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1.
Abstract: The effect of the antidepressant and selective noradrenaline reuptake blocker desipramine (DMI) on noradrenergic transmission was evaluated in vivo by dual-probe microdialysis. DMI (1, 3, and 10 mg/kg, i.p.) dose-dependently increased extracellular levels of noradrenaline (NA) in the locus coeruleus (LC) area. In the cingulate cortex (Cg), DMI (3 and 10 mg/kg, i.p.) also increased NA dialysate, but at the lowest dose (1 mg/kg, i.p.) it decreased NA levels. When the α2-adrenoceptor antagonist RX821002 (1 µ M ) was perfused in the LC, DMI (1 mg/kg, i.p.) no longer decreased but rather increased NA dialysate in the Cg. In electrophysiological experiments, DMI (1 mg/kg, i.p.) inhibited the firing activity of LC neurons by a mechanism reversed by RX821002. Local DMI (0.01–100 µ M ) into the LC increased concentration-dependently NA levels in the LC and simultaneously decreased NA levels in the Cg. This decrease was abolished by local RX821002 administration into the LC. The results demonstrate in vivo that DMI inhibits NA reuptake at somatodendritic and nerve terminal levels of noradrenergic cells. The increased NA dialysate in the LC inhibits noradrenergic activity, which in part counteracts the effects of DMI on the Cg. The modulation of cortical NA release by activity of DMI at the somatodendritic level is mediated through α2-adrenoceptors located in the LC.  相似文献   

2.
Several classes of anxiolytic compounds have the common effect of decreasing the firing of noradrenergic neurons or attenuating the post- synaptic effects of noradrenergic activity. In order to determine whether the benzodiazepines, the most widely used anxiolytics, also decrease noradrenergic activity, the effect of acute intravenous injections of diazepam (0.1–2.0 mg/kg) and chlordiazepoxide (0.5–4.0 mg/kg) were administered to anesthetized rats while spontaneous activity of single neurons in the principal noradrenergic nucleus, the locus coeruleus, was recorded. Diazepam and chlordiazepoxide decreased spontaneous single unit activity in the locus coeruleus at relatively low doses. This net effect on noradrenergic systems is consistent with the actions of several classes of nonbenzodiazepine anxiolytics, and with the involvement of noradrenergic systems in the neural mechanisms of anxiety.  相似文献   

3.
Y H Huang 《Life sciences》1979,25(8):709-715
Chronic administration of tricyclic antidepressant drugs has been shown to exert multiple influences on various mechanisms of noradrenergic nervous systems. To determine the overall effect of these influences, this study examined the effect of long-term desipramine administration on the firing rate of noradrenergic postsynaptic neurons, specifically, those in the rat hippocampus that were inhibited by the nucleus locus coeruleus. Daily injections for 3 weeks of 5 or 10 mg/kg desipramine resulted in a 32% or 49% increase, respectively, of hippocampal cell activity, suggesting that long-term desipramine treatment is antagonistic to noradrenergic functions.  相似文献   

4.
D K Pitts  J Marwah 《Life sciences》1986,38(13):1229-1234
The effects of intravenous (i.v.) cocaine HCl on single identified spontaneously firing noradrenergic neurons in the nucleus locus coeruleus (LC) were studied in rats in vivo. Cocaine (0.25-1 mg/kg) produced inhibition of spontaneously firing LC neurons, which was reversed by the administration of the selective alpha 2-adrenoceptor antagonist, piperoxane (250 micrograms/kg, i.v.). Procaine, a local anesthetic that is structurally related to cocaine, did not inhibit LC neurons in doses up to 4 mg/kg, i.v. These results suggest that cocaine in low doses has significant central sympathomimetic effects at the single noradrenergic neuron level and that the inhibition of spontaneous activity may be mediated by alpha 2-adrenoceptors. Our results also indicate that cocaine in pharmacologically relevant doses, can significantly affect central alpha 2-adrenoceptor regulatory processes.  相似文献   

