Non-dopaminergic catecholaminergic neurons of mesencephalic and medullary nuclei contain different levels of dopamine

The present study addresses the question whether metabolic dopamine can be immunocytochemically detected within nondopaminergic catecholaminergic axonal fibers. For this purpose, confocal microscopy was used to analyze sections treated for the double fluorescence immunostaining of dopamine and either noradrenaline or phenylethanolamine-N- methyltransferase (the enzyme in adrenergic neurons that converts noradrenaline into adrenaline). Our data demonstrate that throughout the brain and spinal cord, the majority of the axonal fibers that reacted with the anti-phenylethanolamine-N-methyltansferase antibodies also exhibited faint to intense dopamine immunoreactivity. Similarly noradrenaline and dopamine immunoreactivities were frequently colocalized within axonal fibers innervating brain and spinal cord regions that receive a dense innervation from medullary noradrenergic neurons. On the contrary, dopamine was rarely detected within noradrenaline-immunoreactive fibers in those regions where the nomdrenergic innervation essentially arises from noradrenergic neurons of the locus coeruleus. A similar differential dopamine immunostaining was observed in the corresponding neuronal perikarya of the medulla oblongata and the locus coeruleus. These data indicate that two types of non-dopaminergic catecholaminergic neurons can be distinguished according to their content in dopamine: (i) the noradrenergic and adrenergic neurons located in the medulla oblongata, whose cell bodies and axons contain high concentrations of metabolic dopamine and (ii) the noradrenergic neurons located in the mesencephalon, which contain low levels of metabolic dopamine.     

Locus coeruleus neurons projecting to the forebrain and the spinal cord in the cat

The intranuclear organization of the cat locus coeruleus neurons was investigated anatomo-physiologically. The locus coeruleus neurons project to the forebrain through the dorsal noradrenergic bundle and to the spinal cord. Horseradish peroxidase, a retrograde tracer, was pressure-injected into either the dorsal noradrenergic bundle or the ventrolateral funiculus of the high cervical cord (C1-C2). The cats (n = 12) were killed after a 2- or 3-day survival period. The frontal sections (100 micron) throughout the locus coeruleus were observed by light microscope after carrying out the diaminobenzidine reaction. The labeled locus coeruleus neurons were located predominantly in the rostral locus coeruleus proper and locus coeruleus alpha when horseradish peroxidase was injected into the dorsal noradrenergic bundle, whereas they were predominantly located in the caudal locus coeruleus alpha and subcoeruleus when horseradish peroxidase was injected into the spinal cord. In the electrophysiological experiments, cats (n = 30) were anesthetized with alpha-chloralose and two stimulating electrodes were placed stereotaxically in the dorsal noradrenergic bundle and the ipsilateral ventrolateral funiculus of the high cervical cord (C1-C2), respectively. Monophasic square-wave pulses (2.5 Hz, 100 microsecond duration, 800 microA) were delivered. A recording glass electrode, filled with 2 M NaCl saturated with Fast Green, was placed in the locus coeruleus. Neurons with different conduction velocities, which were evoked by the antidromic stimulation of the dorsal noradrenergic bundle and spinal cord, were verified in the locus coeruleus and the adjacent areas. The slow conductive neurons with a conduction velocity of less than 1 m/s had a slow firing rate (1.6 +/- 0.9/s). They were located predominantly in the rostral locus coeruleus proper and locus coeruleus alpha by the dorsal noradrenergic bundle stimulation. From the anatomical and electrophysiological experimental results, it was concluded that the conduction velocities of the horseradish peroxidase-labeled neurons observed in locus coeruleus proper and locus coeruleus alpha were mostly slow and less than 1 m/s. Most of the slow conductive neurons were considered to be noradrenergic. Neurons evoked antidromically by both the dorsal noradrenergic bundle and spinal cord stimulation were not observed.     

