Therapeutic effects of HS-3, HS-6, benactyzine, and atropine in soman poisoning of dogs

Rats with intracranial self-stimulation (ICSS) electrodes in the locus coeruleus and adjacent pontine tegmental structures received stereotaxically placed bilateral injections of 6-hydroxydopamine (4 mug/2 mul) into the mesencephalic trajectory of the dorsal tegmental noradrenergic bundle. The consequent depletions of norepinephrine in the cerebral cortices and hippocampi (96.7%) did not result in significant changes in ICSS. Thus, diencephalic and telencephalic noradrenergic projections of the locus coeruleus do not appear to be critical for the occurrence of ICSS from that nucleus or its surrounding region. Nor do these projections appear to be crucially involved in the enhancement of this ICSS by D-amphetamine. Rats in this study showed two-fold increases in responding following injections of D-amphetamine sulfate (0.5 mg/kg) both before and after the lesions of the dorsal tegmental bundle. These results suggest that the ascending projections of the locus coeruleus are not critically involved in ICSS of the dorsal pontine tegmentum.     

Comparison of behaviors elicited by electrical brain stimulation in dorsal brain stem and hypothalamus of rats.

Investigated 4 brain-stimulation phenomena elicited from both dorsal brain stem and hypothalamic sites, using a total of 20 male albino Holtzman Sprague-Dawley rats. Results show that (a) intracranial self-stimulation rate-intensity functions for dorsal brain stem and hypothalamic sites yielded very high (over 1,000 responses/15 min) to moderate (201-500 responses/15 min) response rates; (b) dextroamphetamine produced higher response rates than either levoamphetamine or saline at both dorsal brain stem and hypothalamic sites, indicating that noradrenergic dorsal brain stem fibers (or cell bodies) support intracranial self-stimulation; (c) dorsal brain stem and hypothalamic self-stimulation sites reliably produced escape behavior; (d) simultaneous stimulation of dorsal brain stem and hypothalamic sites at subthreshold intensities interacted to produce suprathreshold response rates. (32 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of amphetamine and food deprivation on self-stimulation of the lateral hypothalamus and medial frontal cortex.

Intracranial self-stimulation of the lateral hypothalamus in 5 male Sprague-Dawley rats was markedly increased by subcutaneous dextroamphetamine administration and by food deprivation. In contrast, similar self-stimulation response rates obtained in the same Ss from the medial frontal cortex were unaffected by food deprivation and only slightly increased by dextroamphetamine administration. Furthermore, a large difference between dextro- vs levoamphetamine on response rate was obtained for lateral hypothalamic but not for medial frontal cortex self-stimulation. Results are consistent with a noradrenergic self-stimulation system for the lateral hypothalamus. Medial frontal cortex self-stimulation, however, appears to be mediated by a neuroanatomical and neurochemical system different from that of the lateral hypothalamus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Thyroid hormones as neurotransmitters

During brain development, before the apparatus of neurotransmission has been set into place, many neurotransmitters act as growth regulators. In adult brain, their role in neurotransmission comes to the fore but neuronal plasticity and other growth-related processes are their continuing responsibility. This has been clearly demonstrated for catecholamines. Previous as well as recent evidence now indicates that thyroid hormones may participate in the developing and adult brain through similar mechanisms. Immunohistochemical mapping of brain triiodothyronine (antibody specificity established by numerous appropriate tests) demonstrated that the hormone was concentrated in both noradrenergic centers and noradrenergic projection sites. In the centers (locus coeruleus and lateral tegmental system) triiodothyronine staining, like that of tyrosine hydroxylase, was heavily concentrated in cytosol and cell processes. By contrast, in noradrenergic targets, label was most prominent in cell nuclei. Combined biochemical and morphologic data allows a construct of thyroid hormone circuitry to unfold: The locus coeruleus is conveniently located just beneath the ependyma of the 4th ventricle. Thyroxine, entering the brain via the choroid plexus, is preferentially delivered to subependymal brain structures. High concentrations of locus coeruleus norepinephrine promote active conversion of thyroxine to triiodothyronine, leading to the preeminence of the locus coeruleus as a site of triiodothyronine concentration. Results of treatment with the locus coeruleus neurotoxin DSP-4 established that axonal transport accounts for delivery of both triiodothyronine and norepinephrine from locus coeruleus to noradrenergic terminal fields. The apparatus for transduction of thyronergic and noradrenergic signals at both membrane and nuclear sites resides in the postsynaptic target cells. Upon internalization of hormone in post-synaptic target cells, genomic effects of triiodothyronine, norepinephrine, and/or their second messengers are possible and expected. The evidence establishes a direct morphologic connection between central thyronergic and noradrenergic systems, supporting earlier proposals that triiodothyronine or its proximate metabolites may serve as cotransmitters with norepinephrine in the adrenergic nervous system.     

