Depletion Of Norepinephrine Research Articles

Differential vulnerability of snake species to MPTP:: A behavioral and biochemical comparison in ratsnakes ( Elaphe) and watersnakes ( Nerodia)

The synthetic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a Parkinsonian-like syndrome in humans and nonhuman primates, and also causes movement disorders in rodents, fish, amphibians and lizards. To date, the effects of MPTP have not been characterized in snakes. In this study, the behavioral and biochemical effects of MPTP were assessed in the black ratsnake Elaphe o. obsoleta and the banded watersnake Nerodia f. fasciata—species that display contrasting behavioral sensitivities to dopaminergic antagonists and to amphibian toxins. We report that MPTP induces depletion of norepinephrine and serotonin in fore, mid and hindbrain regions and depletion of dopamine in fore and midbrain regions in E.o. obsoleta. MPTP also induced a marked reduction in righting ability in E.o. obsoleta. In N.f. fasciata, norepinephrine and dopamine were depleted by MPTP in all three brain regions and serotonin was only significantly reduced in the forebrain. In contrast to E.o. obsoleta, N.f. fasciata demonstrated no behavioral disorders. This study demonstrates a behavioral and biochemical sensitivity to MPTP in E.o. obsoleta that differs from that in N.f. fasciata. The differential sensitivities to monoaminergic modulation may be related to the contrasting diets of these species.

Catecholamine depletion by reserpine blocks the anxiolytic actions of ethanol in the rat

Neurochemical investigations of the anti-anxiety action of ethanol demonstrate that increased dopaminergic, noradrenergic, and serotonergic activity mediates the anxiolytic actions of ethanol. Results of studies with animals and human beings also confirm an involvement of the sympathetic nervous system in the behavioral actions of ethanol. Because enhanced sympathetic activity increases the release of norepinephrine from sympathetic terminals, the interruption of normal sympathetic activity might disrupt the anxiolytic action of ethanol. The present study examined the effect of chemical sympathectomy by reserpine pretreatment on the subsequent anxiolytic action of ethanol. Seventy-one, female, Sprague–Dawley rats were administered reserpine (0 or 5 mg/kg), followed 17–19 h later by ethanol (0, 0.5, or 1.0 g/kg). Animals were then tested in the elevated plus maze. Compared with saline pretreatment, which did not attenuate the anxiolytic actions of a 1.0-g/kg dose of ethanol, reserpine pretreatment completely blocked the anxiolytic action of a 1.0-g/kg dose of ethanol. Reserpine, by itself, did not possess anxiolytic or anxiogenic actions. Because the anxiolytic action of ethanol involves increased catecholamine activity and the depletion of norepinephrine and dopamine from sympathetic nerve terminals by reserpine blocked the anxiolytic action of ethanol, it is concluded that the anxiolytic action of ethanol requires the presence of normal catecholamine activity. We suggest that prostaglandin activity normally evoked by enhanced sympathetic nervous system activity might be involved in the anxiolytic action of ethanol.

Comparative Affinity of Duloxetine and Venlafaxine for Serotonin and Norepinephrine Transporters in vitro and in vivo, Human Serotonin Receptor Subtypes, and Other Neuronal Receptors

The blockade of serotonin (5-HT) and norepinephrine (NE) transporters in vitro and in vivo by the dual 5-HT/NE reuptake inhibitors duloxetine and venlafaxine was compared. Duloxetine inhibited binding to the human NE and 5-HT transporters with Ki values of 7.5 and 0.8 nM, respectively, and with a Ki ratio of 9. Venlafaxine inhibited binding to the human NE and 5-HT transporters with Ki values of 2480 and 82 nM, respectively, and with a Ki ratio of 30. Duloxetine inhibited ex vivo binding to rat 5-HT transporters and NE transporters with ED50 values of 0.03 and 0.7 mg/kg, respectively, whereas venlafaxine had ED50 values of 2 and 54 mg/kg, respectively. The depletion of rat brain 5-HT by p-chloramphetamine and depletion of rat hypothalamic NE by 6-hydroxydopamine was blocked by duloxetine with ED50 values of 2.3 and 12 mg/kg, respectively. Venlafaxine had ED50 values of 5.9 and 94 mg/kg for blocking p-chloramphetamine– and 6-hydroxydopamine–induced monoamine depletion, respectively. Thus, duloxetine more potently blocks 5-HT and NE transporters in vitro and in vivo than venlafaxine.

