Spontaneous unit activity of locus coeruleus neurons after destruction of some nuclei of the medulla oblongata

Bilateral lesions of the nuclei prepositus hypoglossi produced a more than twofold decrease in the mean frequency discharges in the neurons of the nucleus coeruleus. The number of neurons with burst activity and the number of polymodal neurons substantially increased. Lesion of the nucleus tractus solitarius resulted in an increase in the number of neurons with regular activity and certain decrease in the mean discharge frequency of coeruleus neurons. The results confirm the suggestion about a substantial role of the nucleus prepositus hypoglossi in relaying afferent effects to the activity of locus coeruleus neurons.     

Inhibition of locus coeruleus neuronal activity by beta-phenylethylamine

The effect of beta-phenylethylamine (PEA) on brain noradrenaline (NA) neurons in the rat locus coeruleus (LC) was analyzed using single unit recording techniques including microiontophoretic methodology. Systemic injection of low doses of PEA consistently produced an instantaneous and dose-dependent inhibition of firing rate of the LC neurons. The effect was strongly antagonized by administration of the alpha 2-receptor antagonist yohimbine (1 mg/kg, i.v.) or by depletion of endogenous stores of NA by pretreatment with reserpine (10 mg/kg, i.p., 6 h), but unaffected by inhibition of tyrosine hydroxylase (alpha-met-hyl-p-tyrosine (alpha-MT), 250 mg/kg, i.p., 30 min). In contrast, the inhibitory effect of PEA on the LC neurons was strongly potentiated by pretreatment with the selective monoamine oxidase (MAO) - B inhibitor pargyline (2 mg/kg, i.p., 1 h), but, unexpectedly, also by pretreatment with the MAO-A selective inhibitors clorgyline (2 mg/kg, i.p., 1 h) or FLA 336 (2 mg/kg, i.p., 1 h). When microiontophoretically applied directly onto the LC neurons, PEA produced inhibition of a majority of the NA neurons. This action was prevented by intravenous injection of yohimbine (2.5 mg/kg). The results suggests that the action of PEA on NA neurons in the LC is an indirect effect, requiring availability of a reserpine-sensitive storage pool of NA, and mediated via activation of central alpha 2-receptors within the LC.     

Generators of synchronous activity of the locus coeruleus during development

The locus coeruleus is thought to play an important role in the development of the central nervous system through a coordinated release of noradrenaline. The influence of the locus coeruleus on its diverse targets is strongly synchronized by the existence of electrical and chemical coupling between neurones, afferent supply of the nucleus from restricted sources and diffuse innervation of target areas. Extensive coupling between neonatal locus coeruleus neurones produces rhythmic synchronized electrical activity and distributes afferent synaptic activity throughout the entire nucleus. The strength of electrical coupling declines with age but appears to persist to a limited extent in the adult.     

Effect of substances potentiating or inhibiting unit activity in the locus coeruleus on some types of spinal inhibition in cats

Microinjections of aspartic acid and chlorpromazine into the region of the locus coeruleus, which strengthen spontaneous unit activity in that structure, in decerebellate cats anesthetized with chloralose, led to depression of the inhibitory influence of flexor reflex afferents on extensor discharges, but did not change the facilitatory action of these afferents on flexor monosynaptic discharges and had no effect on recurrent inhibition of extensor discharges or reduced it. Microinjection of noradrenalin into this region, which depresses spontaneous unit activity in the locus coeruleus, or of procaine, which blocks action potential generation in neurons, led to potentiation of the inhibitory action of flexor reflex afferents on extensor discharges and to strengthening of recurrent inhibition, but did not affect the facilitatory action of these afferents on flexor discharges. The role of tonic descending influences of the locus coeruleus in the control of spinal inhibition evoked by flexor reflex afferents is discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 13, No. 3, pp. 247–256, May–June, 1981.     

Dual effect of the locus coeruleus on neuronal activity in the visual cortex

The effects exerted by electrical stimulation of the locus coeruleus (LC) on neuronal activity in the visual cortex have been studied in acute experiments on rabbits. The pattern of cortical afterprocesses affecting poststimulus histograms of neuronal activity has been found not always to correspond to the direction of change in the neuronal excitation level in the period of LC stimulation. An analysis of crossed interval histograms for a pair of neurons located in the same microvolume of the cortex has revealed the existence of two independent postsynaptic effects of LC stimulation: a fast (synaptic) effect and a slow (modulatory) effect. The findings are discussed with allowance for morphological features of the synaptic connections and interneuronal transmission in the noradrenergic system of the brain.Neirofiziologiya/Neurophysiology, Vol. 25, No. 4, pp. 243–246, July–August, 1993.     

In vivo catechol activity in the rat locus coeruleus following different nociceptive stimuli and naloxone.

