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PubMed1993

Evidence for the involvement of excitatory amino acid pathways in the development of precipitated withdrawal from acute and chronic morphine: an in vivo voltammetric study in the rat locus coeruleus.

Previous studies have demonstrated that activation of excitatory amino acid (EAA) pathways projecting to the locus coeruleus may be involved in the increased firing of locus coeruleus (LC) neurons during opioid withdrawal. Using differential normal pulse voltammetry to monitor catechol oxidation current (CA.OC), an index of neuronal activity in the LC, the role of EAA pathways in naloxone precipitated withdrawal after acute and chronic morphine treatment was examined. Acute morphine treatment (10 micrograms i.c.v.) significantly reduced the CA.OC signal in the LC to 54.3 +/- 3.1% of baseline. Naloxone challenge (1 mg/kg i.v.) completely reversed the morphine effect and produced a significant increase in the CA.OC signal above baseline, peak 145.4 +/- 10.1% of baseline. This naloxone-induced rebound response was attenuated by pretreatment with the EAA receptor antagonists gamma-D-glutamylglycine (DGG) (2, 20, 200 micrograms i.c.v.) and (-)-2-amino-7-phosphonoheptanoic acid (D-APH), but not L-APH (25 micrograms i.c.v.). In chronically morphine-treated rats (25 micrograms/h i.c.v., 5 days), naloxone challenge (1 mg/kg i.v.) produced a significant increase in CA.OC signal, peak 466.5 +/- 112.7% of baseline. This naloxone-induced response was attenuated by pretreatment with DGG (200 micrograms i.c.v.) or D-APH (25 micrograms i.c.v.). To the extent that CA.OC reflects locus coeruleus neuronal activity, the present findings further suggest that increases in locus coeruleus activity during naloxone precipitated withdrawal after both acute and chronic morphine treatment are mediated at least in part by activation of EAA pathways.

2-Amino-5-phosphonovalerate↗
PubMed1984

Intrinsic regulation of locus coeruleus neurons: electrophysiological evidence indicating a predominant role for autoinhibition.

Locus coeruleus neurons were antidromically activated and the resulting post-stimulation inhibition was compared to the interspike interval and examined for its dependency on antidromic invasion and stimulus intensity. The post-stimulation inhibition seen in these cells following antidromic activation approximated the interspike interval, was critically dependent on the antidromic invasion of the cell under study and was only weakly dependent on stimulus intensity. These results suggest that the post-stimulation inhibition following antidromic activation in the locus coeruleus is mediated principally by autoinhibition and not by hypothesized local inhibitory interactions between locus coeruleus neurons.

Animals↗
PubMed1986

Actions of acetylcholine and nicotine on rat locus coeruleus neurons in vitro.

Intracellular recordings were made from neurons of the rat locus coeruleus in a slice of tissue cut from the pons and superfused in vitro at 37 degrees C. Both acetylcholine, in the presence of a muscarinic antagonist, and nicotine depolarized locus coeruleus neurons and increased the rate of action potential discharge. These effects persisted in a superfusing solution that contained no calcium ions and a raised magnesium ion concentration; because such solutions block synaptic potentials in the locus coeruleus, it was concluded that the acetylcholine and nicotine acted directly on the cell from which the recording was made. Acetylcholine-evoked depolarizations were blocked by hexamethonium or dihydro-beta-erythroidine, but not by alpha-bungarotoxin. Recordings of membrane current showed that acetylcholine and nicotine caused a net inward current, the amplitude of which increased linearly as the membrane potential was changed from -40 to -90 mV; the extrapolated reversal potential was about -20 mV (extracellular potassium concentration was 2.5 mmol/l). Depolarizations caused by nicotine declined during the presence of the agonist when the period of superfusion was continued for more than 2 min; repeated applications of nicotine evoked reproducible depolarizations only when the interval between them was at least 1 h. It is concluded that neurons of the rat locus coeruleus have nicotinic receptors with properties similar to those in peripheral ganglia with respect to reversal potential for the ion channel, insensitivity to alpha-bungarotoxin and propensity to desensitize.