5.
G Engberg  T H Svensson 《Life sciences》1979,24(24):2245-2253
The amphetamine-induced inhibition of brain noradrenaline (NA) containing neurons in the rat locus coeruleus (LC) was pharmacologically analyzed utilizing single unit recording techniques. The presynaptic α-receptor blocking agent yohimbine (10 mg/kg i.p., 30 min before) largely prevented the amphetamine-induced depression of LC units in contrast to prazosin (0.6 mg/kg i.p., 30 min) or phenoxybenzamine (20 mg/kg, 30 min) which both slow preference for postsynaptic α-receptors. The β-receptor blocking agent, propranolol (10 mg/kg, 30 min), as well as the peripherally but not centrally active α-receptor blocking drug phentolamine (10 mg/kg, i.p., 30 min), also did not block the amphetamine effect. The LC inhibition by amphetamine was blocked by pretreatment with reserpine (10 mg/kg, i.p., 5 h), which caused almost total depletion of brain catecholamines. However, unlike the amphetamine-induced inhibition of central dopamine (DA) neurons the NA cell inhibition was not blocked by pretreatment with a tyrosine hydroxylase inhibitor (α-MT, 50 or 250 mg/kg i.p., 30 min). These results suggest that the amphetamine-induced inhibition of NA neurons in the LC is an indirect effect, mediated via activation of central α-receptors of presynaptic character. The lack of antagonism by α-MT indicate that the NA release by amphetamine, unlike its effect on brain DA, is not critically dependent on the rate of tyrosine hydroxylation. Thus the euphoriant action of amphetamine, which is blocked by α-MT, may be associated with release of DA rather than NA in brain.  相似文献   

6.
Abstract: Experiments were performed to confirm that noradrenergic terminals regulate extracellular concentrations of dopamine (DA) in the frontal cortex of rats. The effects of 20 mg/kg 1-[2-[bis(4-fluorphenyl)methoxy]-ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909), a selective inhibitor of DA uptake, and 2.5 mg/kg desipramine (DMI) on the extracellular concentrations of DA in the frontal cortex and striatum were studied in rats given 6-hydroxydopamine (6 µg/µl) bilaterally into the locus coeruleus to destroy noradrenergic terminals. GBR 12909 increased dialysate DA similarly in the striatum of vehicle and 6-hydroxydopamine-treated rats, whereas in the frontal cortex it raised DA concentrations only in lesioned animals. DMI raised extracellular DA concentrations in the frontal cortex but not in the striatum of controls. The effect of DMI on cortical DA was abolished by the 6-hydroxydopamine lesion. GBR 12909, at a subcutaneous dose of 20 mg/kg, further increased cortical dialysate DA in rats given DMI intraperitoneally at 20 mg/kg or through the probe at 10−5 mol/L. The data support the hypothesis of an important regulation of the extracellular concentrations of DA in the frontal cortex by noradrenergic terminals.  相似文献   

7.
Previous work has shown that clonidine effectively supresses many of the signs of opiate withdrawal. The present study was designed to test the hypothesis that the supression of opiate withdrawal by clonidine is mediated by forebrain noradrenergic projections of the locus coeruleus. Two groups of 24 rats each were subjected to either a 6-hydroxydopamine lesion of the dorsal noradrenergic bundle (Lesion group) or a sham, vehicle injection (Sham group). All rats were made dependent on morphine by subcutaneous implantation of one 75 mg silastic morphine pellet for three days followed by 3 more days with two additional 75 mg pellets. Following removal of the morphine pellet, withdrawal was precipitated in all rats by subcutaneous injection of 4 mg/kg of naloxone. Pretreatment 10 min. before withdrawal with clonidine (0.1 or 0.2 mg/kg) produced a significant attenuation of withdrawal signs as compared to saline injected rats; this effect was equally significant in both sham and lesion groups. Lesions of the locus coeruleus had no effect on withdrawal, nor did they affect the ameliorating action of clonidine. These results substantiate the observation that clonidine can effectively attenuate signs of opiate withdrawal in the rat, but fail to support the hypothesis that these effects are mediated by the forebrain projections of the locus coeruleus.  相似文献   