The nucleus locus coeruleus (LC) has been implicated in the processing of spinal reflexes following noxious stimuli. It has been demonstrated that noxious stimuli activate LC neuronal firing, but little is known about the neurochemical changes that might occur following such activation. To determine the effects of different noxious stimuli on LC neuronal activity, anaesthetized rats were exposed to mechanical (tail pinch), thermal (55 degrees C water), and chemical (5% Formalin injected in the hind paw) stimuli; the catechol oxidation current (CA.OC), an index of noradrenergic neuronal activity, in the locus coeruleus was monitored using differential normal pulse voltammetry. In addition, the effect of the opioid antagonist naloxone on the CA.OC in the LC was examined. Exposure to both mechanical and chemical stimuli significantly increased CA.OC indicating an increase in LC noradrenergic neuronal activity, while the thermal stimulus had no effect. Treatment with naloxone (1 mg/kg i.v.) had no effect on CA.OC in the LC. The results show a differential responsiveness of LC noradrenergic neurons to different modes of noxious stimuli and fail to demonstrate a tonic opioid regulation of these neurons in the anaesthetized rat.     

Low nNOS protein in the locus coeruleus in major depression

Disruptions of glutamatergic and noradrenergic signaling have been postulated to occur in depressive disorders. Glutamate provides excitatory input to the noradrenergic locus coeruleus (LC). In this study, the location of immunoreactivity against neuronal nitric oxide synthase (nNOS), an intracellular mediator of glutamate receptor activation, was examined in the normal human LC, and potential changes in nNOS immunoreactivity that might occur in major depression were evaluated. Tissue containing LC, and a non-limbic, LC projection area (cerebellum) was obtained from 11 to 12 matched pairs of subjects with major depression and control subjects lacking major psychiatric diagnoses. In the LC region, nNOS immunoreactivity was found in large neuromelanin-containing neurons, small neurons lacking neuromelanin, and glial cells. Levels of nNOS immunoreactivity were significantly lower in the LC (- 44%, p < 0.05), but not in the cerebellum, when comparing depressed with control subjects. nNOS levels were positively correlated with brain pH values in depressed, but not control, subjects in both brain regions. Low levels of nNOS in the LC may reflect altered excitatory input to this nucleus in major depression. However, pH appears to effect preservation of nNOS immunoreactivity in subjects with depression. This factor may contribute, in part, to low levels of nNOS in depression.     

Effects of applying electrical stimulation to the locus coeruleus on neuronal activity in the parietal association cortex

It was shown during experiments on cats undergoing surgery under ketamine-induced anesthesia and immobilized with myorelaxin that applying trains of stimuli to the locus coeruleus (LC) produces an effect on 79% of parietal cortex neurons. This manifests as inhibition lasting 300–700 msec or a 16–32% decline in the activity rate of neurons with background activity. Hyperpolarization of 5–7 mV lasting 120–500 msec preceded by a latency of 30–90 msec was noted in such neurons as well as "silent" cells during intracellular recording. Duration of the inhibitory pause in neuronal background activity induced by transcallosal stimulation (TCS) increased by 50–200 msec under the effects of conditioned stimuli applied to the LC. Duration of the IPSP triggered by TCS likewise increased (by 50–100 msec) under the effects of LC stimulation. It was concluded that the effects of stimulating the LC on neuronal activity in the parietal cortex may manifest either directly, as inhibition of background activity and hyperpolarization, or else as modulation of influences exerted by other neurotransmitters.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 22, No. 4, pp. 486–494, July–August, 1990.     

Methyl parathion increases neuronal activities in the rat locus coeruleus

Exposure to organophosphate insecticides induces undesirable behavioral changes in humans, including anxiety and irritability, depression, cognitive disturbances and sleep disorders. Little information currently exists concerning the neural mechanisms underlying such behavioral changes. The brain stem locus coeruleus (LC) could be a mediator of organophosphate insecticide-induced behavioral toxicities since it contains high levels of acetylcholinesterase and is involved in the regulation of the sleep-wake cycle, attention, arousal, memory, and pathological processes, including anxiety and depression. In the present study, using a multi-wire recording technique, we examined the effects of methyl parathion, a commonly used organophosphate insecticide, on the firing patterns of LC neurons in rats. Systemic administration of a single dose of methyl parathion (1 mg/kg, i.v.) increased the spontaneous firing rates of LC neurons by 240% but did not change the temporal relationships among the activities of multiple LC neurons. This dose of methyl parathion induced a 50% decrease in blood acetylcholinesterase activity and a 48% decrease in LC acetylcholinesterase activity. The methyl parathion-induced excitation of LC neurons was reversed by administration of atropine sulfate, a muscarinic receptor antagonist, indicating an involvement of muscarinic receptors. The methyl parathion-induced increase in LC neuronal activity returned to normal within 30 min while the blood acetylcholinesterase activity remained inhibited for over 1 h. These data indicate that methyl parathion treatment can elicit excitation of LC neurons. Such excitation could contribute to the neuronal basis of organophosphate insecticide-induced behavioral changes in human.     