Acetylcholine↗
PubMed1985

Characterization of alpha 2-adrenoceptors which increase potassium conductance in rat locus coeruleus neurones.

Intracellular recordings were made from locus coeruleus neurones in a slice of rat pons superfused in vitro. A single-electrode voltage-clamp amplifier was used to measure membrane currents. Superfusion of the slice with clonidine (3-100 nM) or noradrenaline (100 nM-100 microM), or brief application of noradrenaline from a pipette by a pressure pulse, caused dose-dependent membrane hyperpolarizations. Phenylephrine (10 microM) and isoprenaline (10 microM) were ineffective. The hyperpolarizations were accompanied by a decrease in neurone input resistance. The hyperpolarization evoked by pressure ejection of noradrenaline could be reversed by membrane polarization to -110 mV. Clonidine and noradrenaline caused a membrane current which was linearly related to membrane potential between -50 and -120 mV, being outward at resting levels and reversing at -110 mV. The concentration-response curves for clonidine and noradrenaline were shifted rightwards in a parallel manner by alpha 2-adrenoceptor antagonists. The antagonist KeS estimated from the degree of shift were: RX 781094 9 nM, yohimbine 14 nM, phentolamine 20 nM and piperoxane 49 nM. These experiments indicate that in locus coeruleus neurones an increase in potassium conductance results from activation of alpha 2-adrenoceptors similar to those characterized on peripheral neurones.

Animals↗
PubMed1998

Electrophysiological and behavioral effects of Tyr-D-Arg-Phe-Sar on locus coeruleus neurons of the rat.

The effect of Tyr-D-Arg-Phe-Sar (TAPS), a mu-selective tetrapeptide analog of dermorphin, was studied in the rat both in vitro, using slices of the locus coeruleus, and in vivo, after microinjection into the locus coeruleus. In electrophysiological studies, TAPS (1-100 nM) was able to inhibit spontaneous firing, cause hyperpolarization of the membrane potential and reduce the input resistance of neurons of the locus coeruleus, suggesting that there was an effect on the potassium channels. Based on the inhibition of the spontaneous firing rate, the average IC50 for TAPS was calculated to be 1.9 nM, a value lower than that reported for dermorphin or morphine. The TAPS-induced effects were antagonized by naloxone, with a dissociation equilibrium constant of 1.96 +/- 0.14 nM. The results indicate that TAPS binds to mu-opioid receptors on the cell membrane of neurons of the locus coeruleus to cause its inhibitory actions. In behavioral study, TAPS was microinjected bilaterally via chronically implanted cannulae into the locus coeruleus of non-anesthetized rats and its effects on locomotor activity determined. TAPS, at concentrations of 1 microM and 10 microM, but not of 0.1 microM, induced hypolocomotion/sedation and the effect was significantly reversed by naloxone (5 mg/kg i.p.). Taken together, these data suggest that TAPS has an inhibitory effect on neurons of the locus coeruleus and produces hypolocomotive/sedative effects in vivo.

Analgesics↗
PubMed1989

Electrical coupling synchronizes subthreshold activity in locus coeruleus neurons in vitro from neonatal rats.

Locus coeruleus neurons in brain slices prepared from neonatal rats have rhythmic oscillations in membrane potential at frequencies ranging from 0.3 to 3 Hz. Recordings from pairs of neurons separated by 50-300 microns showed that this oscillatory activity was synchronized at ages less than 24 d. Slices cut from rats 24-27 d old showed rhythmic activity which was only partially synchronous between cell pairs, but full synchrony could be restored by superfusion with tetraethylammonium (2 mM) and/or barium (2 mM). No synchronous rhythmic activity was observed between neurons in slices from rats 40 d old, even in the presence of tetraethylammonium and barium. In those cells in which rhythmic potential oscillations were synchronous, action potentials occurring in one cell were not observed in the second cell. Electrotonic coupling was directly demonstrated between 41% of neurons (12 of 29 pairs) in slices from rats less than 10 d old but not in tissue from older rats (4 pairs). The input resistance of neurons from neonatal rats (less than 15 d old) was about half (81 M omega) that measured under identical conditions from neurons from adult rats (213 M omega). The electrotonic potential in cells from rats less than 15 d old was best fit by a double exponential, whereas that from adults was best fit by a single exponential. The results demonstrate that significant electrical coupling occurs among locus coeruleus neurons from neonatal rats; this appears to decline with age. The coupling serves as a low-pass filter and causes the synchronized occurrence of membrane potential oscillations. Such a rhythmic background activity within the entire nucleus may be important for the widespread trophic role of the noradrenergic neurons during development.

