Depletion Of Norepinephrine Research Articles

Neurotransmitter depletion may be a cause of dementia pathology rather than an effect

There is widespread loss of acetylcholine and other neurotransmitters in Alzheimer's disease and vascular dementia. It has generally been assumed that death of neurons causes neurotransmitter loss, but alternatively neurotransmitter depletion itself may at least contribute to neurodegeneration. Transgenic mice and pigs with inducible 50% depletion of acetylcholine, dopamine, norepinephrine, serotonin, gamma-aminobutyric acid (GABA) and corticotrophin releasing factor will reproduce Alzheimer's disease or vascular dementia neuropathology, and pharmacologically restoring neurotransmitters will attenuate neuronal injury. Through nuclear transfer cloning, transgenic mice and pigs would be created with transgenes on one X chromosome, so that transgenes would only be expressed in half of all cells in female animals. Transgenes would encode tetracycline-inducible short hairpin RNA (shRNA) designed to form small interfering RNA (siRNA) to knock down neurotransmitter biosynthesis in late adulthood. Transgene expressing neurons could be readily identified in tissue sections with fluorescent reporter genes. Cholinesterase inhibitors, antidepressants, benzodiazepines and CRF would then be administered in an attempt to rescue degenerating neurons. The mice and pigs could serve as an important new model for the pathogenesis of dementia, especially if pharmacologically restoring neurotransmitters rescues degenerating neurons. The animals may also be useful for as models for other disorders such as multi-system atrophy, Parkinson's disease, and depression.

A novel mechanism involved in 5-hydroxytryptamine-induced nociception: The indirect activation of primary afferents

The aim of this study was to test the hypothesis that 5-hydroxytryptamine induces nociception by an indirect action on the primary afferent nociceptor in addition to its previously described direct action. Injection of 5-hydroxytryptamine into the s.c. tissue of the hind paw of rats produced nociceptive flinch behavior and inflammatory cell migration, that were significantly reduced by the nonspecific selectin inhibitor fucoidan. 5-Hydroxytryptamine-induced nociception was also significantly reduced by local blockade of the 5-HT 3 receptor by tropisetron, by the cyclooxygenase inhibitor indomethacin and by local blockade of the β1-adrenergic receptor or of the D1 receptor by atenolol or SCH 23390, respectively. Neither guanethidine depletion of norepinephrine in the sympathetic terminals nor local blockade of the β2-adrenergic receptor by ICI-118,551 significantly reduced 5-hydroxytryptamine-induced nociception. Taken together, these findings indicate that 5-hydroxytryptamine induces nociception by a novel, indirect and norepinephrine-independent mechanism mediated by neutrophil migration and local release of prostaglandin and dopamine. Furthermore, to test whether dopamine acts on β1-adrenergic and/or D1 receptor to contribute to 5-hydroxytryptamine-induced nociception, dopamine was s.c. injected either alone or combined with atenolol or with SCH 23390. S.c.-injected dopamine also produced a dose-dependent nociceptive behavior that was significantly reduced by both SCH 23390 and atenolol. Based on that it is proposed that dopamine, once released, activates D1 and β1-adrenergic receptors to contribute to 5-hydroxytryptamine-induced nociception.

Novel stressors affected catecholamine stores in socially isolated normotensive and spontaneously hypertensive rats

Catecholamines in some central (hypothalamus and hippocampus) and peripheral tissues (adrenal glands and heart auricles) of long-term socially isolated normotensive and spontaneously hypertensive rats exposed to novel immobilization stress were determined by a simultaneous single isotope radioenzymatic assay. Long-term isolation (21 days) produced depletion of hypothalamic norepinephrine (NE) stores and hippocampal dopamine (DA) stores in both normotensive and spontaneously hypertensive rats. Acute immobilization stress (2 h) significantly decreased NE and DA stores in hypothalamus and hippocampus of naive normotensive and spontaneously hypertensive rats controls. However, novel immobilization stress applied to normotensive rats previously subjected to long-term isolation produced no changes in catecholamine levels in hypothalamus, while resulting in somewhat higher depletion of NE stores in hypothalamus of spontaneously hypertensive rats treated in the same way. Novel immobilization stress decreased NE and DA stores in hippocampus of normotensive but was without effect on NE and DA stores of spontaneously hypertensive rats. Social isolation did not affect catecholamine stores in peripheral tissues but novel immobilization stress produced a significant decrease in catecholamine content. The results suggest that some central and peripherals tissues of spontaneously hypertensive rats and normotensive rats differ with regard to catecholamine content and that there are certain differences in their responsiveness to stress.

