Neuronal-vascular relationships in the raphe nuclei, locus coeruleus, and substantia nigra in primates.

A fluorescence histochemical and electron microscopic study of the monoaminergic cell groups in the squirrel monkey and Rhesus monkey brains has revealed the direct apposition of blood vessels to perikarya and dendrites of monoaminergic neurons. Capillaries and small arterioles or venules, ranging from 8-50 microns in diameter, showed perikarya and dendrites abutting the basement membrane without evidence of glial interposition. This neuronal-vascular relationship was present in 20% to 30% of the small vessels in the serotonergic nuclei raphe dorsalis and centralis superior and in the noradrenergic locus coeruleus. Such contacts were clearly present but observed less frequently in the dopaminergic substantia nigra pars compacta and in the serotonergic nuclei raphe obscurus, pallidus, magnus, and pontis. We postulate that monoamine-containing neurons apposed to blood vessels in certain regions of the brain may be influenced directly by hormones or other substances in blood.     

Electrophysiological evidence for a dopaminergic action of LSD: depression of unit activity in the substantia nigra of the rat.

LSD (25–50 μg/kg, i.v.) significantly decreased the firing rate of 78% of the dopamine-containing neurons in the substantia nigra of chloral hydrate anesthetized rats. In a subgroup of neurons (22%), LSD either had no clear effect or caused a slight excitation. On the other hand, brom-LSD (100 μg/kg, i.v.), a non-hallucinogenic congener of LSD, had no effect on 71% of dopaminergic cells and slightly reduced the firing rate with 29% of the units. Pretreatment with haloperidol (0.1 mg/kg) blocked the inhibitory effects of LSD, and haloperidol injected following LSD reversed its depressive effects. Non-dopaminergic neurons in the region of the substantia nigra typically showed large increases in firing rate in response to LSD administration. The inhibitory effects of LSD on dopamine-containing neurons are probably not attributable to the serotonergic properties of LSD, since 5-methoxy N,N dimethyltryptamine (25–100 μg/kg), which has central serotonergic properties similar to those of LSD, produced exclusively excitatory effects on the firing rate of dopaminergic cells. These electrophysiological results are consistent with recent behavioral and neurochemical data which suggest that LSD can act as a dopamine agonist in the CNS.     

Neuronal Activation in the Central Nervous System of Rats in the Initial Stage of Chronic Kidney Disease-Modulatory Effects of Losartan and Moxonidine

The effect of mild chronic renal failure (CRF) induced by 4/6-nephrectomy (4/6NX) on central neuronal activations was investigated by c-Fos immunohistochemistry staining and compared to sham-operated rats. In the 4/6 NX rats also the effect of the angiotensin receptor blocker, losartan, and the central sympatholyticum moxonidine was studied for two months. In serial brain sections Fos-immunoreactive neurons were localized and classified semiquantitatively. In 37 brain areas/nuclei several neurons with different functional properties were strongly affected in 4/6NX. It elicited a moderate to high Fos-activity in areas responsible for the monoaminergic innervation of the cerebral cortex, the limbic system, the thalamus and hypothalamus (e.g. noradrenergic neurons of the locus coeruleus, serotonergic neurons in dorsal raphe, histaminergic neurons in the tuberomamillary nucleus). Other monoaminergic cell groups (A5 noradrenaline, C1 adrenaline, medullary raphe serotonin neurons) and neurons in the hypothalamic paraventricular nucleus (innervating the sympathetic preganglionic neurons and affecting the peripheral sympathetic outflow) did not show Fos-activity. Stress- and pain-sensitive cortical/subcortical areas, neurons in the limbic system, the hypothalamus and the circumventricular organs were also affected by 4/6NX. Administration of losartan and more strongly moxonidine modulated most effects and particularly inhibited Fos-activity in locus coeruleus neurons. In conclusion, 4/6NX elicits high activity in central sympathetic, stress- and pain-related brain areas as well as in the limbic system, which can be ameliorated by losartan and particularly by moxonidine. These changes indicate a high sensitivity of CNS in initial stages of CKD which could be causative in clinical disturbances.     

