脊髓苯环立啶受体的心血管效应与去甲肾上腺素能系统

本文应用受体阻断、高效液相,6-OHDA 化学损毁神经末梢和放射自显影等多学科技术方法,探讨脊髓苯环立啶受体的心血管效应与去甲肾上腺素能神经系统的关系。结果表明,哌唑嗪、育亨宾均可对抗 ith PCP 的降压和减慢心率作用,ith PCP 产生降压和减慢心率作用时,脊髓脑脊液内 MHPG 的含量升高;用6-OHDA 损毁脊髓 NA 能神经末梢后,ith PCP的降压和减慢心率作用大为减弱,脊髓 PCP 受体密度亦同时大为降低。可以认为,脊髓内有 PCP 受体分布于 NA 能神经末梢上,促进 NA 释放或抑制 NA 重摄取,可能是脊髓 PCP 受体产生心血管抑制效应的重要机理。     

gp130 cytokines stimulate proteasomal degradation of tyrosine hydroxylase via extracellular signal regulated kinases 1 and 2

Injury-induced cytokines act through gp130 in sympathetic neurons to suppress expression of tyrosine hydroxylase (TH) and other genes associated with noradrenergic transmission. These cytokines also trigger the local loss of TH in peri-infarct sympathetic axons after myocardial infarction, but altered gene expression cannot explain the selective loss of TH enzyme in one region of the heart. We hypothesized that inflammatory cytokines, which are highest near the infarct, stimulated local degradation of TH protein. We used cultured sympathetic neurons and neuroblastoma cells to test this hypothesis. The cytokines ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) suppressed TH content in both neurons and neuroblastoma cells. CNTF suppressed TH in a gp130-dependent manner, and decreased the half-life of TH protein by approximately 50%. CNTF stimulated the ubiquitination of TH in both neurons and neuroblastoma cells, and the proteasome inhibitors MG-132 and lactacystin prevented the CNTF-induced loss of TH protein. Inhibiting activation of extracellular signal regulated kinases 1&2 (ERK1/2) with U0126 prevented the CNTF-induced ubiquitination of TH and the associated decrease in protein half-life. Likewise, inhibiting ERK1/2 activation blunted the cytokine-stimulated loss of TH protein in sympathetic neurons, despite enhancing the loss of TH mRNA. These data suggest that gp130 cytokines stimulate proteasomal degradation of TH through an ERK1/2 dependent pathway, and may have important implications for local regulation of neurotransmission at sites of inflammation.     

Characterization of a mouse model overexpressing beta‐site APP‐cleaving enzyme 2 reveals a new role for BACE2

BACE2 is homologous to BACE1, a β‐secretase that is involved in the amyloidogenic pathway of amyloid precursor protein (APP), and maps to the Down syndrome critical region of chromosome 21. Alzheimer disease neuropathology is common in Down syndrome patients at relatively early ages, and it has thus been speculated that BACE2 co‐overexpression with APP would promote the early neurodegenerative phenotype. However, the in vivo function of BACE2 has not yet been elucidated. The aim of the present work has been to analyse the impact of in vivo BACE2 overexpression using a transgenic mouse model. Our results suggest that BACE2 is not involved in the amyloidogenic pathway, cognitive dysfunction or cholinergic degeneration. However, TgBACE2 animals showed increased anxiety‐like behaviour along with increased numbers of noradrenergic neurones in locus coeruleus, thus suggesting an unexpected role of BACE2 overexpression.     

In Vivo Measurement of Extracellular Cyclic AMP in the Brain: Use in Studies of β-Adrenoceptor Function in Nonanesthetized Rats

Microdialysis measurement of extracellular cyclic AMP (cAMP) in the cerebral cortex of conscious rats was evaluated as a method for assessing central beta-adrenoceptor function in vivo. Extracellular levels of the nucleotide were found to average 3 pmol/ml under baseline conditions. Local infusion of the beta-agonists norepinephrine (NE) and isoproterenol produced rapid (3 min) and marked (three- to sevenfold) dose-dependent increases in extracellular cAMP, which were potentiated by the phosphodiesterase inhibitor rolipram, and blocked by the beta-antagonist timolol. Responses to both catecholamines underwent rapid desensitization (6-9 min) and recovered within several hours. Time-course studies revealed that the baseline cAMP level underwent a gradual increase and then a decrease over the course of a single 8-h run, and peaked at 24 h postimplantation. Responses to NE were stable for the first 24 h after implantation, then increased at 48 and 120 h. The causes of the latter changes may include reactions to novelty, local inflammatory responses, and/or reactions of adjacent glial cells to implantation. Overall, the results indicate that the microdialysis-cAMP method can be extended to nonanesthetized animals and may be a useful tool for studying neurotransmission at central adenylate cyclase-coupled membrane receptors during various behavioral states.     

Brain (Na+, K+)-ATPase and Noradrenergic Activity: Effects of Hyperinnervation and Denervation on High-Affinity Ouabain Binding

Abstract: To examine the role of nerve-specific (Na⁺, K⁺)-ATPase in chronic changes in noradrenergic activity, we examined the effects of noradrenergic denervation and hyperinnervation on p -nitrophenylphosphatase activity and on total and nerve-specific ouabain binding. High-affinity and erythrosin B-sensitive binding were compared as measurements of nerve-specific binding. Hyperinnervation and denervation was produced in cerebellum and cerebral cortex, respectively, by 6-hydroxydopamine lesions of the dorsal noradrenergic bundle. Hyperinnervation increased, and denervation decreased, enzyme activity, high-affinity ouabain inhibition, and erythrosin B-sensitive ouabain binding. As (Nat⁺, K⁺)-ATPase has a major role in the regulation of neural excitability and energy metabolism, and the ouabain binding site has been shown to have endogenous ligands, these changes in (Na⁺, K⁺)-ATPase may be important in the long-term regulation of neuron function by norepinephrine.     