Specificity and efficacy of noradrenaline, serotonin depletion in discrete brain areas of Swiss mice by neurotoxins

The aim of this work is to define neurotoxins doses to have efficient and specific depletion of noradrenaline (NA), serotonin (5-HT) neurotransmission in cortex, striatum, hippocampus and hypothalamus of Swiss mice after intraperitoneal administration of, respectively, N-(2-chloroethyl)- N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) and para-chlorophenylalanine methyl ester hydrochloride (PCPA). The neurotransmitters concentrations were determined by high performance liquid chromatography with amperometric detection. The minimal single dose necessary to produce a highly significant decrease of NA levels ( p < 0.01 in comparison with control group) in hypothalamus (−44%), hippocampus (−91%), striatum (−40%) and cortex (−68%) was 50 mg/kg but DA and 5-HT levels were modified, respectively, in hypothalamus and striatum. Three doses of PCPA 300 mg/kg over 3 consecutive days involve a profound depletion of 5-HT transmission in all discrete brain areas but NA and DA levels were also significantly reduced. In conclusion, DSP-4 has a different efficacy in discrete brain areas with a noradrenergic specificity which is not absolute, PCPA has a similar efficacy in all brain areas but is unspecific of 5-HT transmission.

MDMA (‘Ecstasy’) and methamphetamine combined: Order of administration influences hyperthermic and long-term adverse effects in female rats

The acute and long-term dangers of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) and methamphetamine (METH) are well described individually, but their effect in combination is largely unknown. Here groups of female rats were given four MDMA or METH injections within a single session with each injection separated by 2 h. Treatments included MDMA only, METH only, MDMA and METH in a cocktail (MDMA/METH), MDMA (two injections) followed by METH (two injections) (MDMA → METH), or METH followed by MDMA (METH → MDMA). Each injection involved 4 mg/kg of total drug. Drug administration occurred at a high ambient temperature of 28 °C. All treatments produced hyperactivity while the treatments where MDMA was administered first (MDMA, MDMA → METH and MDMA/METH) produced hyperthermia. All treatments involving METH caused significant head weaving. Six weeks after drug treatment all groups showed reduced social interaction relative to controls. MDMA/METH treatment was associated with reduced swimming in the forced swim test. MDMA given alone caused 5-HT depletion in several brain regions while METH given alone caused dopamine depletion in the striatum. The three treatments involving MDMA and METH combinations caused significant depletion of serotonin, dopamine and noradrenaline in several brain regions. Interestingly, the MDMA → METH treatment produced greater hippocampal and cortical 5-HT depletion than the METH → MDMA treatment suggesting an effect of order. These results extend our recent findings of additive toxic effects when METH is combined with MDMA. This has potentially important implications for party drug users who appear to frequently use this combination.

Splenic norepinephrine depletion following acute stress suppresses in vivo antibody response

Exposure to an intense acute stressor immediately following immunization leads to a reduction in anti-KLH IgM, IgG, and IgG2a, but not IgG1. Stress also depletes splenic norepinephrine (NE) content. Immunization during pharmacological (α-methyl-p-tyrosine) or stress-induced splenic NE depletion results in antibody suppression similar to that found in rats immunized prior to stressor exposure. Prevention of splenic NE depletion during stress by tyrosine, but not pharmacological elevation (mirtazapine) of NE, resulted in normal antibody responses. These data support the hypothesis that splenic NE depletion is necessary and sufficient for stress-induced suppression of antibody to a T-cell dependent antigen.