Comparative histological and ultrastructural studies of the Harderian gland of rodents

There is considerable preclinical evidence for a relationship between noradrenergic brain systems and behaviors associated with stress and anxiety. The majority of noradrenergic neurons are located in the locus coeruleus (pons), with projections throughout the cerebral cortex and multiple subcortical areas, including hippocampus, amygdala, thalamus, and hypothalamus. This neuroanatomical formation of the noradrenergic system makes it well suited to rapidly and globally modulate brain function in response to changes in the environment, as occurs during the presentation of stressors. Stress exposure is associated with an increase in firing of the locus coeruleus and with associated increased release and turnover of norepinephrine in brain regions which receive noradrenergic innervation. Increased firing of the locus coeruleus is also associated with behavioral manifestations of fear, such as arched back and piloerection in the cat. Exposure to chronic stress results in long-term alterations in locus coeruleus firing and norepinephrine release in target brain regions of the locus coeruleus. Norepinephrine is also involved in neural mechanisms such as sensitization and fear conditioning, which are associated with stress. These findings are relevant to an understanding of psychiatric disorders, such as panic disorder and post-traumatic stress disorder (PTSD), the symptoms of which have been hypothesized to be related to alterations in noradrenergic function.     

Food intake and lateral hypothalamic self-stimulation covary after medial hypothalamic lesions or ventral midbrain 6-hydroxydopamine injections that cause obesity.

In rats with perifornical lateral hypothalamic (LH) electrodes that induced feeding, self-stimulation through the same electrodes increased immediately after ventromedial hypothalamic (VMH) lesions and did not return to normal until food intake normalized and the rats had become obese. A unilateral far-LH lesion decreased feeding and contralateral perifornical LH self-stimulation. 6-hydroxydopamine (6-OHDA) injected into the midbrain to destroy the ventral noradrenergic bundle (VNAB) caused hyperphagia and increased LH self-stimulation. In summary, VMH or VNAB damage increased feeding and self-stimulation; contralateral far-LH damage decreased both. Results confirm the earlier suggestion that the VMH region is necessary for normal inhibition of feeding and feeding reward as reflected in self-stimulation rate. Although massive 6-OHDA-induced depletion of the dopamine system that passes through the LH can cause starvation and impair self-stimulation, results suggest that selective catecholamine depletion of ventral midbrain neurons with sparing of the A9 and A10 dopaminergic cells can disinhibit feeding and self-stimulation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of strychnine on rat locus coeruleus neurones during sleep and wakefulness

The noradrenergic neurones of the locus coeruleus (LC) discharge tonically during wakefulness, decrease their activity during slow wave sleep and are virtually quiescent during paradoxical sleep. We recently demonstrated an inhibitory glycinergic input to the locus coeruleus and proposed that this could be responsible for inhibition of the LC during paradoxical sleep. To test this proposal, we developed a method combining polygraphic recordings, iontophoresis and single-unit extracellular recordings in the unanaesthetized head-restrained rat. Iontophoretically applied strychnine, a specific glycine antagonist, induced strong excitation of LC neurones during paradoxical sleep, but also during slow wave sleep and wakefulness. These results suggest that glycine tonically inhibits noradrenergic LC neurones throughout the entire sleep-waking cycle and not only during paradoxical sleep.     