Catecholaminergic innervation of guinea pig superior olivary complex

In mammals, olivocochlear neurons in the superior olivary complex project to the cochlea, providing input to outer hair cells and auditory afferents contacting inner hair cells. In the rat it has been demonstrated that olivocochlear neurons receive noradrenergic input, arising from the locus coeruleus and it has been demonstrated in this species using in vitro brain slices that noradrenaline exerts a direct, mostly excitatory effect on an olivocochlear subpopulation. The guinea pig is a more commonly used animal in auditory physiology than the rat and anatomical data on noradrenaline in the auditory brainstem in this species are lacking. Because it has been shown that a compact locus coeruleus is not present in the guinea pig, subtle species differences might be expected. Therefore, using immunohistochemical and tracing techniques we have investigated in the guinea pig (1) the noradrenergic and dopaminergic innervation of the superior olivary complex, (2) the anatomical relationship between noradrenergic fibres and olivocochlear neurons and (3) the origin of the noradrenergic input to this brainstem region. The results show that the guinea pig superior olivary complex receives moderately dense noradrenergic innervation and no dopaminergic innervation. In addition, noradrenergic fibres and varicosities were observed in close contact with both somata and dendrites of olivocochlear neurons, strongly suggestive of synaptic contacts. Finally the results show that a significant component of the noradrenergic innervation of the guinea pig superior olivary complex arises in the locus subcoeruleus, which is a structure likely to be the homologue of the locus coeruleus in rats and other species.     

Projections from the rat cuneiform nucleus to the A7, A6 (locus coeruleus), and A5 pontine noradrenergic cell groups

Stimulation of neurons in the cuneiform nucleus (CnF) produces antinociception and cardiovascular responses that could be mediated, in part, by noradrenergic neurons that innervate the spinal cord dorsal horn. The present study determined the projections of neurons in the CnF to the pontine noradrenergic neurons in the A5, A6 (locus coeruleus), and A7 cell groups that are known to project to the spinal cord. Injections of the anterograde tracer, biotinylated dextran amine in the CnF of Sasco Sprague-Dawley rats labeled axons located near noradrenergic neurons that were visualized by processing tissue sections for tyrosine hydroxylase-immunoreactivity. Anterogradely labeled axons were more dense on the side ipsilateral to the BDA deposit. Both A7 and A5 cell groups received dense projections from neurons in the CnF, whereas locus coeruleus received only a sparse projection. Highly varicose anterogradely labeled axons from the CnF were found in close apposition to dendrites and somata of tyrosine hydroxylase-immunoreactive neurons in pontine tegmentum. Although definitive evidence for direct pathways from CnF neurons to the pontine noradrenergic cell groups requires ultrastructural analysis, the results of the present studies provide presumptive evidence of direct projections from neurons in the CnF to the pontine noradrenergic neurons of the A7, locus coeruleus, and A5 cell groups. These results support the suggestion that the analgesia and cardiovascular responses produced by stimulation of neurons in the CnF may be mediated, in part, by pontine noradrenergic neurons.     

Adrenaline neurons in the rostral ventrolateral medulla innervate thoracic spinal cord: a combined immunocytochemical and retrograde transport demonstration

Adrenaline-containing neurons in the C1 group of the ventrolateral rostral medullary reticular formation which project to the thoracic spinal cord were identified by a combined retrograde transport immunocytochemical technique. No other medullary catecholamine neurons, including the A1 and A2 noradrenaline cells, project to thoracic spinal cord. These data, taken with results of other studies of spinal catecholamine innervation, suggest a segmental segregation of projections to spinal cord by dopaminergic, noradrenergic, and adrenergic neurons.     

Noradrenergic neurons with divergent projections to the motor trigeminal nucleus and the spinal cord: a double retrograde neuronal labeling study

Double retrograde axonal tracing was combined with the indirect immunofluorescence antibody method to determine whether noradrenergic neurons have divergent projections to the motor nucleus of the trigeminal nerve and the spinal cord. Rhodamine-labeled microspheres were injected into the motor trigeminal nucleus and True Blue was deposited into lumbar segments of the spinal cord. After a 10-18-day survival period, brainstem sections were processed for immunofluorescence staining of noradrenergic neurons using antibodies to rat dopamine-beta-hydroxylase. Rhodamine-labeled noradrenergic neurons were observed ipsilaterally throughout the A5 and A7 groups; the contralateral A5 and A7 groups contained few rhodamine-labeled cells. A few rhodamine-labeled noradrenergic neurons were observed in the locus coeruleus and subcoeruleus. True Blue-labeled noradrenergic neurons were identified in the A5 and A7 groups, in the ventral part of the locus coeruleus and in the subcoeruleus. Double retrogradely labeled noradrenergic neurons were observed in the A5 and A7 groups but not in the locus coeruleus and subcoeruleus. Of the total number of rhodamine-labeled noradrenergic cells, a large percentage also contained True Blue: 54% in the caudal A5 group, 59% in the rostral A5 group, and 72% in the A7 group. Of the total number of True Blue-labeled noradrenergic neurons, the percentage of double retrogradely labeled cells was 33% in the caudal A5 group, 46% in the rostral A5 group, and 56% in the A7 group. The findings of this study provide the first anatomic evidence for the existence of a prominent population of noradrenergic cells in the A5 and A7 groups with divergent projections to the motor trigeminal nucleus and the spinal cord. We propose that this subpopulation of noradrenergic neurons in the A5 and A7 groups influences motoneurons at multiple levels of the neuraxis.     