The Role of Adrenergic and Cholinergic Transmission in Volatile Anesthetic-Induced Pain Enhancement

Volatile anesthetic drugs have a biphasic effect on pain transmission. At very small concentrations they enhance pain sensitivity whereas at larger subanesthetic concentrations they have an analgesic effect. Previous work has suggested that nicotinic inhibition could mediate the pronociceptive action of isoflurane. Furthermore, activation of nicotinic receptors facilitates the release of norepinephrine in the spinal cord. We hypothesize that nicotinic modulation of norepinephrine release in the spinal cord mediates isoflurane's pronociceptive action. We used hindpaw withdrawal latency as a measure of pain sensitivity after inhibition of adrenergic activity or treatment with nicotine in mice. Isoflurane's effect on pain is separable by concentration. The 50% effective concentration for pain enhancement is 0.16% isoflurane whereas the 50% effective concentration for the antinociceptive action of isoflurane is 0.8%. Depletion of systemic norepinephrine with the neurotoxin DSP-4 caused a reduction in baseline withdrawal latencies and prevented isoflurane pronociception. Baseline latency was also reduced by intrathecal yohimbine. After treatment with yohimbine, isoflurane had no additional pronociceptive effect. Nicotine administered through intracerebroventricular injection increased baseline latency but did not prevent isoflurane pronociception. Conversely, intrathecal applications of nicotine caused a slight reduction in baseline latency and prevented isoflurane's pronociceptive effect. We conclude that spinal noradrenergic transmission seems to be necessary for isoflurane pronociception to occur. Isoflurane may act by inhibiting tonically active nicotinic receptors that modulate the release of norepinephrine in the spinal cord.

Role of descending noradrenergic system and spinal α2‐adrenergic receptors in the effects of gabapentin on thermal and mechanical nociception after partial nerve injury in the mouse

1. To gain further insight into the mechanisms underlying the antihyperalgesic and antiallodynic actions of gabapentin, a chronic pain model was prepared by partially ligating the sciatic nerve in mice. The mice then received systemic or local injections of gabapentin combined with either central noradrenaline (NA) depletion by 6-hydroxydopamine (6-OHDA) or alpha-adrenergic receptor blockade. 2. Intraperitoneally (i.p.) administered gabapentin produced antihyperalgesic and antiallodynic effects that were manifested by elevation of the withdrawal threshold to a thermal (plantar test) or mechanical (von Frey test) stimulus, respectively. 3. Similar effects were obtained in both the plantar and von Frey tests when gabapentin was injected intracerebroventricularly (i.c.v.) or intrathecally (i.t.), suggesting that it acts at both supraspinal and spinal loci. This novel supraspinal analgesic action of gabapentin was only obtained in ligated neuropathic mice, and gabapentin (i.p. and i.c.v.) did not affect acute thermal and mechanical nociception. 4. In mice in which central NA levels were depleted by 6-OHDA, the antihyperalgesic and antiallodynic effects of i.p. and i.c.v. gabapentin were strongly suppressed. 5. The antihyperalgesic and antiallodynic effects of systemic gabapentin were reduced by both systemic and i.t. administration of yohimbine, an alpha2-adrenergic receptor antagonist. By contrast, prazosin (i.p. or i.t.), an alpha1-adrenergic receptor antagonist, did not alter the effects of gabapentin. 6. It was concluded that the antihyperalgesic and antiallodynic effects of gabapentin are mediated substantially by the descending noradrenergic system, resulting in the activation of spinal alpha2-adrenergic receptors.

Involvement of Supraspinal Imidazoline Receptors and Descending Monoaminergic Pathways in Tizanidine-Induced Inhibition of Rat Spinal Reflexes

The neuronal pathways involved in the muscle relaxant effect of tizanidine were examined by measurement of spinal reflexes in rats. Tizanidine (i.v. and intra-4th ventricular injection) decreased the mono- and disynaptic (the fastest polysynaptic) reflexes (MSR and DSR, respectively) in non-spinalized rats. Depletion of central noradrenaline by 6-hydroxydopamine abolished the depressant effect of tizanidine on the MSR almost completely and attenuated the effect on the DSR. Co-depletion of serotonin by 5,6-dihydroxytryptamine and noradrenaline resulted in more prominent attenuation of tizanidine-induced inhibition of the DSR. Supraspinal receptors were then studied using yohimbineand some imidazoline-receptor ligands containing an imidazoline moiety. Idazoxan (I1, I2, I3, and α2), efaroxan (I1, I3, and α2), and RX821002 (I3 and α2), but not yohimbine, an α2-adrenergic receptor antagonist with no affinity for I receptors, antagonized the inhibitory effects of tizanidine. Thus, supraspinal I receptors (most likely I3) and descending monoaminergic influences are necessary for tizanidine-induced inhibition of spinal segmental reflexes.