Chronic cold stress alters the basal and evoked electrophysiological activity of rat locus coeruleus neurons

In vivo extracellular single-unit recording techniques revealed that chronic cold stress significantly alters both the basal and the evoked electrophysiological activity of noradrenergic neurons in the locus coeruleus of the anaesthetized rat. Following 17-21 days of chronic cold exposure (5 degrees C), the single-unit activity of histologically-identified locus coeruleus neurons in chloral hydrate-anaesthetized rats was recorded and analysed in terms of their basal firing rate and pattern of spike activity, as well as their response to footshock stimulation. There was no significant difference in the incidence of spontaneously active cells/electrode track between cold-stressed rats and control rats. However, the basal spike activity of locus coeruleus cells recorded from cold-stressed rats differed significantly from that of control rats along two dimensions: i) they displayed significantly higher basal firing rates (mean = 1.88 Hz vs 1.20 Hz, respectively); and ii) they frequently exhibited spontaneous burst-firing activity that was not observed in control rats (observed in 15/17 cold-stressed rats vs 1/26 control rats). The evoked spike activity of locus coeruleus cells in cold-stressed rats also differed significantly from that of control rats along two dimensions: i) they were more likely to respond to footshock stimulation (mean = 90.3% vs 74.4%, respectively); and ii) these responses were more likely to consist of multispike bursts of action potentials (mean = 8 bursts/50 stimulations vs 1 burst/50 stimulations, respectively). These results indicate that alterations in the electrophysiological activity of noradrenergic locus coeruleus neurons may contribute to the phenomenon of stress-induced sensitization of norepinephrine release that is thought to underlie some of the neuropathological changes that accompany long-term stress.     

Prostaglandin E1 suppresses tumor necrosis factor-alpha and interleukin-10 production by lipopolysaccharides-stimulated mononuclear cells

Previous studies have shown that the intravenous administration of yohimbine, an alpha 2 antagonist, increases norepinephrine turnover and has related anxiogenic effects in humans. We herein report that yohimbine also increases plasma neuropeptide Y (NPY) in healthy human subjects. This finding is consistent with previous reports in animals, but contrasts with a previously reported study in humans. NPY is a 36 amino acid peptide neurotransmitter located in sympathetic and nonsympathetic nerve fibers, as well as in brain structures such as the locus coeruleus, where it is colocalized with norepinephrine. NPY has been shown to inhibit locus coeruleus neuronal firing, decrease norepinephrine release, and increase postsynaptic noradrenergic signal transduction. When administered centrally, NPY also has anxiolytic properties. This study therefore suggests that yohimbine challenge may be useful in assessing NPY and noradrenergic system interactions in neuropsychiatric disorders such as panic disorder or post traumatic stress disorder in which noradrenergic system dysfunction has been observed.     

The elastic cartilage in the normal rat epiglottis. I. Fine structure

Unilateral electrolytic lesions of the locus coeruleus in rats result in spontaneous ipsiversive rotation, which is then replaced by contraversive rotation. One week after lesioning, when spontaneous turning ceases, apomorphine and d-amphetamine elicit contraversive circling behaviour, which was not affected by noradrenergic receptor blockade but was abolished by dopamine receptor blockade. The drug-induced contraversive circling response was also reproduced by piribedil but not clonidine. Combined unilateral electrolytic locus coeruleus and substantia nigra lesions on the same side resulted in apomorphine- and d-amphetamine-induced ipsilateral rotational behaviour which was indistinguishable from that seen with substantia nigra lesions alone. In rats with unilateral locus coeruleus lesions, the dose of intrastriatally injected apomorphine required to produce circling was less on the lesioned than the non-lesioned side. Direct injection of noradrenaline into one substantia nigra caused contraversive circling. Direct injection of phenoxybenzamine into one substantia nigra followed by apomorphine caused ipsiversive circling. The results suggest that the circling behaviour seen after unilateral locus coeruleus lesions depends on an asymmetry of striatal dopamine receptor activity and are consistent with a proposed coeruleus-nigral noradrenergic pathway, which enhances impulse flow in the dopaminergic nigrostriatal system.     

