alpha 2-adrenoceptors present in the locus coeruleus. In contrast, administration of (+)-3-PPP resulted in a weak activation of these receptors which was possibly the result of an enhanced release of NA.

Animals↗
PubMed1999

Activation of rat locus coeruleus neuron GABA(A) receptors by propofol and its potentiation by pentobarbital or alphaxalone.

The action of propofol on the rat locus coeruleus was examined using intracellular recording from in vitro brain slice preparations. Concentrations of propofol between 3 and 300 microM were tested. At 100 microM, propofol completely inhibited the firing of all neurons tested (n=34); this was associated with a 5.7-mV hyperpolarization (range 0-16 mV, n=33) and a 35.6% reduction in input resistance (range 7.3-66.1%, n=33). The propofol-induced responses were not affected by 2-hydroxysaclofen (50 microM) or BaCl(2) (300 microM), but were completely blocked by bicuculline methiodide (100 microM) or picrotoxin (100 microM), indicating that propofol acts on GABA(A) receptors. As assessed by inhibition of the spontaneous firing rate, propofol was 5.6-fold more potent than GABA (gamma-aminobutyric acid). Potentiation of the propofol effect by other general anesthetics or other drugs was also investigated. When pentobarbital (100 microM) was tested alone on locus coeruleus cells, no change in membrane potential or input resistance was seen and there was only a 20.3+/-7.2% (n=8) inhibition of firing rate; however, in combination with 30 microM propofol, it caused a 6.1-fold greater increase in membrane hyperpolarization and a 9.7-fold greater reduction in input resistance than 30 microM propofol alone. A relatively low concentration of alphaxalone (10 microM), when tested alone, had little effect on the membrane potential or input resistance and only produced a 46.0+/-8.9% (n=8) inhibition of firing rate; however, in combination with 30 microM propofol, it caused a 9.3-fold greater hyperpolarization and an 8.6-fold greater reduction in input resistance compared with 30 microM propofol alone. In contrast, diazepam caused no potentiation of either propofol- or GABA-induced responses. Our data also indicate that locus coeruleus neuron GABA(A) receptors possess distinctive pharmacologic characteristics, such as blocking of the propofol effects by zinc and insensitivity to diazepam and the direct action of pentobarbital. On the basis of these pharmacologic properties, we suggest that locus coeruleus neuron GABA(A) receptors do not contain the gamma subunit.

Anesthetics↗
PubMed1995

Image analyser-assisted morphometry of the locus coeruleus in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

Several observations suggest that neuronal shrinkage rather than cell death is the major phenomenon in neurodegenerative diseases. In order to make this distinction, smaller cells should also be included in cell counts. Also, morphometric determination of total cell numbers of brain structures is required. Morphometry was performed on the locus coeruleus using a newly developed method to delineate this nucleus from five patients who had died with Alzheimer's disease, five with Parkinson's disease, five with amyotrophic lateral sclerosis and from five control subjects who had died from causes that would not have affected the locus coeruleus. The length and volume of the locus coeruleus and its total number of large pigmented neurons, small unpigmented neurons and glial cells were determined. Since reliable delineation of the boundaries of the locus coeruleus is a requirement for the determination of total cell numbers, an image analyser-assisted procedure was developed. In Alzheimer's disease we found an 82% decrease in the number of large pigmented neurons and a 39% decrease of small unpigmented neurons. In Parkinson's disease, we found a 39% decrease of large pigmented neurons but also a 44% (though not significant) increase of small unpigmented neurons, which is indicative of a shift from large pigmented neurons to small unpigmented neurons in Parkinson's disease. The large pigmented/small unpigmented neuron number ratio was greatly and significantly reduced in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. These findings support the hypothesis that the decrease of large pigmented neurons of the locus coeruleus in some neurodegenerative diseases is not entirely due to cell death, but rather to cell shrinkage and a loss of phenotype. This hypothesis may have consequences for the development of therapeutic strategies since atrophied cells can be activated. On the other hand our data confirm that, at least in Alzheimer's disease, large pigmented neurons do also undergo cell death.