Effects of low dose N-(2-chloroethyl)- N-ethyl-2-bromobenzylamine administration on exploratory and amphetamine-induced behavior and dopamine D 2 receptor function in rats with high or low exploratory activity

Individual differences in behavioral traits are associated with sensitivity to various neurochemical and psychopharmacological manipulations. In this study exploratory and amphetamine-induced behavior in rats with persistently high or low exploratory activity (HE and LE, respectively) was examined before and after a partial denervation of the locus coeruleus (LC) projections with the selective neurotoxin DSP-4 ( N-(2-chloroethyl)- N-ethyl-2-bromobenzylamine; 10 mg/kg). Partial LC denervation prevented the increase in exploratory activity over repeated test sessions in the LE animals, but had no effect in HE-rats. Amphetamine- (0.5 mg/kg) induced locomotor activity was attenuated by DSP-4 pretreatment only in HE-rats. These results suggest differential involvement of LC noradrenergic transmission in novelty- and amphetamine-induced behavior in animals with persistent differences in novelty-related behavior. In addition to partial noradrenaline depletion in the frontal cortex and hippocampus, which occurred in both HE- and LE-rats, DSP-4 treatment also decreased the content of dopamine and its metabolites in the nucleus accumbens, and the metabolite levels in striatum, but only in the LE-animals. 5-HIAA levels were also reduced in the nucleus accumbens and striatum in LE-rats by the neurotoxin. D 2 receptor function, as determined by dopamine-stimulated [ 35S]GTPγS binding, was increased by DSP-4 treatment in the striatum of LE-rats, but reduced in HE-rats. No effect of partial LC denervation was found on dopamine-stimulated [ 35S]GTPγS binding in the nucleus accumbens. Together these findings suggest that LC noradrenergic neurotransmission is differently involved in dopaminergic mechanisms which mediate novelty-related vs amphetamine-induced behavior.

Effects of 25 mT static magnetic field on blood pressure in reserpine‐induced hypotensive Wistar‐Kyoto rats

We investigated the interrelated antihypotensive effects of static magnetic fields (SMF) and plasma catecholamine levels in reserpine-induced hypotensive Wistar-Kyoto rats. Seven-week-old male rats were exposed to two different ranges of SMF intensities, 3.0-10 mT (Bmax) or 7.5-25 mT (Bmax) for 12 weeks. Six experimental groups of 10 animals each were examined: (1) no exposure with intraperitoneal (ip) saline injection (sham exposed control); (2) 10 mT SMF exposure with ip saline injection (10 mT); (3) 25 mT SMF exposure with ip saline injection (25 mT); (4) no exposure with ip reserpine injection (RES); (5) 10 mT SMF exposure with ip reserpine injection (10 mT + RES); (6) 25 mT SMF exposure with ip reserpine injection (25 mT + RES). Reserpine (5 mg/kg) was administered three times a week for 12 weeks, and 18 h after each injection, arterial blood pressure (BP), heart rate, skin blood flow, plasma nitric oxide metabolites, plasma catecholamine levels, and behavioral parameters of a functional observational battery (FOB) were monitored. The action of reserpine significantly decreased BP, reduced plasma norepinephrine (NE), increased the FOB hunched posture score and decreased the number of rearing events in the RES group, compared with the respective age-matched control group. Exposure to 25 mT, but not 10 mT, for 2-12 weeks significantly prevented the reserpine-induced decrease of BP in the 25 mT + RES group compared with the respective RES group. Moreover, exposure to 25 mT for 5 weeks partially suppressed the reserpine-induced NE reduction, but did not bring about a complete reversal of reserpine effects. NE levels for the 25 mT + RES group for 5 weeks were significantly higher compared with the RES group, but still lower compared with the control group. In addition, the FOB hunched posture score for the 25 mT + RES group was significantly lower and the number of rearing events was higher compared with the RES group, but these behavioral parameters did not revert to control levels. There were no significant differences in any of the physiological or behavioral parameters measured between the 10 mT + RES and RES groups, nor between the two different SMF groups and the control group. These results indicate that 25 mT SMF with spatial gradients significantly suppressed the reserpine-induced hypotension and bradykinesia. The antihypotensive effects of SMF on the reserpine-treated group might be at least partially related to the inhibition of NE depletion.

Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats.