Uraemia suppresses central dopaminergic metabolism and impairs motor activity in rats.

Uraemia often provokes various neurological disorders, such as mental changes, malperception, confusion, seizures and coma. Since changes in neurotransmissions induce neurological symptoms, we investigated changes in the monoamine metabolism and motor activity in uraemic rats. Prospective, randomised, controlled animal study. Male Wistar rats. Acute renal failure was induced by occlusion of bilateral renal arteries for 60 min, and the motor activity and brain monoamine turnover were examined 48 h later. The brain monoamine turnover was evaluated by the depletion of norepinephrine (NE) and dopamine (DA) induced by alpha-methyl-p-tyrosine (alpha-MT), or the accumulation of 5-hydroxyindoleacetic acid (5-HIAA) induced by probenecid. Marked damage in renal function was found in animals subjected to renal ischaemia 48 h after the operation. The motor activity of the uraemic rats was impaired. The turnover of DA in the striatum, mesencephalon and hypothalamus was decreased in these rats. The turnover of NE and 5-hydroxytryptamine (5-HT) was unchanged in all regions examined. Suppression of the central DA turnover appears to be involved in the impairment of motor activity in uraemic rats.

Biological Perspectives

Adrenergic Receptors There are many adrenergic receptors in the human body. The appropriately named fight-or-flight response is a system of messages and codes that assists the body in dealing with crises requiring heightened levels of somatic activity (Martini, 1998). The sympathetic division of the autonomic nervous system (ANS) enables the body to handle this type of stress. Activation of the sympathetic nervous system stimulates membrane proteins known as adrenergic receptors. These receptors are sensitive to the catecholamines norepinephrine and epinephrine. Adrenergic receptors can be grouped into two main systems of the body: the central nervous system (CNS) and the peripheral nervous system. While the primary emphasis of this article is central functions, peripheral adrenergic receptor function is of interest due to adverse responses to psychotropic agents, which are mediated by these receptors. Central Adrenergic Receptors Norepinephrine (NE) is produced in the CNS. There are two central norepinephrine or noradrenergic systems. The first and best recognized NE system is found in a group of pontine pigmented neurons called the locus ceruleus. It contains about half the total number of norepinephrine-synthesizing neurons in the brain. The second NE system begins in the lateral tegmentum of the medulla. NE fibers from both the pons and the medulla travel pathways to synapse with adrenergic receptors in the spinal cord; brain stem, cerebellum, diencephalon, basal forebrain (i.e., the septum, amygdala, olfactory bulbs, and hippocampus), limbic area, and the cortex. Because NE plays an important role in the psychiatric realm of health, damage to this area of the brain can have serious repercussions, especially in disorders that have a mood component. In addition, because of the extensive connection that the locus ceruleus makes with the hippocampus and cortex, the adrenergic nervous system has been implicated in mechanisms that underlie cortical activation, learning, memory, and attention (Cameron, 1994). Depressive illness was first recognized as a biochemical phenomenon in 1965, when Schildkraut published an article describing what he called the catecholamine hypothesis of depression. Over the years, Schildkraut's hypothesis was broadened to the monoamine hypothesis (which included serotonin) and then to the monoamine receptor hypothesis of depression (Stahl, 1998). Stahl suggests it is not the increase in intrasynaptic monoamine availability that accounts for the effectiveness of antidepressants, but rather the changes (i.e., downregulation) in adrenergic receptors. In 1948 Alquist classified adrenergic responses and receptors into two overarching categories, alpha and beta (Insel, 1987), subsequently refined further to include alpha-l, alpha-2, beta-l, and beta-2. Alpha-1 and beta-1 receptors are located throughout the cerebrum and in the diencephalon. Depletion of NE, whether drug induced (e.g., reserpine) or idiopathic, has been associated consistently with an increase in both alpha-1 and beta-1 receptor sites. Long-term use of antidepressants downregulate alpha-1 and beta-1 receptors (a decrease in numbers and sensitivity). This change occurs after 2 to 4 weeks of therapy, or roughly about the same amount of time required for a clinical response to occur. Alpha-2 receptors are located in the cortex, limbic system, and locus ceruleus. Alpha-2 receptors serve as autoreceptors and, when stimulated, decrease the release of NE. While peripheral alpha-2 receptors are located presynaptically, centrally they are located postsynaptically. The mechanism by which they influence presynaptic neurons to release or not release NE from their postsynaptic position is not clear. Peripheral Adrenergic Receptors There are three primary neurotransmitters in the peripheral nervous system: NE, epinephrine, and acetylcholine (dopamine receptors play a less important role peripherally). …