8.
Inhibition of locus coeruleus neuronal activity by beta-phenylethylamine   总被引:1,自引:0,他引:1  
The effect of beta-phenylethylamine (PEA) on brain noradrenaline (NA) neurons in the rat locus coeruleus (LC) was analyzed using single unit recording techniques including microiontophoretic methodology. Systemic injection of low doses of PEA consistently produced an instantaneous and dose-dependent inhibition of firing rate of the LC neurons. The effect was strongly antagonized by administration of the alpha 2-receptor antagonist yohimbine (1 mg/kg, i.v.) or by depletion of endogenous stores of NA by pretreatment with reserpine (10 mg/kg, i.p., 6 h), but unaffected by inhibition of tyrosine hydroxylase (alpha-met-hyl-p-tyrosine (alpha-MT), 250 mg/kg, i.p., 30 min). In contrast, the inhibitory effect of PEA on the LC neurons was strongly potentiated by pretreatment with the selective monoamine oxidase (MAO) - B inhibitor pargyline (2 mg/kg, i.p., 1 h), but, unexpectedly, also by pretreatment with the MAO-A selective inhibitors clorgyline (2 mg/kg, i.p., 1 h) or FLA 336 (2 mg/kg, i.p., 1 h). When microiontophoretically applied directly onto the LC neurons, PEA produced inhibition of a majority of the NA neurons. This action was prevented by intravenous injection of yohimbine (2.5 mg/kg). The results suggests that the action of PEA on NA neurons in the LC is an indirect effect, requiring availability of a reserpine-sensitive storage pool of NA, and mediated via activation of central alpha 2-receptors within the LC.  相似文献   

9.
Noradrenergic and corticotropin-releasing factor (CRF) neuronal systems within the brain have been implicated in stress and anxiety. Synaptic release of cerebral norepinephrine (NE) is increased during stress, and following intracerebral CRF administration. Benzodiazepines are commonly used anxiolytic drugs but information on their effects on the stress- and CRF-related release of NE is limited. We have used in vivo microdialysis to test the effects of the benzodiazepine, chlordiazepoxide (CDP) on the noradrenergic responses to footshock and intracerebroventricular CRF in the medial hypothalamus and the medial prefrontal cortex (PFM) of freely moving rats. Footshock (60 x 0.1-0.2 mA shocks in 20 min) significantly increased microdialysate concentrations of NE in the first sample collected after initiating the footshock. In the hypothalamus, microdialysate NE was augmented 64% above baseline. A second footshock session (100 min after the first footshock) increased microdialysate NE to 313% of the baseline. Thus the noradrenergic responses to footshock were enhanced by preceding footshocks. CRF (100 ng) administered into the locus coeruleus (LC) almost tripled microdialysate concentrations of NE in the PFM. CDP (5mg/kg, i.p.) had no statistically significant effects on the basal dialysate concentrations of NE, but it significantly attenuated both footshock- and CRF-induced increases in dialysate NE. CDP may exert a direct inhibitory effect on the noradrenergic neurons, alter the input to LC noradrenergic neurons, or alter the ability of CRF to activate the LC noradrenergic system.  相似文献   

10.
The role of glial cell-line derived neurotrophic factor (GDNF) and neurotrophins in the development of locus coeruleus noradrenergic neurons was evaluated. We found that two neurotrophic factors previously reported to prevent the degeneration of lesioned adult central noradrenergic neurons, GDNF and neurotrophin 3 (NT3), do not play significant roles in the prenatal development of locus coeruleus noradrenergic neurons, as demonstrated by: (1) the lack of alterations in double Gdnf/Nt3 null mutant mice; and (2) the lack of survival-promoting effects of GDNF and/or NT3 in rat E13.5 primary cultures. In contrast, null mutant mice for TrkB, the tyrosine kinase receptor for brain-derived neurotrophic factor and neurotrophin 4, displayed a clear loss of locus coeruleus noradrenergic neurons. In accordance with this, treatment of rat E13.5 primary cultures with TrkB ligands prevented the early loss of noradrenergic neurons and maintained their survival for up to 6 days in vitro. Moreover, an additional 5-10-fold increase in the number of tyrosine hydroxylase positive noradrenergic neurons was detected after 12 hours in culture. This second effect of TrkB ligands involved neither proliferation nor survival, because the number of BrdU- or TUNEL-positive noradrenergic neurons did not change and the effect was elicited by delayed administration of either factor. Because TrkB ligands increased the number of tyrosine hydroxylase-positive cells expressing Phox2a, a paired homeodomain protein required for the development of locus coeruleus noradrenergic neurons, but did not affect the number of Phox2a-positive tyrosine hydroxylase-negative cells, our results suggest that the second effect of TrkB ligands may involve promoting or inducing a noradrenergic phenotype. In summary, our findings suggest that, unlike NT3 and GDNF, TrkB ligands are required and sufficient to promote the development of central noradrenergic neurons.  相似文献   