Effects of the noradrenaline neurotoxin DSP4 on the postnatal development of central noradrenaline neurons in the rat

The effect of the noradrenaline neurotoxin DSP4 on the postnatal development of central noradrenergic neurons in the rat has been investigated using neurochemical techniques. The results demonstrated a preferential effect of DSP4 on the locus coeruleus noradrenergic neuron system without any notable effects on the dopamine and adrenaline neurons and only a minor neurotoxic effect on the serotonin neurons. The effect of DSP4 on the serotonin neurons could be completely prevented by pretreatment with the uptake blocker zimelidine, without affecting the action of DSP4 on noradrenergic neurons. Neonatal DSP4 treatment systemically led to permanent depletions of noradrenaline in the cerebral cortex and spinal cord and marked increases of noradrenaline in the cerebellum and ponsmedulla. These effects of DSP4 were dose-dependent and could be blocked by pretreatment with the noradrenaline uptake blocker desipramine. The alterations in endogenous noradrenaline levels were quantitatively similar to changes observed in [ ³H]noradrenaline uptake in slices in vitro. There were no significant changes of these noradrenergic parameters when analysing the whole CNS after neonatal DSP4 treatment, in spite of marked regional changes in both directions. Administration of DSP4 to rats of different ages produced acutely marked depletions of noradrenaline in all regions including the pons-medulla and the cerebellum at all developmental stages. Marked and permanent depletions of noradrenaline were found in the distant noradrenergic nerve terminal projections after treatment at all ages, whereas increases in noradrenaline levels in the pons-medulla and cerebellum were only observed in rats treated with DSP4 up to the age of 3–5 days, whereas a DSP4 administration in older rats led to substantial and permanent depletions of noradrenaline in both these regions.The results indicate that the alteration of the postnatal development of noradrenergic neurons after treatment of rats up to the age of 3–5 days is mainly related to a ‘pruning effect’ of DSP4, in which prevention of the development of distant nerve terminal projections causes an increased outgrowth of nerves in collateral systems spared by the neurotoxin. The results indicate that DSP4 may be a useful denervation tool for studying various aspects of noradrenergic neurotransmission of developing locus coeruleus neurons.     

Fetal locus coeruleus transplanted into the transected spinal cord of the adult rat: some observations and implications

The 16-day-old fetal locus coeruleus can survive and grow, when transplanted into the spinal cavity created by transection of the adult spinal cord. The implants usually break up into smaller cell groups which become lodged in the host spinal cord, mainly in the caudal region. There was a marked proliferation of the damaged coerulospinal noradrenergic fibers in the rostral, ventral horn region of the cord. A neurotrophic substance produced by the locus coeruleus implants is probably responsible for this effect. Evidence for vigorous axonal growth of noradrenergic fibers derived from the implants in the caudal region of the cord was obtained. In 2/12 cases, the surviving locus coeruleus did not grow into the host tissue. Neosympathetic innervation of the caudal region of the cord occurred both in cases in which the implants survived, or did not survive. The survival rate of the transected, implanted animals is greater than 90%. The success rate of fusion of the implant with the host tissue is 40%. Based on these results, and other reports published recently, it is concluded: (1) that the purely technical difficulties of transplantation and survival of the fetal locus coeruleus in the transected spinal cord of the young adult rat on a long-term basis can be successfully solved. (2) For optimum reinnervation, the transplant should be placed in the lumbar intumescence, and not in the spinal cavity created by transection. (3) The spinal cavity created by transection must be bridged by some other method. The use of fetal spinal cord tissue on fetal mesencephalic tissue may prove to be useful for this purpose. (4) Transection of the cord must be done sub-pially, in order to minimize retraction and compression of the cord. The damaged pia must be resutured. (5) A second fetal locus coeruleus implant should be placed adjacent to the exposed surface of the rostral region of the cord. The results are discussed both in the context of recent efforts to try to restore functional activity to the damaged spinal cord, and in terms of efforts to try to understand the problems involved in fostering the growth of fetal brain tissue in the damaged spinal cord of an adult host animal.     