Galanin potentiates electrical stimulation and exogenous norepinephrine-induced contractions in the rat vas deferens

In order to evaluate the mode of action of galanin (GAL) on the neuroeffector mechanism of peripheral sympathetic nerve fibers, the effects of this peptide were tested on the electrical stimulated and the unstimulated preparations of the isolated rat vas deferens in the presence of 10(-7) M atropine. The contractile responses, which were mediated predominantly by activation of postganglionic noradrenergic nerve fibers were dose-dependently potentiated by GAL in concentrations ranging from 1 to 50 nM. The facilitatory action induced by GAL in high concentrations (greater than 10 nM) usually returned to the control level at 2-3 min and were tachyphylactic. The potentiating action of GAL was not modified by pretreatment with 10(-7) M propranolol. Contractions produced by exogenous norepinephrine (NE) in the unstimulated preparations were not affected by pretreatment with low concentrations (less than 5 nM) of GAL. On the other hand, the contractions were dose-dependently potentiated 1 min after pretreatment with higher concentrations (greater than 10 nM) of GAL, which recovered 15 min after constant flow washout. Contractions developed by exogenous 5-hydroxytryptamine were not affected, or slightly inhibited, by GAL (1-50 nM). In some preparations without electrical stimulation, high concentrations of GAL caused a slight contraction, which was not blocked by pretreatment with 10(-6) M phentolamine and 10(-6) M tetrodotoxin. These results suggest that GAL receptors exist presynaptically in the rat vas deferens and that stimulation of the receptors by GAL potentiates the release of NE from the nerve terminals during postganglionic sympathetic nerve stimulation. Other mechanisms for GAL action, such as influence on neuronal uptake and catecholamine metabolism, cannot be ruled out.     

Effects of Stimulation of the Periaqueductal Gray and <Emphasis Type="Italic">Locus Coeruleus</Emphasis> on Postsynaptic Reactions of Cat Somatosensory Cortex Neurons Activated by Nociceptors

In cats, we studied the influences of stimulation of the periaqueductal gray (PAG) and locus coeruleus (LC) on postsynaptic processes evoked in neurons of the somatosensory cortex by stimulation of nociceptive (intensive stimulation of the tooth pulp) and non-nociceptive (moderate stimulations of the infraorbital nerve and ventroposteromedial nucleus of the thalamus) afferent inputs. Twelve cells activated exclusively by nociceptors and 16 cells activated by both nociceptive and non-nociceptive influences (hereafter, nociceptive and convergent neurons, respectively) were recorded intracellularly. In neurons of both groups, responses to nociceptive stimulation (of sufficient intensity) looked like an EPSP-spike-IPSP (the latter, of significant duration, up to 200 msec) complex. Electrical stimulation of the PAG (which could itself evoke activation of the cortical neurons under study) resulted in long-term suppression of synaptic responses evoked by excitation of nociceptors (inhibition reached its maximum at a test interval of 600 to 800 msec). We observed a certain parallelism between conditioning influences of PAG activation and effects of systemic injections of morphine. Isolated stimulation of LC by a short high-frequency train of stimuli evoked primary excitatory responses (complex EPSPs) in a part of the examined cortical neurons, while in other cells high-amplitude and long-lasting IPSP (up to 120 msec) were observed. Independently of the type of the primary response to PAG stimulation, the latter resulted in long-term (several seconds) suppression of the responses evoked in cortical cells by stimulation of the nociceptive inputs. The mechanisms of modulatory influences coming from opioidergic and noradrenergic brain systems to somatosensory cortex neurons activated due to excitation of high-threshold (nociceptive) afferent inputs are discussed.Neirofiziologiya/Neurophysiology, Vol. 37, No. 1, pp. 61–73, January–February, 2005.     

Effect of corticosterone on noradrenergic nuclei in the pons-medulla and [3H]NA release from terminals in hippocampal slices

The aim of the present study was to investigate possible membrane and genomic effects of corticosterone on the noradrenergic system of the rat brain. Corticosterone effects were studied in vivo by treating rats s.c. with 10 mg/kg corticosterone for 7 or 14 days. In the first two experiments corticosterone significantly decreased th noradrenaline (NA) and dopamine (DA) levels in the pons-medulla, an area which contains the A1-A7 noradrenergic cell groups, while the NA and DA levels in the dorsal hippocampus remained unchanged. In a third experiment where the locus coeruleus (LC) and the A1 and A2 nuclei (A1,A2) were analysed separately, NA levels were unchanged but total MHPG levels and the total MHPG/NA ratio were decreased in the A1,A2 area. Chronic corticosterone treatment (14 days) did not alter the ₂-adrenoceptor-mediated modulation of [³H]NA release from dorsal hippocampal slices. Neither the spontaneous outflow nor the electrically stimulated release of [³H]NA from dorsal hippocampal slices of untreated rats was affected by exposure of the slices to corticosterone (10^–7 M–10^–4 M) in the superfusion buffer. Thus, chronic corticosterone treatment of rats altered the noradrenergic system of the pons-medulla, but did not change the ₂-adrenoceptor-mediated modulation of NA release in the dorsal hippocampus, a major terminal area of the LC neurons. Corticosterone also did not appear to have a direct membrane effect on the NA terminals in the dorsal hippocampus of the rat.