Synthesis of N-propargylphenelzine and analogues as neuroprotective agents

A series of N 1- and N 2-propargylphenelzine derivatives and analogues ( 1– 7) was synthesized. In addition to their activity as monoamine oxidase inhibitors, two of the compounds, N 1- and N 2-propargylphenelzines ( 3 and 6), were found to be potent at preventing DSP-4-induced noradrenaline (NA) depletion in mouse hippocampus, suggesting that they have neuroprotective properties.

Medullary A1 noradrenergic neurones may mediate oxytocin release after noxious stimuli.

Noxious stimuli facilitate oxytocin release from the pituitary. Oxytocin cells receive excitatory synaptic inputs from the noradrenergic neurones located in the medulla oblongata. Oxytocin release after noxious stimuli is blocked by noradrenaline depletion in the brain. Here, we examined effects of noxious stimuli upon noradrenaline release within the supraoptic nucleus. Electric footshocks or mustard oil application to the foot pad facilitated noradrenaline release in the nucleus. Noradrenaline release after noxious stimuli was impaired by microinjections with a GABA(A) receptor agonist, muscimol, or an alpha 2 adrenoceptor agonist, clonidine, into the A1 noradrenergic cell regions. From these and reported data, we conclude that the medullary A1 noradrenergic neurones contribute, at least in part, to oxytocin release from the pituitary after noxious stimuli.

Effects of central noradrenaline depletion by the selective neurotoxin DSP-4 on the behaviour of the isolated rat in the elevated plus maze and water maze.

Social isolation of the rat from weaning influences behaviour following central noradrenaline (NA) depletion by the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). The study characterised the effects of DSP-4 on the behaviour of isolates in the elevated plus maze and water maze. Male Lister hooded rats were reared singly or in groups after weaning. Two weeks postweaning, the rats were injected with DSP-4 (25 mg/kg, i.p.) or saline. From week 4, rats were tested in the plus maze and in the water maze. DSP-4 significantly reduced cortical and hippocampal NA but had no effect on hypothalamic NA. Isolation rearing alone had no significant effects on behaviour in the elevated plus maze but enhanced retention of platform placement in the water maze as measured by increased entries to the platform annulus during the probe test. DSP-4 in group-reared rats increased activity in the open arms and increased general activity in the elevated plus maze with no effect on water maze performance. DSP-4-treated isolates spent less time in the open arms and were hypoactive in the plus maze compared to group-reared DSP-4-treated rats, and had impaired retention of spatial memory in the water maze compared to isolate controls. DSP-4 treatment had an 'anxiolytic' effect in group-reared rats in the elevated plus maze. In the water maze, isolation rearing enhanced retention of spatial information, an effect normalised by NA depletion. The results demonstrate the importance of noradrenergic function in the regulation of responsiveness to environmental cues.

Monoamine oxidase inhibition and neuroprotection by N1‐propargylphenelzine

AbstractThe ability of N1‐propargylphenelzine and related N1‐propargylhydrazines to inhibit monoamine oxidase‐A (MAO‐A) and ‐B (MAO‐B) and to prevent N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP‐4)‐induced noradrenergic neurotoxicity was examined. N1‐Propargylphenelzine strongly inhibited MAO‐A and MAO‐B in in vitro assays using rat brain or liver as the enzyme source. In ex vivo studies in rats, both intraperitoneal and oral administration of N1‐propargylphenelzine strongly inhibited brain and liver MAO‐A and MAO‐B. The extent of ex vivo MAO inhibition and increased levels of noradrenaline and 5‐hydroxytryptamine by N1‐propargylphenelzine was comparable to that of phenelzine. Unlike phenelzine, however, N1‐propargylphenelzine did not elevate γ‐aminobutryic acid (GABA) concentrations in rat brain. A single intraperitoneal administration of N1‐propargylphenelzine to mice, 1 week prior to sacrifice, reduced DSP‐4‐induced depletion of noradrenaline in the hippocampus. The brains of N1‐propargylphenelzine‐treated mice from the DSP‐4 neurotoxicity experiments had normal MAO‐B activity, but MAO‐A was significantly inhibited; this was in contrast to animals that had received (–)‐deprenyl, who showed normal MAO‐A activity but a decrease of MAO‐B. The present results indicate that N1‐propargylphenelzine may be a useful neuroprotective compound with a long‐term in vivo propensity to inhibit MAO‐A. Drug Dev. Res. 53:15–21, 2001. © 2001 Wiley‐Liss, Inc.