大白鼠脚内核的传入性联系

众所周知,肉食动物和大白鼠的脚内核,相当于灵长类的内侧苍白球(Nagy et al.1978;Fox and Schmitz 1944);它们的细胞形态、传入及传出均相同。早期以及近年来的一些研究工作者,虽然在研究其他核团的投射时,联系到一些本核团的传入,但是尚缺乏对本核团传人的系统研究。本实验即是应用辣根过氧化物酶的逆行传递法来研究大白鼠脚内核的传入性联系。     

Chloral hydrate anesthesia alters the responsiveness of dorsal raphe neurons to psychoactive drugs

The effects of several psychoactive drugs on raphe unit activity in freely moving cats was compared with drug-induced effects in chloral hydrate anesthetized cats. The anesthesia greatly potentiated the depressant effects of LSD, phenoxybenzamine, clonidine, methiothepin, clozapine, and chlorimipramine on raphe units, but partially antagonized the depressant effects of diazepam. These results demonstrate that apparently discrepant reports of the affects of these drugs on raphe neurons in anesthetized rats versus freely moving cats are attributable to the use of anesthesia in rat studies. These data underscore the importance of conducting such drug studies in awake, freely moving animals, for which the results would be far more relevant to the issue of human drug use.     

Autoradiograhic localization of the opiate receptor in rat brain.

One hour after injection of the potent opiate antagonist ³H-diprenorphine (125 μCi, 13 Ci/mmole) 75–85% of the drug is associated with opiate receptor sites. Autoradiography of fresh frozen unfixed brain has been carried out to visualize receptor distribution. Dense clusters of autoradiographic grains are highly localized in the caudate-putamen, locus coeruleus, zona compacta of the substantia nigra and the substantia gelatinosa.     

Monoamine Metabolism in the Locus Coeruleus Measured Concurrently with Behavior During Opiate Withdrawal: An In Vivo Microdialysis Study in Freely Moving Rats

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.     

Influence of the alpha-2 agonist oxaminozoline (S3341) on firing rate of central noradrenergic and serotonergic neurons in the rat. Comparison with clonidine

The firing rate of central locus coeruleus (LC) noradrenergic neurons and dorsal raphe (DR) serotonergic neurons was recorded in rats anaesthetized with chloral hydrate. The iontophoretic application or the i.v. perfusion of S3341, a new antihypertensive drug or clonidine decreased the frequency of discharge of LC neurons. Depending on the mode of administration clonidine was 54-63 times more potent than S3341. The selectivity of action of both drugs on alpha-2 vs. alpha-1 adrenoceptors was confirmed using yohimbine and prazosin: yohimbine completely blocked the inhibitory effect of S3341 or clonidine while prazosin did not prevent this effect. S3341 and clonidine regularly reduced the firing rate of DR neurons during i.v. perfusion but not during iontophoretic application. From these experiments is it concluded that S3341 and clonidine have a direct inhibitory effect on LC neurons via stimulation of alpha-2 autoreceptors and that both drugs have an indirect inhibitory effect on DR neurons, probably via impairment of noradrenergic transmission. Clinical studies show that S3341 induces much less sedative side effects than clonidine. In view of the great difference in the potency of these drugs to inhibit the firing rate of monoaminergic neurons which are known to be involved in sleep mechanisms, it is possible that the electrophysiological effects reported here relate to the sedative effects of these drugs.     

Electrophysiological and microiontophoretic studies with buspirone: influence on the firing rate of central monoaminergic neurons and their responsiveness to dopamine, clonidine or GABA

The influence of an i.v. perfusion of buspirone on the firing rate of central monoaminergic neurons was studied in rats anaesthetized with chloral hydrate. Buspirone increased the firing rate of A10 dopaminergic neurons and blocked the inhibitory effect of iontophoretically applied dopamine on these neurons. A slight attenuation of the inhibitory effect of iontophoretically applied GABA was also observed. Buspirone increased the firing rate of locus coeruleus (LC) noradrenergic neurons and induced an attenuation of the inhibitory effect of iontophoretically applied clonidine. A slight attenuation of the inhibitory effect of iontophoretically applied GABA was also observed. Furthermore buspirone was a very potent inhibitor of the firing rate of dorsal raphe (DR) serotonergic neurons. It is concluded that activation of A10 neurons by buspirone is due to blockade of dopaminergic autoreceptors and that activation of LC neurons is related to blockade of alpha-2 autoreceptors. The significance of the interaction with gabaergic inhibition is unclear. The mechanisms involved in the inhibition of DR neurons remain to be investigated.     