Aged↗
PubMed1977

Ascending projections of the locus coeruleus in the rat. I. Axonal transport in central noradrenaline neurons.

Axonal transport of protein and metabolites of L-[3H(G)]3, 4-dihydroxyphenylalanine ([3H]DOPA) was studied in the central noradrenaline neurons of the pontine nucleus locus coeruleus and was correlated with regional alterations of noradrenaline content following destruction of the nucleus. Unilateral lesions of the locus coeruleus produce a partial depletion of noradrenaline in the ipsilateral hypothalamus and telencephalon, indicating that these neurons project widely to the ipsilateral forebrain. Twenty-four to 48 h following local injections of 50 micronCi [3H]proline, locus coeruleus neurons take up labeled material and transport it, presumably as protein, to ipsilateral structures in the midbrain, diencephalon and telencephalon including the neocortex. Similarly 8 h after injection of 25 micronCi [3H]DOPA into the locus coeruleus, transport of material including catecholamines occurs to ipsilateral diencephalon and telencephalon. Axonal transport of proteins to telencephalic structures is greatly diminished by selective lesions of catecholamine terminals with 6-hydroxydopamine (6-OHDA) and following destruction of the medial forebrain bundle. These results provide further support for the view that noradrenaline neurons of the locus coeruleus nucleus project widely within the neuraxis to ipsilateral structures of the brain stem, diencephalon and telencephalon, including all cortical areas. In addition, evidence is presented for a contralateral projection with a similar distribution. The rate of axonal transport of labeled protein and metabolites of [3H]DOPA including [3H]catecholamines in central noradrenaline neurons is estimated to be 3-4 mm/h and is accordingly similar to that reported for noradrenaline neurons of the peripheral sympathetic nervous system.

Adrenergic Fibers↗
PubMed1987

Locus coeruleus stimulation modulates olfactory bulb evoked potentials.

Field-evoked potentials from the main olfactory bulb in response to stimulation of the olfactory nerve and lateral olfactory tract were measured without and with conditioning stimulation of the locus coeruleus noradrenergic system. The locus coeruleus conditioning stimulus suppressed or inhibited the late components of the olfactory bulb potential evoked by orthodromic olfactory nerve stimulation; this inhibitory effect was suppressed by the microinjection of the alpha-adrenergic blocker prazosin into the olfactory bulb. Results indicate that noradrenergic fibers projecting from the locus coeruleus exert modulatory influences on neuronal networks underlying orthodromic evoked responses in the main olfactory bulb.

Adrenergic Fibers↗
PubMed2004

Effects of sustained gamma-hydroxybutyrate treatments on spontaneous and evoked firing activity of locus coeruleus norepinephrine neurons.

BACKGROUND: Gamma-hydroxybutyrate is currently used to promote nighttime sleep in the treatment of narcolepsy; however, it is also a drug of abuse ("Liquid Ecstasy") associated with a withdrawal syndrome with anxiety features. Of interest, the activity of locus coeruleus neurons is a reflective index of these above mentioned behavioral states. METHODS: Using in vivo extracellular unitary recordings, sustained administration of gamma-hydroxybutyrate (40 mg/kg/day via minipump implanted subcutaneously) on the spontaneous and sensory-evoked burst firing of locus coeruleus norepinephrine neurons was assessed in rats. RESULTS: A 2-day and 10-day gamma-hydroxybutyrate administration decreased the spontaneous firing activity of locus coeruleus neurons by 52% and 54%, respectively, when compared with controls. A similar degree of attenuation on evoked burst firing of norepinephrine neurons also occurred in these rats (2-day gamma-hydroxybutyrate: 47% and 10-day gamma-hydroxybutyrate: 58%), when compared with controls. In contrast, rats treated with gamma-hydroxybutyrate for 10 days followed by removal of the minipump for 36 hours resulted in a 33% augmentation in spontaneous locus coeruleus activity as compared with controls. Furthermore, a robust 79% increase in burst firing in response to paw-pinch was exhibited in theses rats. CONCLUSIONS: Chronic gamma-hydroxybutyrate treatment inhibits the spontaneous and sensory-evoked burst firing of locus coeruleus norepinephrine neurons, whereas these indices are enhanced during drug withdrawal. The alteration in norepinephrine activity during chronic gamma-hydroxybutyrate administration may contribute to the ability of this agent to induce sleep and regulate narcoleptic episodes. Enhanced norepinephrine activity during withdrawal may be related to symptoms of anxiety on rapid termination of this drug in abusers.