Protective effect of 7-nitroindazole against DSP-4 induced noradrenaline depletion in mouse hippocampus.

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) is a selective noradrenaline (NA) uptake blocker, capable of inducing a long-lasting depletion of NA in some noradrenergic axon terminals originating from the locus coeruleus in rodents. Pretreatment with 7-nitroindazole, a fairly selective inhibitor of neuronal nitric oxide synthase in vivo, partially prevented DSP-4 induced NA depletion in mouse hippocampus measured seven days after the neurotoxic insult. Administration of L-arginine, the substrate of nitric oxide synthase, altered neither the NA depletion induced by DSP-4, nor the protective effect of 7-nitroindazole. Inhibition of nitric oxide synthesis by N(G)-nitro-L-arginine methyl ester did not attenuate the NA depleting effect of DSP-4. Thus, the contribution of neuronal nitric oxide synthase inhibition to the protective effect of 7-nitroindazole needs further studies. As 7-nitroindazole did not block NA uptake, this cannot play a part in the protective effect. The possible contribution of monoamine oxidase B enzyme inhibition by 7-nitroindazole to the protective effect is also discussed.

Biogenic amines in the human neocortex in patients with neocortical and mesial temporal lobe epilepsy: identification with in situ microvoltammetry

Biogenic amines in well defined subtypes of human temporal lobe epilepsy (TLE) have not been well characterized. Specimens from five patients with neocortical TLE (NTLE) and nine with mesial TLE (MTLE) were immediately placed in Ringer’s lactate; stearate indicator microelectrodes were placed in temporal gray matter, Ag/AgCl reference microelectrodes and auxiliary microelectrodes were placed 3–7 mm contralaterally to the indicator microelectrode. Dopamine (DA), ascorbic acid (AA), norepinephrine (NE) and serotonin (5-HT) were identified by their characteristic oxidative potentials in vitro. Four of five patients with NTLE had NE depletion in temporal neocortex while eight of nine patients with MTLE had high concentrations of NE (chi-square P<0.01). Significant concentrations of DA were present in the temporal lobes of three of five NTLE patients but in only one of the nine MTLE patients (chi-square P<0.05). 5-HT was present in the neocortex of both NTLE and MTLE patients in similar concentrations. AA was found in the neocortex of one NTLE patient. These data support an association between NE depletion and NTLE. The relative NE deficiency along with the consistent presence of DA in NTLE patients suggest an impairment in the catecholamine pathway. The presence of AA, a co-factor in NE synthesis, in the neocortex of one NTLE patient may also be related since AA is a cofactor in NE synthesis.

Brain alpha(2)-adrenoceptors in monoamine-depleted rats: increased receptor density, G coupling proteins, receptor turnover and receptor mRNA.

1. This study was designed to assess the molecular and cellular events involved in the up-regulation (and receptor supersensitivity) of brain alpha(2)-adrenoceptors as a result of chronic depletion of noradrenaline (and other monoamines) by reserpine. 2. Chronic reserpine (0.25 mg kg(-1) s.c., every 48 h for 6 - 14 days) increased significantly the density (B(max) values) of cortical alpha(2)-adrenoceptor agonist sites (34 - 48% for [(3)H]-UK14304, 22 - 32% for [(3)H]-clonidine) but not that of antagonist sites (11 - 18% for [(3)H]-RX821002). Competition of [(3)H]-RX821002 binding by (-)-adrenaline further indicated that chronic reserpine was associated with up-regulation of the high-affinity state of alpha(2)-adrenoceptors. 3. In cortical membranes of reserpine-treated rats (0.25 mg kg(-1) s.c., every 48 h for 20 days), the immunoreactivities of various G proteins (Galphai(1/2), Galphai(3), Galphao and Galphas) were increased (25 - 34%). Because the high-affinity conformation of the alpha(2)-adrenoceptor is most probably related to the complex with Galphai(2) proteins, these results suggested an increase in signal transduction through alpha(2)-adrenoceptors (and other monoamine receptors) induced by chronic reserpine. 4. After alpha(2)-adrenoceptor alkylation, the analysis of receptor recovery (B(max) for [(3)H]-UK14304) indicated that the increased density of cortical alpha(2)-adrenoceptors in reserpine-treated rats was probably due to a higher appearance rate constant of the receptor ((Delta)r=57%) and not to a decreased disappearance rate constant ((Delta)k=7%). 5. Northern- and dot-blot analyses of RNA extracted from the cerebral cortex of saline- and reserpine-treated rats (0.25 mg kg(-1), s.c., every 48 h for 20 days) revealed that reserpine markedly increased the expression of alpha(2a)-adrenoceptor mRNA in the brain (125%). This transcriptional activation of the receptor gene expression appears to be the cellular mechanism by which reserpine induces up-regulation in the density of brain alpha(2)-adrenoceptors.