5-Hydroxytryptamine (serotonin) (5-HT) and norepinephrine (NE) are implicated in modulating descending inhibitory pain pathways in the central nervous system. Duloxetine is a selective and potent dual 5-HT and NE reuptake inhibitor (SNRI). The ability of duloxetine to antagonize 5-HT depletion in para-chloramphetamine-treated rats was comparable with that of paroxetine, a selective serotonin reuptake inhibitor (SSRI), whereas its ability to antagonize NE depletion in alpha-methyl-m-tyrosine-treated rats was similar to norepinephrine reuptake inhibitors (NRIs), thionisoxetine or desipramine. In this paradigm, duloxetine was also more potent than other SNRIs, including venlafaxine or milnacipran and amitriptyline. Low doses of the SSRI paroxetine or the NRI thionisoxetine alone did not have an effect on late phase paw-licking pain behavior in the formalin model of persistent pain; however, when combined, significantly attenuated this pain behavior. Duloxetine (3-15 mg/kg intraperitoneal) significantly attenuated late phase paw-licking behavior in a dose-dependent manner in the formalin model and was more potent than venlafaxine, milnacipran, and amitriptyline. These effects of duloxetine were evident at doses that did not cause neurologic deficits in the rotorod test. Duloxetine (5-30 mg/kg oral) was also more potent and efficacious than venlafaxine and milnacipran in reversing mechanical allodynia behavior in the L5/L6 spinal nerve ligation model of neuropathic pain. Duloxetine (3-30 mg/kg oral) was minimally efficacious in the tail-flick model of acute nociceptive pain. These data suggest that inhibition of both 5-HT and NE uptake may account for attenuation of persistent pain mechanisms. Thus, duloxetine may have utility in treatment of human persistent and neuropathic pain states.

Bone marrow norepinephrine mediates development of functionally different macrophages after thermal injury and sepsis.

We sought to determine the influence of thermal (burn) injury with sepsis and norepinephrine on the clonogenic potential and functional cytokine response to lipopolysaccharide (LPS) stimulation in nonmyeloid committed (CD117) and myeloid committed (ER-MP12) bone marrow progenitor cells. We have previously demonstrated that norepinephrine stimulated myelopoiesis after burn injury and sepsis, but the site of this stimulation in monocyte development is unknown. In the present study the influence of norepinephrine on the developmental hierarchy of bone marrow cells after thermal injury and sepsis was determined by assessing the clonogenic potential and LPS-stimulated cytokine responses of mature macrophages derived from CD117 and ER-MP12 bone marrow progenitor cells. Tissue and bone marrow norepinephrine content was ablated by chemical sympathectomy with 6-hydroxydopamine treatment. CD117 and ER-MP12 bone marrow cells were isolated using antibody-linked magnetic microbeads. Clonogenic potential in response to colony-stimulating factors was determined. Both progenitor cell types were differentiated to mature macrophages in vitro and tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 cytokine responses to LPS provocation were determined. The macrophage- and granulocyte-macrophage colony-stimulating factor responsive clonogenic potential was increased with burn sepsis, suggesting an expansion of both progenitor populations. Such increases were greatly reduced with prior depletion of norepinephrine. TNF-alpha and IL-6 cytokine responses to LPS were markedly influenced by the specific progenitor cells involved as well as the injury conditions and the status of norepinephrine prior to injury. In burn sepsis the depletion of norepinephrine resulted in a dramatic decrease in both IL-6 and TNF-alpha production by both progenitor-derived macrophages. Depletion of norepinephrine attenuated burn and burn sepsis-induced bone marrow progenitor clonal growth in response to macrophage- and granulocyte-macrophage colony-stimulating factor. Functional phenotypes of bone marrow progenitor-derived macrophages are greatly influenced by norepinephrine and the milieu created by thermal injury and sepsis.