Animals↗
PubMed2006

Light and electron microscopic observation of intracytoplasmic inclusion bodies in the locus coeruleus of the hamster.

The authors previously demonstrated that intracytoplasmic inclusion bodies (1-3 microm) in the mouse locus coeruleus under light and electron microscopy are characteristically stained using the Holmes modified method. We reported that one inclusion body existed in almost all neurons of the locus coeruleus. The present study examined whether similar inclusion bodies are present in the Syrian hamster (weight, about 60 g). Paraffin sections stained with the modified Holmes' method dis played numerous small inclusion bodies in the cytoplasm of cells in the locus coeruleus. Epon sections (1 microm thick) stained using toluidine blue were observed under light microscopy, and numerous small inclusion bodies were again observed. Under electron microscopy observation, inclusion bodies (<1 microm in diameter) predominantly comprised small granular materials, similar to those described by previous investigators. Although inclusion bodies were devoid of a limiting membrane, the relation ship to cytoplasmic organelles was unclear. However, free and polyribosomes were occasionally noted in close proximity to inclusion bodies. Inclusion bodies may thus be formed from ribosomes. Intracytoplasmic inclusion bodies in the hamster locus coeruleus differed in appearance compared with inclusion bodies in the mouse locus coeruleus.

Animals↗
PubMed1990

Electrophysiological effects of dermorphin on locus coeruleus neurons of rat.

Intracellular recording was used to study the effects of dermorphin on neurons of the locus coeruleus in the rat, in a totally submerged brain slice preparation. Dermorphin caused the inhibition of spontaneous firing of all neurons of the locus coeruleus tested, with an IC50 of 7 nM. Based on the inhibition of spontaneous firing rate, dermorphin was 16.5 times more potent than morphine. Larger concentrations of dermorphin (30-100 nM) further hyperpolarized the neurons of the locus coeruleus and simultaneously caused a reduction in input resistance. These effects were antagonized by naloxone, with a dissociation equilibrium constant of 0.8 nM. The hyperpolarization of neurons of the locus coeruleus, caused by dermorphin, was reversed at a membrane potential of -112 mV in this preparation. Furthermore, this hyperpolarization was blocked by cesium chloride and barium chloride. Thus, these data suggest that dermorphin binds to mu-opioid receptors on the cell membrane of neurons of the locus coeruleus. This leads to opening of the inward-going rectification potassium channels, resulting in the observed hyperpolarization of the membrane.

Analgesics, Opioid↗
PubMed1992

Pimozide prevents the development of conditioned place preferences induced by rewarding locus coeruleus stimulation.

Electrical stimulation in the vicinity of the cell bodies of the locus coeruleus (LC) has been shown to support self-stimulation behaviors in rats. In the present study, a Conditioned Place Test, sensitive to both rewarding and aversive qualities of brain stimulation, was employed to determine (a) whether rewarding locus coeruleus stimulation would result in place preferences and (b) if so, whether dopamine receptor antagonism would affect the development of such place preferences. Animals were pretreated with pimozide (0.0, 0.5 or 1.0 mg/kg) prior to exposure to two distinctive environments only one of which was paired with locus coeruleus stimulation. Rats that received vehicle injections prior to stimulation/place pairings developed strong preferences for the stimulation-paired environment while those animals pretreated with 0.5 mg/kg pimozide showed no reliable shift in preference from baseline performance. Additionally, animals injected with the 1.0 mg/kg dose of pimozide exhibited mild place aversions to the stimulation-paired environment. It is hypothesized that dopamine neurotransmission is important for the rewarding effects of locus coeruleus stimulation without which such stimulation appears to be aversive.