Locus coeruleus projections to the dorsal motor vagus nucleus in the rat.

The origin of the noradrenergic innervation of the preganglionic autonomic nuclei in the medulla oblongata and spinal cord is still controversial. In this investigation descending connections of the locus coeruleus to the dorsal motor vagus nucleus in the rat are studied with Phaseolus vulgaris leucoagglutinin and horseradish peroxidase as neuroanatomical tracers. Locus coeruleus projections in the motor vagus nucleus are found in the medial part at rostral levels and in the lateral part at intermediate levels of this nucleus. The terminal labeling in the lateral intermediate part of the vagus nucleus appears in an area where possibly preganglionic parasympathetic cardiac neurons are located, suggesting that the locus coeruleus might be involved in regulation of cardiovascular functions. After small iontophoretic injections of horseradish peroxidase in the motor vagus nucleus, retrogradely labeled cells are found in the ventral part of the locus coeruleus and occasionally in the dorsal part of the nucleus. The results show that the locus coeruleus-dorsal motor vagus nucleus pathway may participate in the inhibition of the cardiac preganglionic neurons in the dorsal motor vagus nucleus by the hypothalamic paraventricular nucleus.     

Conditions for adrenergic hyperinnervation in hippocampus: I. Histochemical evidence from intraocular double grafts

Summary The developing hippocampal anlage of rats was homologously grafted to the anterior chamber of the eye of adult recipients. After intraocular maturation of the hippocampal graft and removal of the sympathetic innervation of the eye by ipsilateral superior cervical ganglionectomy, four types of monoamine neurons were transplanted to the eye chamber: Peripheral sympathetic neurons, central adrenergic neurons of locus coeruleus, central dopaminergic neurons of substantia nigra, and central 5-hydroxytryptamine neurons of the lower raphé nuclei. All four classes of monoamine neurons were able to reinnervate the hippocampal graft, but the fiber ingrowth differed markedly. Although peripheral sympathetic neurons produced a pattern of adrenergic innervation in the hippocampal graft which resembled innervation of the hippocampus by the locus coeruleus in the brain, locus coeruleus neurons themselves produced an extremely dense plexus of fibers within the graft. This hyperinnervation remained intact for up to 9 months, the longest period of time studied. The locus coeruleus graft itself received fibers from the hippocampus graft, as demonstrated by the retrograde transport of horseradish peroxidase. We conclude that the hippocampal graft exerts a much stronger growth stimulation on the locus coeruleus neurons than on the peripheral sympathetic neurons. The difference between innervation patterns suggest that both presynaptic and postsynaptic influences determine fiber ingrowth in the central nervous system.     

Degree of hyperinnervation of area dentata by locus coeruleus in the presence of septum or entorhinal cortex as studied by sequential intraocular triple transplantation

Summary In situ area dentata receives a sparse noradrenergic innervation from locus coeruleus. Embryonic area dentata co-transplanted with locus coeruleus to the anterior eye chamber receives an abundant ingrowth of nerves from the noradrenergic neurons of the locus graft. We sought to identify restrictive forces acting on coeruleo-dentate axons by arranging for the innervation of area dentata transplants by either entorhinal cortex or septal nuclei transplants prior to locus coeruleus transplantation. The noradrenergic hyperinnervation was not inhibited when locus coeruleus transplants were placed on the opposite side of area dentata from the entorhinal or septal transplant. Noradrenergic innervation of area dentata was restricted when the locus coeruleus transplant was placed in contact with the septal transplant. This inhibitory interaction seemed to take place between the septal and locus coeruleus transplants rather than in the area dentata neuropil. This type of interaction points towards one means by which axonal growth may be inhibited during development or in the adult.     

Survival and growth of neurons with enkephalin-like immunoreactivity in fetal brain areas grafted to the anterior chamber of the eye

Areas of fetal rat brain and spinal cord known to contain enkephalin-like immunoreactive cell bodies and/or terminal fields were transplanted to the anterior chamber of the eye of adult rats. Enkephalin-like immunoreactive neurons survive and produce an enkephalin-like immunoreactive fiber network within grafts of spinal cord, ventral medulla oblongata, ventrolateral pons, tectum, locus coeruleus, substantia nigra and the areas containing columna fornicis and globus pallidus. Although single intraocular grafts of neocortex do not apparently contain enkephalin-like immunoreactive fibers, such grafts contain a variable amount of sparsely distributed enkephalin-like fibers when sequentially grafted in oculo with either locus coeruleus or spinal cord. Combinations of locus coeruleus and globus pallidus contained a rich enkephalin fiber network in the locus coeruleus part and a sparse innervation of the globus pallidus part.