11.
Behavioral, i.e. non-cognitive, disturbances, such as anxiety, agitation, sleep disturbances and depression occur in the majority of Alzheimer's disease (AD) patients, but their neurobiological basis is unknown. Disturbance of stress regulating systems, like the locus coeruleus, could play an important role. The locus coeruleus, the main production site of noradrenaline in the central nervous system, is involved in phenomena like attention, arousal and the response to the environment. In Alzheimer's disease, there is a marked reduction of noradrenergic neurons in the locus coeruleus. We studied the activity in the remaining locus coeruleus neurons and found an inverse relationship between the number of remaining neurons and the noradrenergic activity. This could indicate compensatory activity and loss of flexibility of this system. Clinically, the loss of flexibility could result in an impairment to focus attention and to respond to the environment. These results can be related to another stress related system, the hypothalamo-pituitary-adrenal-(HPA)axis. This means that further evaluation of both of these systems is necessary.  相似文献   

12.
Abstract: Using microdialysis, changes in monoamine metabolism were monitored in the locus coeruleus of freely moving rats during opiate withdrawal concomitantly with behavioral symptoms. Rats were infused with morphine (2 mg/kg/h, s.c.) or saline for 5 days and challenged with naltrexone (100 mg/kg, s.c.) on day 6. Following naltrexone challenge, the classic behavioral symptoms of morphine withdrawal were observed in rats treated with morphine but not in saline-infused rats. In morphine-dependent rats, naltrexone induced a marked increase (280%) in dialysate concentrations of 3,4-dihydroxyphenylacetic acid, an index of the functional activity of the noradrenergic neurons in the locus coeruleus. The local concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were also increased (70%) during morphine withdrawal. Taken together, these results (a) confirm in unanesthetized rats the hypothesis of an activation by opiate withdrawal of noradrenergic neurons in the locus coeruleus and (b) suggest an increase in serotonergic transmission in the same nucleus during morphine withdrawal.  相似文献   

13.
The effects of ethanol (2 or 3 g/kg) on plasma corticosterone and free fatty acids were examined in rats with bilateral electrolytic lesions of locus coeruleus or pretreated with the noradrenergic neurotoxin DSP 4 (50 mg/kg). Both lesions and DSP 4 significantly attenuated ethanol induced elevation of free fatty acids. No changes in basal levels of free fatty acids or corticosterone were observed nor did either treatment alter the elevating effect of ethanol on corticosterone. The results indicate that ethanol alters plasma free fatty acids through mechanisms involving noradrenergic neurons in the central nervous system.  相似文献   

14.
In the present study, we investigated the involvement of rhombomere 1 patterning proteins in the regulation of the major noradrenergic centre of the brain, the locus coeruleus. Primary cultures of rat embryonic day 13.5 locus coeruleus were treated with fibroblast growth factor-8, noggin and members of the bone morphogenetic and Wnt protein families. We show that bone morphogenetic proteins 2, 5 and 7 increase and noggin decreases the number of tyrosine hydroxylase-positive locus coeruleus neurons. Interestingly, from all Wnts expressed in the first rhombomere by embryonic day 12.5 in the mice, we only found expression of wnt5a mRNA in the vicinity of the locus coeruleus. In agreement with this finding, from all Wnts studied in vitro, only Wnt5a increased the number of tyrosine hydroxylase-positive neurons in locus coeruleus cultures. Finally, we also found that fibroblast growth factor-8 increased the number of tyrosine hydroxylase-positive cells in locus coeruleus cultures. Neither of the identified factors affected the survival of tyrosine hydroxylase-positive locus coeruleus noradrenergic neurons or the proliferation of their progenitors or neurogenesis. Instead, our results suggest that these patterning signals of rhombomere 1 may work to promote the differentiation of noradrenergic progenitors at later stages of development.  相似文献   