Animals↗
PubMedDate not supplied

Ethanol suppression of locus coeruleus neurons: relevancy to the fetal alcohol syndrome.

The effect of intraperitoneal injection and microiontophoretic application of ethanol on spontaneous single neuron activity of adult rat locus coeruleus was studied. Systemic administration of ethanol (1-2 g/kg) markedly slowed a majority of locus coeruleus neurons. Direct application of ethanol also substantially suppressed locus coeruleus cell firing in the absence of any detectable membrane effects. Percent inhibition of firing rate ranged from 6% to 100% with ejection currents up to 40NA for 40 sec. These data demonstrate ethanol can directly suppress locus coeruleus unit activity. Since locus coeruleus neurons are present at a relatively early fetal age, maternal consumption of ethanol during gestation could profoundly influence the development and function of fetal central noradrenergic processes.

Animals↗
PubMedDate not supplied

[Effect of an analog of vasopressin on the fixation of temporary connections in the intact rat and after destruction of the locus coeruleus].

Subcutaneous injection to intact rats and rats with destroyed locus coeruleus of 10 mcg of triglycide-glycinamide-lysinevasopressin (TGDGA-LVP) immediately after elaboration of labyrinth defensive conditioned reflex improves consolidation of temporary connections and raises its resistance to extinction. Improved consolidation of temporary connection is retained in animals with destroyed locus coeruleus for a shorter time than in intact animals. At the same time according to some characteristics, TGDGA-LVP has a more expressed influence of positive character on animals with destroyed locus coeruleus than on intact rats.

Adrenergic Fibers↗
PubMed1990

Concomitant depression of locus coeruleus neurons and of flexor reflexes by an alpha 2-adrenergic agonist in rats: a possible mechanism for an alpha 2-mediated muscle relaxation.

The alpha 2-agonist tizanidine, clinically used as an antispastic drug, also strongly reduces polysynaptic flexor reflexes. The hypothesis was tested that the noradrenergic coerulespinal system exerts a tonic facilitation on spinal reflexes and that the depressant effects of tizanidine may be explained by an alpha 2-mediated autoinhibition of the tonic activity of locus coeruleus neurons, resulting in a disfacilitation of the spinal reflexes. The following results support this working hypothesis: (1) systemic injections of tizanidine markedly decreased the spontaneous activity of locus coeruleus neurons, but not of non-locus coeruleus neurons. The alpha 2-antagonist yohimbine reversed this effect. (2) The time course of diminished locus coeruleus activity paralleled that of depressed flexor reflexes. (3) Flexor reflexes were also markedly depressed by the alpha 1-adrenergic antagonist prazosin, administered alone, which is in line with the proposition that the noradrenergic system exerts a tonic facilitation on spinal neurons by way of alpha 1-adrenergic receptor activation. (4) Flexor reflexes were facilitated by conditioning microstimulation of locus coeruleus neurons, and this effect was reversed by prazosin. (5) Flexor reflexes significantly diminished in size following placement of an irreversible lesion in the ipsilateral locus coeruleus. Although these results strongly support the above hypothesis regarding a descending modulatory function of the descending locus coeruleus system on spinal reflexes, possible additional mechanisms, perhaps also involving the ascending projection of the locus coeruleus to supraspinal motor structures, remain to be elucidated.

Adrenergic alpha-Agonists↗
PubMed1988

The role of alpha 1-adrenoceptor-mediated collateral excitation in the regulation of the electrical activity of locus coeruleus neurons.