We conclude that enkephalin-like immunoreactive neurons in small areas of fetal rat brain can be successfully transplanted to the anterior chamber of the eye. They are able to survive and develop to maturity in complete isolation from the rest of the brain. In general, the enkephalin-like immunoreactive fiber density in the various single grafts approximated that of their brain counterparts in situ. Fiber formation can be reinitiated in mature enkephalin-like immunoreactive neurons by addition of new brain target areas. Thus, the technique permits establishment of isolated, defined enkephalin systems and pathways accessible to functional analysis.     

Innervation of forebrain regions by medullary noradrenaline neurons, a biochemical study in cats with central tegmental tract lesions

In order to determine quantitatively the relative contribution of medullary noradrenaline neurons to the noradrenaline terminal innervation of forebrain regions in the cat, bilateral lesions of the central tegmental tract were performed at the level of the caudal pons in adult cats. The results indicate that the medullary neurons provide approximately 75% of the total noradrenaline innervation to the hypothalamus, only 20–25% of that of the thalamus and midbrain and no measurable contribution to the noradrenaline innervation of the cerebral cortex or hippocampus. These results are comparable to previous ones of bilateral locus coeruleus lesions in the cat which showed that the locus coeruleus neurons provide approx. 15% of the total noradrenaline innervation to the hypothalamus, 60% of that to the thalamus and midbrain and the entire innervation to the cerebral cortex and hippocampus.     

大鼠脊髓及脑干内膀胱支配中枢的跨突触示踪研究

目的　跨突触示踪正常大鼠脊髓和脑干内膀胱支配相关中枢,为进一步阐明膀胱功能重建术后中枢重塑奠定研究基础。 方法　成年雌性SD大鼠15只,膀胱壁内分三个点共注射GFP-PRV 4.5 μl（1×108 PFU /ml）。注射后不同时间（72、84、96、108、120 h）分别取大脑、脊髓及背根神经节,荧光显微镜下观察标记结果。 结果　病毒注射后72~120 h,阳性神经元主要分布于L6~S1、L1~L2脊神经背根神经节; L6~S1、L1~L2脊髓节段骶副交感核、中间外侧核及后连合核;脑干的巴氏核、中缝巨细胞核、巨细胞网状核、锥旁网状结构、去甲肾上腺素能细胞群A5及A7、蓝斑、中脑导水管周围灰质和红核腹侧区域。 结论　本实验中标记的相关核团与膀胱存在解剖上的神经联系,可能直接或间接参与膀胱的支配。     

Behavioural, biochemical and histochemical effects of locus coeruleus transplantation in rats with neurotoxic lesions of the catecholaminergic system

Exploratory activity in the open field and noradrenaline concentration in the neocortex and brain stem were investigated in intact rats (n = 10) and in the following groups of rats with early postnatal neurotoxic (6-hydroxydopamine) lesion of the catecholaminergic system: (i) rats with embryonal locus coeruleus grafts in the frontal neocortex (n = 5); (ii) rats with the same grafts in lateral ventricles (n = 4); (iii) a control group with intracortical hippocampal tissue grafts (n = 3); (iv) sham-operated rats (n = 3). Experiments were performed by four independent groups of investigators using a double-blind method. In sham-operated rats as well as in rats with hippocampal grafts, and with locus coeruleus grafts in the ventricles, both exploratory activity and noradrenaline content of the forebrain were significantly lowered. In the rats with intracortical locus coeruleus grafts the level of exploratory activity was much higher (almost as in intact controls). This improvement of exploratory behaviour correlated highly with increased noradrenaline concentration in the forebrain. In all animals with locus coeruleus in lateral ventricles a significant increase in noradrenaline level of the brain stem was present, but no change of exploratory behaviour was observed. The grafts with the 3-mm-thick slabs of the adjacent tissue were dissected from the brain and used for histological analysis. The presence of typical locus coeruleus cells was shown in neocortex of all animals which received the grafts of corresponding tissue. The data show the possibility of stable compensation of the forebrain noradrenaline level and exploratory behaviour by embryonic noradrenergic neurons grafted into the neocortex, but not into lateral ventricles.     