Conditioned responses of monkey locus coeruleus neurons anticipate acquisition of discriminative behavior in a vigilance task

Impulse activity was recorded extracellularly from noradrenergic neurons in the nucleus locus coeruleus of three cynomolgus monkeys performing a visual discrimination (vigilance) task. For juice reward, the subjects were required to release a lever rapidly in response to an improbable target stimulus (20% of trials) that was randomly intermixed with non-target stimuli presented on a video display. All locus coeruleus neurons examined were phasically and selectively activated by target stimuli in this task. Other task events elicited no consistent response from these neurons (juice reward, lever release, fix spot stimuli, non-target stimuli). With reversal of the task contingency, locus coeruleus neurons ceased responding to the former target stimuli, and began responding instead to the new target (old non-target) stimuli. In addition, the latency of locus coeruleus response to target stimuli increased after reversal (by about 140 ms) in parallel with a similar increase in the latency of the behavioral response. These results indicate that the conditioned locus coeruleus responses reflect stimulus meaning and cognitive processing, and are not driven by physical sensors attributes. Notably, the reversal in locus coeruleus response to stimuli after task reversal occurred rapidly, hundreds of trials before reversal was expressed in behavioral responses. These findings indicate that conditioned responses of locus coeruleus neurons are plastic and easily altered by changes in stimulus meaning, and that the locus coeruleus may play an active role in learning the significance of behaviorally important stimuli.     

Destruction of catecholamine-containing neurons by 6-hydroxydopa, an endogenous amine oxidase cofactor

The amino acid, 6-hydroxydopa (6-OHDOPA), found at the active site of amine oxidases, exists as a keto-enol. Exogenously administered 6-OHDOPA is an excitotoxin like beta-N-oxalylamino-L-alanine (BOAA) and beta-N-methylamino-L-alanine (BMAA), acting at the non-N-methyl-D-aspartate (non-NMDA) alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor. BMAA and BOAA are causal factors of neurolathyrism in humans. Much exogenously administered 6-OHDOPA is biotransformed by aminoacid decarboxylase (AADC) to the highly potent and catecholamine-(CA) selective neurotoxin, 6-hydroxydopamine (6-OHDA). 6-OHDOPA destroys locus coeruleus noradrenergic perikarya and produces associated denervation of brain by norepinephrine-(NE) containing fibers. Opiopeptides and opioids enhance neurotoxic effects of 6-OHDOPA on noradrenergic nerves, by a naloxone-reversible process. An understanding of mechanisms underlying neurotoxic effects of 6-OHDOPA can be helpful in defining actions of known and newfound amino acids and for investigating their potential neurotoxic properties.     

Association of an odor with an activation of olfactory bulb noradrenergic β-receptors or locus coeruleus stimulation is sufficient to produce learned approach responses to that odor in neonatal rats.

These experiments examined the sufficiency of pairing an odor with either intrabulbar activation of noradrenergic β-receptors or pharmacological stimulation of the locus coeruleus to support learned odor preferences in Postnatal Day 6–7 rat pups. The results showed that pups exposed to odor paired with β-receptor activation limited to the olfactory bulb (isoproterenol, 50 μM) displayed a conditioned approach response on subsequent exposure to that odor. Furthermore, putative stimulation of the locus coeruleus (2 μM idazoxan or 2 mM acetylcholine) paired with odor produced a subsequent preference for that odor. The effects of locus coeruleus stimulation could be blocked by a pretraining injection of the β-receptor antagonist propranolol (20 mg/kg). Together these results suggest that convergence of odor input with norepinephrine release from the locus coeruleus terminals within the olfactory bulb is sufficient to support olfactory learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Determination of acrolein in human urine by headspace gas chromatography and mass spectrometry