The physiological role of two types of autoreceptors, alpha 1- and alpha 2-adrenoceptors, located on the somadendritic membranes of locus coeruleus neurons, was studied in the developing and adult rat brain. Animals from birth to adulthood were anesthetized with urethan, and single-unit activity was recorded extracellularly in the locus coeruleus. The spontaneous firing of most locus coeruleus neurons was inhibited by iontophoretic application of noradrenaline at a high concentration, while noradrenaline at a low concentration frequently caused excitation of the neurons, predominantly in the developing brain. A similar excitation was also produced by iontophoretic application of the alpha 1-agonist phenylephrine. These excitations were antagonized by the alpha 1-antagonist, 2-beta [4-hydroxyphenylethylaminomethyl]-tetralone, while this antagonist had little effect on glutamate-induced excitation. The noradrenaline- and phenylephrine-induced excitation occurred more frequently in the neurons having little or no spontaneous activity. Electrical stimulation of the dorsal noradrenergic bundle arising in the locus coeruleus produced both inhibition and excitation. The excitatory responses were manifest primarily in early developmental stages, and occurred predominantly when the neurons had little or no spontaneous activity. When the neurons began firing at relatively high rates, the effects of dorsal noradrenergic bundle stimulation became principally inhibitory. Since the excitation evoked by dorsal noradrenergic bundle of stimulation was blocked by the alpha 1-antagonist, the excitation was thought to result from activation of alpha 1-adrenoceptors by noradrenaline released from the terminals of recurrent axon collaterals of locus coeruleus neurons themselves.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed2005

In vivo measurement of noradrenaline in the locus coeruleus of rats during the formalin test: a microdialysis study.

The locus coeruleus is involved in the regulation of the sense of pain. To demonstrate the changes in noradrenaline level in the locus coeruleus during the formalin test, a microdialysis probe was implanted into the left locus coeruleus of rats. Formalin was subcutaneously injected into the plantar surface of the right hind paw and pain ratings were recorded. The concentrations of noradrenaline and its metabolite 3-methoxy-4-hydroxyphenylethylenglycol (MHPG) were measured. The results showed an almost four-fold elevation in noradrenaline release in the early phase of the formalin test; levels return to baseline in the late phase. Levels of MHPG changed in a similar fashion.

Animals↗
PubMed1991

Host regulation of noradrenaline release from grafts of seizure-suppressant locus coeruleus neurons.

Intrahippocampal implants of noradrenaline-rich neural tissue from the fetal locus coeruleus region suppress development of seizures induced by hippocampal kindling stimulation in hyperexcitable, noradrenaline-depleted rats. In the present study the intracerebral microdialysis technique has been used to monitor seizure-induced release of noradrenaline from such grafts. The steady-state output of noradrenaline in the hippocampus of grafted animals (previously treated with intraventricular 6-hydroxydopamine) was similar to the baseline level in normal rats. A generalized seizure gave rise to a threefold increase of hippocampal noradrenaline levels as compared to baseline (15-min samples) in both normal and grafted animals. The maximal increase of extracellular noradrenaline levels occurred within 2-4 min after the onset of seizure activity and the levels then tapered off, reaching baseline after another 6-8 min. In 6-hydroxydopamine-treated animals without grafts baseline noradrenaline levels were markedly reduced compared to those of normal rats and only minor changes were observed in response to seizures. This supports the theory that the high extracellular noradrenaline concentrations measured in conjunction with seizures originate from the grafts. A knife cut transecting the ascending bundle from the locus coeruleus led to a marked attenuation of the seizure-induced increase of noradrenaline release in normal animals. In the intact brain, and probably also in the grafts, this response thus seems to be dependent on impulse flow in locus coeruleus neurons and only to a minor extent on local regulatory mechanisms in the hippocampus. In conclusion, the present study demonstrates that grafted locus coeruleus neurons are able to restore both basal and seizure-induced extracellular noradrenaline levels in the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Variations in 3,4-dihydroxyphenylacetic acid concentration are correlated to single cell firing changes in the rat locus coeruleus.