Central beta-amyloid peptide-induced peripheral interleukin-6 responses in mice.

beta-Amyloid peptides (Abetas) share with lipopolysaccharide, a potent pro-inflammatory agent, the property of stimulating glial cells or macrophages to induce various inflammatory mediators. We recently reported that central administration of lipopolysaccharide induces peripheral interleukin-6 responses via both the central and peripheral norepinephrine system. In this study, the effect of intracerebroventricular injection of various synthetic Abetas on plasma interleukin-6 levels was examined in mice. Abeta(1-42) dose-dependently increased plasma interleukin-6 levels: 'aged' Abeta(1-42) was more effective than fresh, whereas Abeta(42-1) had no effect. 'Aged' Abeta(1-42) (205 pmol/mouse i.c.v.)-induced plasma interleukin-6 peaked at 2 h post injection, which is earlier than the peak time of the Abeta(1-42)-induced brain interleukin-6, tumor necrosis factor-alpha and interleukin-1beta levels, which was 4, 4 and 24 h, respectively. Among various peripheral organs, Abeta(1-42) (205 pmol/mouse i.c.v.) significantly increased interleukin-6 mRNA expression in lymph nodes and liver. Abeta(1-42) (205 pmol/mouse i.c.v.) significantly increased norepinephrine turnover in both hypothalamus and spleen. Either central or peripheral norepinephrine depletion effectively inhibited the Abeta(1-42)-induced peripheral interleukin-6 response. Pretreatment with prazosin (alpha(1)-adrenergic antagonist), yohimbine (alpha(2)-adrenergic antagonist), and ICI-118,551 (beta(2)-adrenergic antagonist), but not with betaxolol (beta(1)-adrenergic antagonist), inhibited Abeta(1-42)-induced plasma interleukin-6 levels. These results demonstrate that centrally administered Abeta(1-42) effectively induces the systemic interleukin-6 response which is mediated, in part, by central Abeta(1-42)-induced activation of the central and the peripheral norepinephrine systems.

Microglial response to the neurotoxicity of 6-hydroxydopamine in neonatal rat cerebellum

Depletion of noradrenaline in newborn rats by 6-hydroxydopamine (6-OHDA) affects the postnatal development and reduces the granular cell area in the neocerebellum (lobules V–VII). During the first postnatal month, Bergmann glial fibers guide the migration of immature granule cells to the internal granule cell layer. Microglia and Bergmann glia may play an important role in this process, but the exact mechanism behind this phenomenon is not known. We studied the effect of systemic administration of 6-OHDA on the expression and localization on microglia and Bermann glia in the neonatal cerebellum by immunohistochemistry. In the neocerebellum, 6-OHDA treatment caused a significant increase in the number of activated microglia. The increase was observed mainly in the granule cell layer and the cerebellar medulla. Bergmann glial cells in treated brains were abnormally located, did not form intimate associations with Purkinje cells, and the glial fibers were structurally different. Our findings indicate that a noradrenergic influence may be necessary for the normal maturation and migration of granule cells, and abnormal migration may be the result of Bergmann glia destruction and the activation of microglia. Activated microglia in the granule cell layer may be used as a marker for an injured cerebellar area.