Lamina-selective changes in the density of synapses following perturbation of monoamines and acetylcholine in the rat medial prefrontal cortex

The rat medial prefrontal cortex is known to have diverse brain functions such as learning and memory, attention, and behavioral flexibility. Although these functions are affected by monoamines (dopamine (DA), noradrenaline (NA) and serotonin (5-HT)) and acetylcholine (ACh), the detailed mechanisms remain unclear. These neuromodulators also have effects on synapse formation and maintenance, and regulate plasticity in the central nervous system (CNS). To clarify the effects of these neuromodulators on changes in the density of synapses in the rat medial prefrontal cortex, we separately administered a D1- or D2-antagonist, NA neurotoxin, 5-HT synthetic inhibitor, or muscarinic ACh antagonist for 1 week, and counted the number of synapses on electron microscopic photographs taken from the prelimbic area of the medial prefrontal cortex. The density of synapses in lamina I was regulated by DA via D1-like receptors, and that in laminae II/III was decreased by depletion of NA or ACh. However, 5-HT did not have a regulatory effect on the synaptic density throughout the layers in this brain region. The data in this study and our previous studies indicate that there are appreciable regional differences in the magnitude of biogenic amine-mediated synaptic plasticity in the rat CNS. These neuromodulators may have a trophic-like effect on the selected neuronal circuit to maintain synaptic contacts in the rat CNS. The synaptic density in the medial prefrontal cortex regulated by monoamines and ACh could be important not only for synaptic plasticity in this region but also for pharmacotherapeutic drug treatment.

A Central Role for Norepinephrine in the Modulation of Cerebellar Learning Tasks

Norepinephrine (NE) is a central nervous system neuromodulator that enhances the actions of other neurotransmitters such as gamma-aminobutyric acid and glutamate. Based on the Marr-Albus theories, Gilbert suggested that NE influences consolidation of cerebellar learning. NE depletion or blockade of postsynaptic noradrenergic receptors decreases the rate of learning in several cerebellar-dependent learning tasks. Loss of cerebellar beta-adrenergic receptor function correlates with a loss of function in related learning tasks. Interventions that improve beta-adrenergic receptor function also improve performance in cerebellum-dependent learning tasks. Thus, the authors propose that NE has a central role in the modulation of learning within the cerebellum.

Lamina-selective changes in the density of synapses following perturbation of monoamines and acetylcholine in the rat medial prefrontal cortex

The rat medial prefrontal cortex is known to have diverse brain functions such as learning and memory, attention, and behavioral flexibility. Although these functions are affected by monoamines (dopamine (DA), noradrenaline (NA) and serotonin (5-HT)) and acetylcholine (ACh), the detailed mechanisms remain unclear. These neuromodulators also have effects on synapse formation and maintenance, and regulate plasticity in the central nervous system (CNS). To clarify the effects of these neuromodulators on changes in the density of synapses in the rat medial prefrontal cortex, we separately administered a D1- or D2-antagonist, NA neurotoxin, 5-HT synthetic inhibitor, or muscarinic ACh antagonist for 1 week, and counted the number of synapses on electron microscopic photographs taken from the prelimbic area of the medial prefrontal cortex. The density of synapses in lamina I was regulated by DA via D1-like receptors, and that in laminae II/III was decreased by depletion of NA or ACh. However, 5-HT did not have a regulatory effect on the synaptic density throughout the layers in this brain region. The data in this study and our previous studies indicate that there are appreciable regional differences in the magnitude of biogenic amine-mediated synaptic plasticity in the rat CNS. These neuromodulators may have a trophic-like effect on the selected neuronal circuit to maintain synaptic contacts in the rat CNS. The synaptic density in the medial prefrontal cortex regulated by monoamines and ACh could be important not only for synaptic plasticity in this region but also for pharmacotherapeutic drug treatment.

Effects of Norepinephrine Depletion in Rats During Cerebral Post-ischemic Reperfusion

The present paper reports the effects of norepinephrine depletion in rats, after treatment with N-(2-chloroethyl)- N-ethyl 2-bromobenzylamine (DSP-4) neurotoxin, on partial cerebral ischemia and reperfusion. Histological observations made under experimental conditions of noradrenergic (NA)-depletion demonstrated that neuronal lesions were not exacerbated; in fact, in DSP-4-treated ischemic animals, a minor number of neurons appeared damaged. Our results suggest that neuronal recovery after post-ischemic reperfusion is not affected by NA-depletion. DSP-4 neurotoxin does not induce 5-hydroxy-triptamine (5-HT) depletion.