15.
SSR 146977 is a potent and selective antagonist of the tachykinin NK3 receptor. In Chinese hamster ovary cells expressing the human tachykinin NK3 receptor, SSR 146977 inhibited the binding of radioactive neurokinin B to NK3 receptors (Ki = 0.26 nM), senktide (10 nM) induced inositol monophosphate formation (IC50 = 7.8-13 nM), and intracellular calcium mobilization (IC50 = 10 nM). It antagonized [MePhe7]neurokinin B induced contractions of guinea pig ileum (pA2 = 9.07). Senktide (30 nM) induced firing rate increase of noradrenergic neurons in the guinea pig locus coeruleus and dopaminergic neurons in the guinea pig substantia nigra was also blocked by SSR 146977 (50 and 100 nM, respectively). In vivo, in the respiratory system, SSR 146977 inhibited bronchial hyperresponsiveness to acetylcholine, bronchial microvascular permeability hypersensitivity to histamine (doses of 0.1-1 mg/kg i.p.), and cough (doses of 0.03-1 mg/kg i.p.) provoked by citric acid in guinea pigs. In the central nervous system, SSR 146977 inhibited turning behaviour (ID50 = 0.2 mg/kg i.p. and 0.4 mg/kg p.o.) and prevented the decrease of locomotor activity (10 and 30 mg/kg i.p) mediated by the stimulation of NK3 receptors in gerbils. In guinea pigs, SSR 146977 antagonized senktide-induced acetylcholine release in the hippocampus (0.3 and 1 mg/kg i.p) and norepinephrine release in the prefrontal cortex (0.3 mg/kg i.p.). It also prevented haloperidol-induced increase of the number of spontaneously active dopamine A10 neurons (1 and 3 mg/kg i.p.).  相似文献   

16.
The spontaneous activity of locus coeruleus (LC) noradrenergic neurons was assessed by single unit recording in adult recovered rats undernourished at perinatal age as compared with wellnourished animals. Locus coeruleus activity, measured by the firing rate of noradrenergic neurons and the number of spontaneously active cells/track was significantly higher in deprived rats than in controls. In addition, dose-response curves for the inhibitory LC activity of clonidine showed a shift to the right in deprived animals indicating a subsensitivity of alpha2-adrenergic autoreceptors. This fact suggests an alteration in the negative feedback mechanism mediated by somatodentritic alpha2 autoreceptors that modulate the activity of LC neurons, and may account for the behavioral alterations attributed to early undernutrition. Repeated desipramine (DMI) administration to deprived rats reduced LC activity to values comparable to controls, which were not affected after a similar treatment. These data extend to previous reports on long-lasting or permanent plastic changes in the CNS induced by early undernutrition, which may be reverted by pharmacological manipulations. In addition, these results support the hypothesis that alterations induced by early undernutrition are in the same direction as and resemble those described for patients with panic disorders. Furthermore, together with behavioral alterations and selective anxiolytic effect of DMI and other drugs with antipanic effects described in early malnourished rats, the present data support the proposal that perinatally deprived rats may be a useful model for screening drugs with potential antipanic activity.  相似文献   

17.
The nucleus locus coeruleus (LC) has been implicated in the processing of spinal reflexes following noxious stimuli. It has been demonstrated that noxious stimuli activate LC neuronal firing, but little is known about the neurochemical changes that might occur following such activation. To determine the effects of different noxious stimuli on LC neuronal activity, anaesthetized rats were exposed to mechanical (tail pinch), thermal (55 degrees C water), and chemical (5% Formalin injected in the hind paw) stimuli; the catechol oxidation current (CA.OC), an index of noradrenergic neuronal activity, in the locus coeruleus was monitored using differential normal pulse voltammetry. In addition, the effect of the opioid antagonist naloxone on the CA.OC in the LC was examined. Exposure to both mechanical and chemical stimuli significantly increased CA.OC indicating an increase in LC noradrenergic neuronal activity, while the thermal stimulus had no effect. Treatment with naloxone (1 mg/kg i.v.) had no effect on CA.OC in the LC. The results show a differential responsiveness of LC noradrenergic neurons to different modes of noxious stimuli and fail to demonstrate a tonic opioid regulation of these neurons in the anaesthetized rat.  相似文献   