Separation-induced body weight loss, impairment in alternation behavior, and autonomic tone: effects of tyrosine

We have investigated the effects of tyrosine on alternation behavior and hippocampal adrenergic and cholinergic tone in a model of self-induced weight loss caused by separation stress. Separation decreased body weight in mice ( P<.001) and spontaneous alternations in the T-maze ( P<.001). This impairment was associated with depletion of both norepinephrine (NE, P<.001) and dopamine ( P<.01) while increasing MHPG ( P<.05) and the ratio of MHPG/NE ( P<.05). Increasing tyrosine availability restored performance to control levels ( P<.001) and repleted dopamine ( P<.05) and presumably also NE (indicated by increases in both MHPG, P<.001, and MHPG/NE, P<.05). Stress increased adrenergic α 2-receptor density ( P<.001) without changing its K d and the B max and K d of β-receptors, suggesting that it decreased NE transmission through action on α 2-receptors. The balance between β- and α 2-receptors appeared to be related to alternation behavior as shown by the decrease ( P<.01) and increase ( P<.05) in their ratios induced by stress and tyrosine, respectively. With regard to cholinergic tone, separation stress increased M1 receptor density ( P<.05) and its mRNA signal ( P<.001). Tyrosine further increased M1 receptor density of stressed mice ( P<.05). Tyrosine might be a potential therapy for cognitive and mood problems associated with the maintenance of a reduced body weight in the treatment of obesity and in the extreme case of anorexia nervosa.

β‐Adrenergic blockade in the dentate gyrus in vivo prevents high frequency‐induced long‐term potentiation of EPSP slope, but not long‐term potentiation of population spike amplitude

High frequency (HF)-induced and norepinephrine (NE)-induced long-term potentiation have been hypothesized to utilize common mechanisms of induction and expression in the dentate gyrus. In vitro data tend to support this hypothesis, but few studies have been done in vivo. The present study records perforant path-evoked potentials simultaneously on two micropipettes, one filled with saline and the other with the beta-antagonist, timolol. Stimulation of the paragigantocellularis nucleus (PGi) was used as a method of producing NE release in the dentate gyrus, and thus, to assess the efficacy of beta-receptor blockade on the timolol pipette. Beta-blockade by timolol attenuated PGi-induced spike potentiation. HF-induced potentiation of the excitatory post-synaptic potential (EPSP) slope was also blocked by timolol, but HF-induced spike amplitude potentiation was unaffected. These results are consistent with an earlier report examining HF-long-term potentiation (LTP) following 6-OHDA-induced NE depletion, which showed that the EPSP slope LTP depended, for its full expression, on NE, but potentiation of the population spike amplitude component of HF-induced LTP did not. In the present study, PGi-induced potentiation of spike amplitude on the saline pipette was normal after HF-induced saturation of spike amplitude potentiation, suggesting that the mechanisms for expression of spike potentiation, as well as induction of spike potentiation, are separate for HF and NE stimulation.

Dorsomedial medulla is more susceptible than rostral ventrolateral medulla to hypoxic insult in cats.

We investigated the responses of systemic arterial pressure and vertebral sympathetic nerve activity to glutamate microinjections (0. 1 M, 70 nl) in the dorsomedial (DM) and the rostral ventrolateral medulla (RVLM) before hypoxia and after reoxygenation (posthypoxia) after various degrees of hypoxia in anesthetized cats. Hypoxia was produced by ventilating 5% O(2) and 95% N(2) for different durations (hypoxia I-III). In intact cats, the glutamate-induced systemic arterial pressure and vertebral nerve activity responses of the DM were depressed after all degrees of hypoxia. Posthypoxic depression in the RVLM, however, was not observed until hypoxia II and III. Precollicular decerebration prevented depression in the RVLM, but, for the DM, it was effective only for hypoxia I. Baro- and chemoreceptor denervation abolished all posthypoxic depression in both the DM and the RVLM. Pressor responses to tyramine (100-400 microg/kg iv) remained unchanged after all degrees of hypoxia. These results suggest that the DM is more susceptible to hypoxia than the RVLM. The peripheral baro- and chemoreceptors and the suprapontine structures apparently play an important role in posthypoxic depression. Moreover, the depression is not due to the postganglionic norepinephrine depletion.