Serotonin reuptake inhibitors do not prevent 5,7-dihydroxytryptamine-induced depletion of serotonin in rat brain

Although the selective toxicity of 5,7-dihydroxytryptamine (5,7-DHT) is thought to depend on the drug's transport into serotonin (5HT) neurons via the 5HT transporter, few studies have critically examined this postulation. We therefore evaluated if 5,7-DHT-induced reductions in 5HT concentrations and synthesis rate in rat brain are blocked by pretreatment with 5HT-selective reuptake inhibitors. Rats pretreated with desipramine (DMI) (to prevent norepinephrine depletion) received intracerebroventricular injections of 5,7-DHT (5, 50, 100, 200 μg/rat) 30 min after fluoxetine (20 mg/kg ip). Forty-eight hours later, they received m-hydroxybenzylhydrazine 30 min before sacrifice. The concentrations of 5HT and 5-hydroxytryptophan (5HTP, an index of 5HT synthesis) were measured in hypothalamus, cortex and brainstem. Each 5,7-DHT dose produced significant reductions in 5HT and 5HTP concentrations in all regions examined (5 μg reduced 5HT but not 5HTP), effects that were not blocked by fluoxetine. Two other 5HT reuptake blockers (chlorimipramine, alaproclate) also failed to block the 5HT and 5HTP depleting actions of 5,7-DHT. Desipramine blocked 5,7-DHT-induced norepinephrine (NE) depletion. Pretreatment with the 5HT receptor antagonist metergoline, or the 5HT 1A agonist 8-hydroxy-(di- n-propylamino)tetralin (to slow 5HT neuronal firing rate) also failed to antagonize the 5HT depleting action of 5,7-DHT. Together, the data strongly suggest that the mechanism by which 5,7-DHT depletes the brain of serotonin does not involve 5HT-transporter-mediated concentration of neurotoxin in 5HT neurons, may not involve 5HT receptor interaction, and does not depend on the firing rate of the 5HT neuron.

Infarction alters both the distribution and noradrenergic properties of cardiac sympathetic neurons.

Regional changes occur in the sympathetic innervation of the heart after myocardial infarction (MI), including loss of norepinephrine (NE) uptake and depletion of neuronal NE. This apparent denervation is accompanied by increased cardiac NE spillover. One potential explanation for these apparently contradictory findings is that the sympathetic neurons innervating the heart are exposed to environmental stimuli that alter neuronal function. To understand the changes that occur in the innervation of the heart after MI, immunohistochemical, biochemical, and molecular analyses were carried out in the heart and stellate ganglia of control and MI rats. Immunohistochemistry with panneuronal markers revealed extensive denervation in the left ventricle (LV) below the infarct, but sympathetic nerve fibers were retained in the base of the heart. Western blot analysis revealed that tyrosine hydroxylase (TH) expression (normalized to a panneuronal marker) was increased significantly in the base of the heart and in the stellate ganglia but decreased in the LV below the MI. NE transporter (NET) binding sites, normalized to total protein, were unchanged, except in the LV, where [3H]nisoxetine binding was decreased. TH mRNA was increased significantly in the left and right stellate ganglia after MI, while NET mRNA was not. In the base of the heart, increased TH coupled with no change in NET may explain the increase in extracellular NE observed after MI. Coupled with substantial denervation in the LV, these changes likely contribute to the onset of cardiac arrhythmias.

Psychological stress exerts an adjuvant effect on skin dendritic cell functions in vivo.

Psychological stress affects the pathophysiology of infectious, inflammatory, and autoimmune diseases. However, the mechanisms by which stress could modulate immune responses in vivo are poorly understood. In this study, we report that application of a psychological stress before immunization exerts an adjuvant effect on dendritic cell (DC), resulting in increased primary and memory Ag-specific T cell immune responses. Acute stress dramatically enhanced the skin delayed-type hypersensitivity reaction to haptens, which is mediated by CD8(+) CTLs. This effect was due to increased migration of skin DCs, resulting in augmented CD8(+) T cell priming in draining lymph nodes and enhanced recruitment of CD8(+) T cell effectors in the skin upon challenge. This adjuvant effect of stress was mediated by norepinephrine (NE), but not corticosteroids, as demonstrated by normalization of the skin delayed-type hypersensitivity reaction and DC migratory properties following selective depletion of NE. These results suggest that release of NE by sympathetic nerve termini during a psychological stress exerts an adjuvant effect on DC by promoting enhanced migration to lymph nodes, resulting in increased Ag-specific T cell responses. Our findings may open new ways in the treatment of inflammatory diseases, e.g., psoriasis, allergic contact dermatitis, and atopic dermatitis.