The aim of the present study is to examine whether noradrenergic neurons of the locus coeruleus (LC) of the rat contain monoamine oxidase (MAO) activity. Sections were processed initially for MAO enzyme histochemistry using tyramine as a substrate, followed by fluorescence immunohistochemistry for tyrosine hydroxylase (TH). In the LC, virtually all TH-immunoreactive neurons (i.e., noradrenergic neurons) were also positive for MAO. No MAO activity was found in any TH-negative neurons. Neurons in the LC have previously been shown to form dopamine during noradrenaline biosynthesis and to produce serotonin from exogenously administered l-5-hydroxytryptophan. Moreover, dopamine- and serotonin-degrading MAO activity has also been found in LC neurons. Therefore, our results indicate that MAO activity is localized within noradrenergic neurons in the LC and is likely involved in the degradation of dopamine that is endogenously synthesized, and also in the elimination of serotonin that is produced from exogenous precursors.     

Microbial degradation of tetraethyl lead in soil monitored by microcalorimetry

Fos immunohistochemistry was used to stain neurons in the caudal diencephalon, midbrain and hindbrain driven by rewarding stimulation of the lateral hypothalamus (LH). Increases in Fos-like immunoreactivity were most pronounced ipsilateral to the site of stimulation and tended to be confined within discrete structures such as the posterior LH, arcuate nucleus, ventral tegmental area (VTA), central gray, dorsal raphé, pedunculopontine area (PPTg), parabrachial nucleus, and locus coeruleus. At least two of these structures, the VTA and PPTg, have been implicated in medial forebrain bundle self-stimulation.     

Mutual interactions among cholinergic, noradrenergic and serotonergic neurons studied by ionophoresis of these transmitters in rat brainstem nuclei

In urethane-anesthetized rats, single neuronal activity was recorded in or around the central gray of the caudal mesencephalon to rostral pons with multibarrel microelectrodes for ionophoretic application of acetylcholine, noradrenaline and serotonin. Neurons were classified by spike shape into broad-spike and brief-spike neurons. In the laterodorsal tegmental nucleus, locus coeruleus or dorsal raphe, broad-spike neurons, marked by Pontamine Sky Blue and discriminated in sections processed for histochemistry of reduced nicotinamide adenine dinucleotide phosphate diaphorase or Nissl staining, were presumed to be cholinergic, noradrenergic or serotonergic, respectively. The majority of these neurons were inhibited through autoreceptors, except some laterodorsal tegmental neurons which might not be furnished by autoreceptors. Noradrenaline and serotonin inhibited more than two-thirds of the laterodorsal tegmental neurons tested, while a few neurons were excited by noradrenaline. Though effects of noradrenaline on dorsal raphe neurons and those of serotonin on locus coeruleus neurons were not clear in many neurons tested, neurons affected in these examinations (30%) were all inhibited clearly and no excitatory effect was observed. Acetylcholine exerted inhibition on about one-half of dorsal raphe neurons, while effects of acetylcholine on locus coeruleus neurons were the only case in the present study in which excitation was the major effect, though more than a half of locus coeruleus neurons were not sensitive to this drug. Thus, in this study some new data on the pharmacological properties of the cholinergic laterodorsal tegmental neurons were obtained. In addition, mutual interactions between brainstem cholinergic, noradrenergic and serotonergic neurons were assayed by comparing the pharmacological properties of these neurons tested with a uniform procedure. The interactions between these diffuse projection neurons may be involved in neural mechanisms controlling vigilance, wakefulness and/or sleep.     

Identification of two Y-box binding proteins that interact with the promoters of columbid annexin I genes