Anesthetics, Intravenous↗
PubMed1990

Modulation of neuronal activity of locus coeruleus in rats induced by excitatory amino acids.

The excitatory actions on the unit activities of locus coeruleus induced by excitatory amino acids were studied. Quinolinic acid 10 nmol and N-methyl-D-aspartate (NMDA) 4 nmol icv markedly increased unit discharge of locus coeruleus neurons. The excitatory action was fully antagonized by icv 4 nmol D,L-2-amino-7-phosphonoheptanoic acid, a specific NMDA receptor antagonist. Excitatory effect induced by quinolinic acid is possibly mediated by excitatory amino acid receptors in locus coeruleus.

2-Amino-5-phosphonovalerate↗
PubMed1994

The human locus coeruleus and anxiogenesis.

Electrical stimulation of locus coeruleus (LC), via permanently implanted electrodes with confirmed localization and effectiveness, did not elicit any subjective or behavioral manifestations of anxiety. This is evidence against the hypothesis that LC is a mediator of anxiogenesis in man.

Adult↗
PubMed1986

Reversal of behavioral depression by infusion of an alpha-2 adrenergic agonist into the locus coeruleus.

This experiment demonstrated that behavioral depression produced by exposure of rats to strong uncontrollable shocks could be reversed by infusion of the alpha-2 adrenergic agonist clonidine into the region of the locus coeruleus (LC). A 20-min infusion, through bilateral cannulae, into the locus coeruleus of clonidine, piperoxane (alpha-2 antagonist) or inactive vehicle (0.85% saline), was given beginning 70 min after the animals were removed from the stress situation. The dose and volume of drug given in the infusion (0.16 microgram/microliter, 0.1 microliter/min) had been previously shown to produce effects specific to the locus coeruleus (Weiss, Simson, Hoffman, Ambrose, Cooper and Webster, 1986; Neuropharmacology 25: 367-384). At the conclusion of the infusion, active behavior of animals was measured in a 15-min swim test. Results showed that stressed animals infused with vehicle exhibited significantly less active behavior in the swim test than did non-stressed animals infused with vehicle, thereby showing the usual behavioral depression seen after exposure to an uncontrollable stress. Stressed animals infused with clonidine showed no difference in active behavior in comparison to non-stressed animals infused with vehicle and showed significantly more activity than did the stressed animals infused with vehicle. Stressed animals infused with piperoxane showed no significant difference in activity in comparison to the stressed animals infused with vehicle and were significantly less active than either the non-stressed animals infused with vehicle or the stressed animals infused with clonidine. Thus, infusion into the locus coeruleus of the alpha-2 agonist clonidine, but not the alpha-2 antagonist piperoxane, eliminated behavioral depression.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Distribution of locus coeruleus axons in the rat spinal cord: a combined anterograde transport and immunohistochemical study.

The distribution of locus coeruleus axons in the rat spinal cord was studied by anterograde transport of Phaseolus vulgaris leucoagglutinin in combination with dopamine-beta-hydroxylase immunohistochemistry. Locus coeruleus axons were observed primarily in the superficial laminae of the dorsal horn. Few locus coeruleus fibers were seen in the vicinity of motoneuron pools or in the intermediolateral cell column of the thoracic spinal cord. The results of this study suggest a selective action of the coeruleo-spinal projection upon sensory inputs to the spinal cord.

Animals↗
PubMed2004

Baseline spike activity of neurons in the locus coeruleus of the rat after lesions to a number of medulla oblongata nuclei.