18.
DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) treatment (50 mg/kg i.p., 10 days previously) significantly decreased the noradrenaline (NA) content of the rostral part of the nucleus accumbens. The medial and caudal areas were not affected. The nucleus accumbens appears to receive noradrenergic innervation predominantly from subcoeruleus nuclei of the pons-medulla while the locus coeruleus neurons project to the rostral area. The isoproterenol-induced enhancement of the K+-evoked release of [3H]dopamine (DA) was not affected by DSP4 treatment. Noradrenergic denervation does not appear to have been sufficient to cause up-regulation of postsynaptic -adrenoceptors.  相似文献   

19.
Several studies have shown anatomical and functional interconnections between catecholaminergic and somatostatinergic systems. To assess whether somatostatin (SS) may act presynaptically on catecholamine neurons, SS receptors were measured using radioligand test-tube binding assays on synaptosomes from hippocampus and frontoparietal cortex--areas that are innervated by catecholaminergic neurons with different densities and that have a high number of SS receptors--from control and 6-hydroxydopamine (6-OHDA)-treated rats. Intracerebroventricular (i.c.v.) injection of the catecholamine neurotoxin 6-OHDA (0.78 mg free base/kg of body weight in saline with 0.1% ascorbic acid) lowered hippocampal and frontoparietal cortical noradrenaline (NA) and dopamine (DA) levels at 1 week following the injection. Pretreatment of rats with desmethylimipramine (DMI) (40 mg/kg, intraperitoneal) prevented the drop in NA levels, but was not effective in attenuating DA depletion in the two brain areas studied. Treatment with 6-OHDA lowered the number of 125I-Tyr11-SS receptors in the hippocampus (130 +/- 19 vs. 266 +/- 16 fmol/mg protein, P < 0.001), whereas in the frontoparietal cortex a non significant 20% reduction in receptor number was found. The dissociation constants of 125I-Tyr11-SS binding to synaptosomes from frontoparietal cortex (0.65 +/- 0.06 vs. 0.60 +/- 0.04, P not significant) and hippocampus (0.44 +/- 0.04 vs. 0.63 +/- 0.14, P not significant) were similar in control and treated groups. Pretreatment with DMI reversed up to 80% of the effect of 6-OHDA on hippocampus SS receptors. DMI alone had no observable effect on the number and affinity of SS receptors. The 6-OHDA and the DMI treatment did not affect SLI levels in the brain areas studied. These results suggest that a portion of the hippocampal SS receptors may be localized presynaptically on the noradrenergic and dopaminergic nerve terminals.  相似文献   

20.
The response of brain serotonergic (dorsal raphe), noradrenergic (locus coeruleus) and dopaminergic (pars compacta, substantia nigra) neurons to lisuride hydrogen maleate, a non-hallucinogenic ergot, was studied in the rat using extracellular single cell recording techniques. As has been previously reported for LSD, minute intravenous infusions of lisuride (1–5 μg/kg) produced a complete but reversible suppression of raphe unit spontaneous firing. A similar depressant response was noted when lisuride was applied to raphe units by microiontophoresis. In contrast, locus coeruleus neurons were accelerated by the drug at somewhat higher doses (25–50 μg/kg). Pars compacta neurons demonstrated a predominately depressant response to lisuride but many of the cells tested were only partially suppressed and a few units were accelerated. It is suggested that the marked alterations in central monoamine turnover which have been observed with lisuride are directly paralled by changes in impulse flow in monoaminergic neurons. The fact that lisuride has powerful suppressant effects on central serotonergic neurons but no psychotomimetic actions in man challenges the “serotonin theory” of hallucinogensis; however, other pharmacological properties may account for lisuride's lack of hallucinogenic effects. Further studies with lisuride may provide insight into those drug characteristics critical to the presence or absence of hallucinogenic action.  相似文献   

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