The purpose of this study is to see whether variations in the catechol oxidation peak in the locus coeruleus would be closely related with variations in single cell firing, and would be independent of the mechanism triggering the variation of neuronal activity. Single unit and electrochemical (differential pulse voltammetry) recordings were performed, respectively on the left and right locus coeruleus of anaesthetized rats. The variations in single unit activity were induced using well known stimulatory mechanisms (yohimbine, hypovolemia, indirect activation using a 5-hydroxytryptamine central agonist RU 24969, RU 24722 known to activate noradrenergic metabolism), or inhibitory (clonidine, morphine) models. This was done in addition to successive activation or inhibition (reversal of oxotremorine with scopolamine, antagonism of clonidine by piperoxane). In all the experimental conditions, variations in the catechol oxidation current followed variations in single cell activity. Furthermore, the catechol oxidation current variations correlated significantly to changes in the firing rate. Such a close correlation between a catechol oxidation peak, and the electrical activity of the locus coeruleus cell bodies supports the use of catechol oxidation current variations as a good indirect index of functional activity in noradrenergic locus coeruleus perikarya. This suggests a close relationship between dopamine metabolism and electrical activity in locus coeruleus cell bodies.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Differential effects of locus coeruleus lesions upon metabolic activity in CNS nuclei involved in cardiovascular regulation.

The alterations of local cerebral glucose utilization in 5 medullary and 6 supramedullary regions involved in cardiovascular regulation, which result from unilateral electrolytic lesions of the locus coeruleus, have been examined in conscious rats, using the quantitative autoradiographic [14C]2-deoxyglucose technique. Unilateral lesions of the locus coeruleus (72 h prior to study) did not result in any significant alteration in glucose utilization in any of medullary (e.g. nucleus of the tractus solitarius, dorsal motor nucleus of the vagus) or diencephalic (e.g. periventricular and paraventricular hypothalamic nuclei, lateral habenular nucleus) regions which were examined. However, the increased glucose utilization which occurred in some medullary nuclei (e.g. nucleus of the solitary tract, dorsal motor nucleus of the vagus) following administration of the alpha-receptor antagonist, phenoxybenzamine (30 mg/kg, i.v.), was significantly attenuated by lesions of the locus coeruleus, whereas the increased glucose utilization elicited in hypothalamic nuclei by the drug was unaffected by locus coeruleus lesions. In contrast, glucose utilization in the lateral habenular nucleus was elevated significantly following phenoxybenzamine only in animals bearing unilateral locus coeruleus lesion; the drug being without effect in this region in sham-lesioned rats. These differential consequences of locus coeruleus lesions upon glucose utilization in nuclei involved in cardiovascular regulation emphasize the complex nature of the influence of the locus coeruleus upon blood pressure control.

Animals↗
PubMed1988

Characterization of a developmentally transient adrenergic depolarizing response in cultured locus coeruleus neurons.

The effects of iontophoretically applied noradrenaline have been tested on intracellularly recorded locus coeruleus neurons grown in explant cultures from neonatal mice. In addition to hyperpolarizing responses mediated by alpha 2-adrenergic receptors, as observed in locus coeruleus neurons in vivo and in brain slices from adult animals, alpha 1-mediated depolarizations were observed to succeed the initial hyperpolarizations in some cultures. It was shown that the depolarizing responses were only present in younger cultures, i.e., less than 26 days in vitro. In cultures less than 20 days old, all cells displayed the biphasic hyperpolarizing-depolarizing responses. Both components of the response appear to be direct, since they were present when synaptic transmission was blocked by including tetrodotoxin or by altering divalent cations in the perfusate. The depolarizing responses were frequently reduced in solutions with altered divalent cation content, and this might reflect a calcium dependency of this response. The hyperpolarizing and depolarizing components of the responses to noradrenaline were progressively blocked by increasing concentrations of the selective antagonists yohimbine and prazosin, respectively, in the dose ranges of 100 mM - 1 microM (yohimbine) and 20-200 nM (prazosin). Recent results from electrophysiological studies of locus coeruleus neurons in brain slices suggest that similar changes occur in the animal as well as in culture. It is possible that the transient depolarizing responses reflect a developmentally important enhanced responsiveness of locus coeruleus neurons during the early postnatal period.

Adrenergic alpha-Agonists↗