Bilateral lesioning of the presublingual nucleus (nucleus praepositus hypoglossi) of the medulla oblongata induced significant changes in the nature of baseline spine activity in the locus coeruleus. After lesioning, the mean frequency of spike activity of locus coeruleus neurons decreased more than two-fold. The numbers of neurons with train-grouped activity and polymodal neurons increased significantly. Exclusion of the solitary tract nucleus led to an increase in the number of neurons with regular activity and some decrease in the mean discharge frequency in locus coeruleus neurons. These data support the suggestion that the presublingual nucleus plays a significant role in the transmission of afferent influences on the activity of locus coeruleus neurons.

Animals↗
PubMed1997

Local opiate withdrawal in locus coeruleus in vivo.

Hyperactivity of noradrenergic locus coeruleus (LC) neurons following withdrawal from chronic opiates has been implicated in the opiate withdrawal syndrome. Here, we report that local withdrawal induced in vivo by microinfusion of an opiate antagonist into the LC of morphine-dependent rats marginally, but significantly, activated LC neurons above the level obtained with local naloxone microinfusion in naive rats. This local withdrawal response contributes a significant fraction (approximately 19%) of the total LC hyperactivity induced by systemic naloxone.

Animals↗
PubMed1989

Organotypic Co-Cultures of Rat Locus Coeruleus and Hippocampus.

Slices from the brainstem at the level of the locus coeruleus and from the hippocampus of 5 - 7 day old rats were co-cultured using the roller tube technique. After 2 - 6 weeks in vitro the co-cultures were examined with antibodies raised against tyrosine-hydroxylase (TH). The cultures derived from the brainstem consistently contained a bilateral cluster of TH-positive neurons with 3 - 5 long slender dendrites. These neurons typically gave rise to several fine varicose fibres reminiscent of catecholaminergic axons. A morphologically distinct group of TH-positive neurons was detected in the hippocampal slices. The vast majority of them were located in the subicular region and a smaller number in the CA1/CA3 region of the hippocampal explant. TH-positive neurons were also present in mono-cultures of hippocampus or brainstem. In the vast majority of co-cultures, a variable number of TH-immunoreactive fibres of neurons derived from the locus coeruleus grew over considerable distances to terminate finally within the co-cultured hippocampus where they branched to form a diffuse innervation plexus with club-like endings. Even after several weeks in vitro, TH-positive fibres could still be seen exploring sites which were not related to their target, including the cell-free areas surrounding the cultures. Fibres in these outgrowth areas formed whirl-like endings. TH-positive fibres arising from neurons located in the hippocampus, on the other hand, did not branch extensively and never projected over long distances. Nerve growth factor had no apparent trophic effect on TH-positive cells in the hippocampus, the locus coeruleus, or in the co-cultures.

Journal Article↗
PubMed1985

DMI, Wy-45,030, Wy-45,881 and ciramadol inhibit locus coeruleus neuronal activity.

Wy-45,030 and Wy-45,881 block the uptake of norepinephrine and serotonin in rat brain synaptosomal preparations and share several in vivo and in vitro effects with known tricyclic antidepressants. To further characterize their activity, these compounds were compared to desipramine and ciramadol in electrophysiological studies of their acute effects on noradrenergic neuronal activity. All four compounds inhibited locus coeruleus neuronal activity with a rank order of potency of desipramine greater than Wy-45,881 greater than Wy-45,030 greater than ciramadol. Administration of the alpha-adrenergic blocking drug, piperoxane, increased locus coeruleus firing rate after desipramine, Wy-45,030 and Wy-45-881. Pretreatment with naloxone prevented the reduction in locus coeruleus impulse flow observed after ciramadol administration but had no effect on the inhibition produced by Wy-45,030. Wy-45,030 and Wy-45,881, like classical antidepressants, appear to inhibit locus coeruleus neuronal firing by potentiating neuroinhibitory transmission of locus coeruleus neurons by blocking the uptake of norepinephrine into presynaptic terminals.

Animals↗