Functional recuperation of the serotoninergic innervation in the rat locus coeruleus

1. 5,6-dihydroxytryptamine (5,6-DHT) or a lesion of the raphe centralis superior (RCS) cause significant decreases in the serotonin (5-HT) content and significant increases in the tyrosine hydroxylase activity in the locus coeruleus (LC) of the rat. This suggests that noradrenaline (NA) synthesis is controlled by serotonin-containing neurons in the raphe system via their terminals in the LC. 2. Radioautography after intraventricular infusion of tritiated serotonin (3H-5-HT) and biochemical determinations of endogenous 5-HT content showed an almost complete disappearance of serotoninergic axonal varicosities and content in the LC region 10-15 days after intraventricular administration of 75 micrograms of 5,6-DHT. Two to 4 months after neurotoxin administration, 5-HT fibers had regrown in the LC but, contrary to the normal innervation pattern, the majority of them invaded the medial most portion of the nucleus and the adjacent subependymal region. The LC region regained almost all of its endogenous 5-HT content in the same time period. 3. Functional recuperation of these 5-HT fibers was demonstrated by the fact that the RCS had, after regeneration, the same functional control on NA synthesis as in the normal animal.     

Afferent pathway from locus coeruleus to the nucleus solitarius

After the destruction of the nucleus tractas solitarii, just caudally to the writing pen by means of a stereotaxic instrument, the system of afferent fibres to the nucleus in question was investigated by the methods of Nauta and Fink--Heimer. The fibre terminals were revealed near locus coeruleus. Investigation of the locus coeruleus by Golgi method demonstrated that it usually has neurons of reticular type and transitional ones which resemble by their form the neurons specific for sensory formations. It is possible to conclude that locus coeruleus posesses connections of visceral origin which may play a part in the afferent influence of locus coeruleus on the brain cortex.     

Effect of a high-frequency electrical current on the activity of the raphe nuclei and the locus coeruleus

Recovery cycles of primary evoked potentials to light flashes in the visual cortical area of waking rats were studied under conditions of pharmacological and electrical influences on serotonin (5-HT)- and noradren (NA)ergic brain systems. All factors used induced oscillations of the recovery cycles. Periods of oscillations were similar (300-400 ms) during pharmacological suppression of the NA-system and during high-frequency (500 Hz) electrical stimulation or lesion of locus coeruleus. Analogous influences on 5-HT-system were accompanied by oscillations of recovery cycles with a period of 200 ms. Mechanism of inhibitory action of high-frequency electrical stimulation on activity of monoaminergic systems is discussed.     

Topography of catecholamine-containing neurons of the locus coeruleus in the cat

Topography of catecholamine-containing (CA) neurons of the cat locus coeruleus was studied using a combination of the catecholamine histofluorescence method and rapid embedding of the brain tissue into the paraffin wax. The distribution of CA neurons was examined at frontal and sagittal sections of the brain stem. Unlike that shown previously the quantity of CA neurons in the rostral pole of the locus coeruleus was somewhat higher while at the frontal level of P--2.0-P--4.0 the significant number of CA cells of the locus coeruleus was localized more ventromedially.     

Morphine interference with noradrenaline-mediated inhibition from the locus coeruleus.

The effect of morphine on inhibition of relay neurons in the spinal trigeminal nucleus (STN) produced by conditioning stimulation of the locus coeruleus (LC) was studied in cats. Alterations in orthodromic and antidromic spike generations in STN were absent. However, the narcotic did selectively reduce the inhibitory effect of LC conditioning stimulation on STN neurons without affecting that of the sensory ortex. Nalorphine partially antagonized this effect of the narcotic. A reduction in orthodromic spike number of STN neurons induced by intraventricular noradrenaline in reserpinized animals was unaltered by morphine treatment. These data demonstrate that morphine selectively interferes with LC-induced inhibition of STN neurons and in addition may block noradrenaline release from terminals of LC neurons.     

蓝斑对迷走—心血管反射的影响

实验用家兔３６只,采用低频和高频电流刺激颈部迷走神经中枢端,建立迷走－减压和迷走－升压反射,两种频率电刺激均导致肾交感神经传出活动减少。以迷走－血压反射和迷走－交感反射为指标,连续电流刺激蓝斑或ＬＣ微量注射谷氨酸钠均抑制迷走－血压反射和迷走－交感反射。     

Hyperphagia and hyperdipsia after locus coeruleus lesions in the stumptailed monkey.

Bilateral lesions of the nucleus locus coeruleus in 7 female stumptail monkeys were followed by long lasting hyperphagia and hyperdipsia. The percentage increase in weight at five weeks after lesioning correlated highly with 3-methoxy-4-hydroxy-phenethylene glycol (MHPG) concentration in the cerebral cortex. This relationship suggests that the effects are due to the locus coeruleus system and are not the result of variable destruction of the ventral noradrenergic or adjacent non-noradrenergic pathways.