The aim of this study was to investigate the role of noradrenergic descending nervous pathways in external anal sphincter motility. For this purpose, the effects of intravenously injected adrenoceptor antagonist and agonist on the tonic electrical activity of this sphincter were studied in anesthetized cats. The effects of stimulating the region of the locus coeruleus and the effects of intravenous, intracerebroventricular and intrathecal injection of the above drugs on the electromyographic responses of this muscle to pudendal nerve stimulation were also investigated. The tonic sphincteric activity and the reflex response triggered by electrically stimulating pudendal afferent nerve fibers were inhibited by alpha1-adrenoceptor antagonist nicergoline and enhanced by alpha1-adrenoceptor agonist phenylephrine. Stimulation of the locus coeruleus area either inhibited or enhanced the reflex responses. Intracerebroventricular and intrathecal injection of the alpha2-adrenoceptor agonists, morphine and leu-enkephalin decreased the amplitude of these reflex responses. All the effects of opioids were blocked by naloxone and by spinalization performed at the cervical and lumbar levels. The direct response elicited by stimulating the sphincteric motor axons was not affected either by these drugs or by the brainstem stimulation. These results suggests the existence of a pontine neuronal network controlling the motility of the external anal sphincter via noradrenergic and opioid neurons.     

The hyaluronan receptor RHAMM in noradrenergic fibers contributes to axon growth capacity of locus coeruleus neurons in an intraocular transplant model

The hyaluronan receptor for hyaluronic acid-mediated motility (RHAMM) plays a role in cell migration and motility in many systems. Recent observations on the involvement of RHAMM in neurite motility in vitro suggest that it might also be important in axon outgrowth in situ. This was addressed directly by investigating both RHAMM expression in the rat CNS and the ability of anti-RHAMM reagents to interfere with tissue growth and axon outgrowth in intraocular brainstem transplants. By western blotting, anti-RHAMM antibody detected a RHAMM isoform of 75,000 mol. wt in both whole brain homogenate and synaptosome preparations, and a 65,000 mol. wt isoform in synaptosomes. Immunofluorescence of adult brain sections revealed RHAMM-like immunoreactivity in varicose fibers that were also positive for the noradrenergic marker dopamine-beta-hydroxylase. Not all noradrenergic fibers contained RHAMM, nor was RHAMM detected in other monoaminergic fiber types. Lesions of noradrenergic fiber systems with beta-halobenzylamine-N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) eliminated RHAMM-positive fibers, but noradrenergic axons that sprouted extensively after this treatment were strongly RHAMM-positive. To assess RHAMM's role in fiber outgrowth, fetal brainstem tissue containing noradrenergic neurons was grafted into the anterior chamber of the eye. Treatment of grafts with anti-RHAMM antibody caused significant inhibition of tissue growth and axon outgrowth, as did a peptide corresponding to a hyaluronan binding domain of RHAMM. These agents had no such effects on transplants containing serotonergic and dopaminergic neurons. These results suggest that RHAMM, an extracellular matrix receptor previously shown to contribute to migratory and contact behavior of cells, may also be important in the growth and/or regenerative capacity of central noradrenergic fibers originating from the locus coeruleus.     

Noradrenergic neuromodulation in the olfactory bulb modulates odor habituation and spontaneous discrimination.

Noradrenergic projections from the locus coeruleus (LC) project to the olfactory bulb (OB), a cortical structure implicated in odor learning and perceptual differentiation among similar odorants. The authors tested the role of OB noradrenaline (NA) in short-term olfactory memory using an animal model of LC degeneration coupled with intrabulbar infusions of NA. Specifically, the authors lesioned cortical noradrenergic fibers in mice with the noradrenergic neurotoxin N-Ethyl-N-(2-chloroethyl)-2-bromobenzylamine hydrochloride (DSP4) and measured the effects on an olfactory habituation/spontaneous discrimination task. DSP4-treated mice failed to habituate to repeated odor presentations, indicating that they could not remember odors over the 5-min intertrial interval. The authors then infused NA bilaterally into the OBs of both DSP4-treated and nonlesioned control animals at two concentrations (10-3M and 10-5M, 2 μl/side). In DSP4-treated animals, NA administration at either concentration restored normal habituation and spontaneous discrimination performance, indicating that noradrenergic neuromodulation mediates these aspects of perceptual learning and that its efficacy does not require activity-dependent local regulation of NA release. Functional OB learning mechanisms may be necessary for normal odor recognition and differentiation among physically similar odorants. (PsycINFO Database Record (c) 2010 APA, all rights reserved)