Depletion of brain norepinephrine does not reduce spontaneous ambulatory activity of rats in the home cage

6-Hydroxydopamine (6-OHDA) lesions of brain noradrenergic neurons and terminals were made in rats to assess the importance of forebrain norepinephrine (NE) for mediating circadian patterns of spontaneous ambulatory activity that rats show in the home cage. 6-OHDA was injected intracranially into the fibers of the ascending noradrenergic dorsal and ventral bundle pathways or infused into the lateral ventricle or both. Rats living in a 12/12 h light/dark cycle exhibit a marked increase in ambulatory activity during the dark period in comparison to the light period and a ‘W-shaped’ pattern of activity during the 12 h of the dark phase. Results showed that near-total depletion of brain NE did not impair the capacity to generate normal patterns of spontaneous ambulatory activity that occur in the home cage. In the animals that sustained the most complete NE lesions, the amounts of activity generated at times of peak activity were exaggerated in comparison to the control animals, which is consistent with the possibility that NE in the brain exerts a moderating influence on behavior.

Intrathecal S-nitroso- N-acetylpenicillamine and l-cysteine attenuate nerve injury-induced allodynia through noradrenergic activation in rats

Spinal norepinephrine release and activation of spinal α 2-adrenergic receptors represent important components of descending control of nociception. Recent studies have shown that nitric oxide is capable of stimulating neuronal norepinephrine release in the presence of thiol-containing compounds such as l-cysteine. In the present study, we tested a hypothesis in a rodent model of neuropathic pain that intrathecal injection of the nitric oxide donor S-nitroso- N-acetylpenicillamine and l-cysteine produces an antiallodynic action mediated by the spinal α 2-adrenergic receptors. Allodynia was induced in rats by ligation of the left lumbar L5/L6 spinal nerves. Mechanical allodynia was quantified by application of von Frey filaments to the left hindpaw. Intrathecal injection of 20–100 μg of S-nitroso- N-acetylpenicillamine in the presence of 200 μg of l-cysteine, but not d-cysteine, dose-dependently attenuated the allodynia. Intrathecal injection of a combination of 100 μg of S-nitroso- N-acetylpenicillamine and 50–200 μg of l-cysteine also inhibited the allodynia in a dose-dependent manner. Pretreatment with a nitric oxide scavenger, carboxy-PTIO, or depletion of norepinephrine with a specific neurotoxin, N-(2-chloroethyl)- N-ethyl-2-bromobenzylamine, prevented the antiallodynic action of intrathecal S-nitroso- N-acetylpenicillamine and l-cysteine. Furthermore, the antiallodynic effect produced by intrathecal injection of a combination of S-nitroso- N-acetylpenicillamine and l-cysteine was abolished by pretreatment with intrathecal injection of a non-specific α-adrenergic receptor antagonist, phentolamine, or an α 2 receptor antagonist, idazoxan. This study provides the first functional evidence that spinal nitric oxide interacts with the thiol-containing compounds to produce an antiallodynic effect in neuropathic pain. We propose that such an action is mediated by endogenous norepinephrine and spinal α 2-adrenergic receptors.

In vivo characterization of the novel neuropeptide Y Y1 receptor antagonist H 409/22.

We studied the effects of the novel neuropeptide Y (NPY) Y1 receptor antagonist H 409/22, and its inactive enantiomer H 510/45, on vascular responses evoked by endogenous and exogenous NPY in the pig in vivo. H 409/22 and H 510/45 were given as 30-min infusions, and the antagonistic effects and circulating plasma concentrations were measured. The initial and terminal half-lives of H 409/22 in plasma were approximately 3 and 30 min, respectively. In pigs pretreated with reserpine and transection of sympathetic nerves (depletion of noradrenaline), sympathetic nerve stimulation evoked nonadrenergic vasoconstrictor responses in kidney and hindlimb, mediated by neuronally released NPY. Significant inhibition of these vasoconstrictor responses, as well as of vascular responses to injections of exogenous NPY, were seen during a low-dose infusion of H 409/22 (1.8 nmol/kg/min), when plasma levels of the antagonist reached 77 +/- 8 nM. Greatest inhibitory effects were seen at the highest dose of H 409/22 (180 nmol/kg/min, giving plasma levels of 7.4 +/- 0.6 microM) when all vascular responses evoked by NPY were strongly attenuated or largely abolished. H 510/45 did not affect any of the vascular responses studied. It is concluded that H 409/22 potently and dose-dependently antagonizes vascular responses to exogenous and endogenous NPY in the pig, and thus represents an interesting tool for studies on NPY Y1 receptor-mediated effects in vivo.