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)     

Locus coeruleus neurons in the rat containing neuropeptide Y, tyrosine hydroxylase or galanin and their efferent projections to the spinal cord, cerebral cortex and hypothalamus

The efferent projections of locus coeruleus neurons which contain neuropeptide Y-, tyrosine hydroxylase- or galanin-like immunoreactivity were investigated using the indirect immunofluorescence technique combined with the retrograde transport of the fluorescent substance Fast Blue. Four groups of rats received injections of Fast Blue: (1) bilaterally into the mid-thoracic spinal cord (T6-T7); (2) unilaterally into the low cervical spinal cord (C4-C5); (3) unilaterally into the paraventricular, periventricular and dorsomedial hypothalamic nuclei; and (4) unilaterally into five sites in the cerebral cortex (frontal, cingulate and striate cortex). Efferent projections to the spinal cord, hypothalamus and cerebral cortex from neuropeptide Y-, tyrosine hydroxylase- and galanin-containing locus coeruleus cells were observed. A higher percentage of the peptidergic locus coeruleus neurons projected to the hypothalamus than to the spinal cord or cerebral cortex. The distribution and morphology of the neuropeptide Y- and galanin-containing neurons in the locus coeruleus were also investigated. Neuropeptide Y-like immunoreactivity and galanin-like immunoreactivity were found in small, medium and large multipolar neurons, as well as in fusiform locus coeruleus cells. The neuropeptide Y- and galanin-immunoreactive neurons were found throughout the locus coeruleus. In the caudal locus coeruleus, they were primarily located in the dorsal portion. Neuropeptide Y-like immunoreactivity and galanin-like immunoreactivity were only seen in a few tyrosine hydroxylase-positive neurons of the subcoeruleus group. The data show that the peptide-containing locus coeruleus neurons have efferent projections to the spinal cord, hypothalamus and cerebral cortex. The locus coeruleus may be divided into functional subdivisions dependent on the region of the locus coeruleus, the neurotransmitter/neuropeptide(s) contained within the neurons and their efferent projections.     

Impaired recovery of noradrenaline levels in apolipoprotein E-deficient mice after N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine lesion

We investigated the effect of the noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) (1 or 3 x 50 mg/kg, intraperitoneally), on hippocampal, cortical and cerebellar noradrenaline levels after recovery of one, five and 11 months in control and apolipoprotein E-deficient mice. Apolipoprotein E-deficient mice had lower hippocampal noradrenaline levels than control mice. DSP-4-lesioned control mice had a more extensive recovery of hippocampal and cortical noradrenaline levels than DSP-4-lesioned apoE-deficient mice after five months' survival. Furthermore, the hippocampal noradrenaline levels after five and 11 months and cortical noradrenaline levels after five months of recovery had slightly recovered in control but not in apolipoprotein E-deficient mice treated with a single dose of DSP-4 compared with mice treated with three doses of DSP-4. These results show that apolipoprotein E-deficient mice have impaired recovery capacity in their locus coeruleus neurons.     

Seizure suppression in kindling epilepsy by intrahippocampal locus coeruleus grafts: evidence for an alpha-2-adrenoreceptor mediated mechanism

Summary Intrahippocampal cell suspension grafts, prepared from the locus coeruleus region of rat fetuses, have previously been shown to retard seizure development in rats made hypersensitive to hippocampal kindling by a lesion of the forebrain noradrenergic system. The objective of the present study was to provide evidence that the seizure-suppressant effect elicited by the grafts is mediated via noradrenergic mechanisms. Two groups of rats received 6-hydroxydopamine in the lateral ventricle and then bilateral intrahippocampal locus coeruleus grafts. After 3 months, the grafted animals and a group of normal rats were subjected to hippocampal kindling. One group of grafted animals and the normal rats were injected intraperitoneally with the alpha-2 adrenergic receptor blocker idazoxan before each kindling stimulation. The other grafted rats received vehicle injections. The development of seizures was significantly faster in the grafted and normal rats that had been given idazoxan than in the grafted rats that had not been subjected to alpha-2 receptor blockade. Our data suggest that the seizure-suppressant action exerted by grafts of fetal locus coeruleus in hippocampal kindling is mediated via noradrenergic mechanisms, most likely via activation of postsynaptic alpha-2 adrenoreceptors.     

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.