Specific Neurochemical Derangements of Brain Projecting Neurons in Apolipoprotein E-Deficient Mice

Abstract: Apolipoprotein E (apoE)-deficient mice provide a useful system for studying the role of apoE in neuronal maintenance and repair. Previous studies revealed specific memory impairments in these mice that are associated with presynaptic derangements in projecting forebrain cholinergic neurons. In the present study we examined whether dopaminergic, noradrenergic, and serotonergic projecting pathways of apoE-deficient mice are also affected and investigated the mechanisms that render them susceptible. The densities of nerve terminals of forebrain cholinergic projections were monitored histochemically by measurements of acetylcholinesterase activity, whereas those of the dopaminergic nigrostriatal pathway, the noradrenergic locus coeruleus cortical projection, and the raphe-cortical serotonergic tract were measured autoradiographically using radioligands that bind specifically to the respective presynaptic transporters of these neuronal tracts. The results obtained revealed that synaptic densities of cholinergic, noradrenergic, and serotonergic projections in specific brain regions of apoE-deficient mice are markedly lower than those of controls. Furthermore, the extent of presynaptic derangement within each of these tracts was found to be more pronounced the further away the nerve terminal is from its cell body. In contrast, the nerve terminal density of the dopaminergic neurons that project from the substantia nigra to the striatum was unaffected and was similar to that of the controls. The rank order of these presynaptic derangements at comparable distances from the respective cell bodies was found to be septohippocampal cholinergic > nucleus basalis cholinergic > locus coeruleus adrenergic > raphe serotonergic ? nigrostriatal dopaminergic, which interestingly is similar to that observed in Alzheimer's disease. These results suggest that two complementary factors determine the susceptibility of brain projecting neurons to apoE deficiency: pathway-specific differences and the distance of the nerve terminals from their cell body.     

蓝斑核和中缝背核参与电剌激弓状核引起的大鼠...

The effect of electrical stimulation of hypothalamic arcuate nucleus (ARC) on intragastric pressure (IGP) was observed on 80 Wistar rats anaesthetized with urethan. The main results are as follows: (1) Electrical stimulation of ARC could cause an obvious decrease of IGP. (2) The reduction of IGP induced by electrical stimulation of ARC was not affected by intracerebroventricular injection of naloxone. (3) After lesioning of locus coeruleus or dorsal raphe, the effect of ARC stimulation was depressed. The results suggest that the locus coeruleus and dorsal raphe nucleus may be involved in the reduction of IGP induced by ARC stimulation, but without the involvement of beta-endorphinergic neurons.     

帕金森病大鼠中缝背核5-羟色胺能神经元电活动的变化

本实验采用玻璃微电极细胞外记录法,观察了帕金森病(Parkinson’s disease,PD)大鼠中缝背核(dorsal raphe nucleus, DRN)5-羟色胺(5-hydroxytryptamine,5-HT)能神经元电活动的变化。在大鼠右侧中脑黑质致密部内微量注射6-羟多巴胺(6- hydroxydopamine,6-OHDA)制作PD模型。结果显示,对照组和PD组大鼠DRN中5-HT能神经元的放电频率分别是(1．76±0．11)spikes／s(n=24)和(2．43±0．17)spikes／(n=21),PD组大鼠的放电频率显著高于对照组(P<0．001)。在对照组大鼠,92％(22／24)的神经元呈规则放电,8％(2／24)为爆发式放电;在PD组大鼠,具有规则、不规则和爆发式放电的神经元比例分别为9％(2／21)、43％(9／21)和48％(10／21),爆发式放电的5-HT能神经元比例明显高于对照组(P<0．001)。在对照组大鼠,DRN内局部注射5-HT1A拮抗剂WAY-100635(3μg/200nL)显著增加5-HT能神经元的放电频率而不影响其放电形式(n=19,P<0．002);而WAY-100635不改变PD组大鼠5-HT能神经元的放电频率和放电形式(n=17,P>0．05)。结果提示,用6-OHDA损毁黑质致密部造成的PD模型大鼠中神经元5-HT1A受体功能失调,并且DRN参与PD的病理生理学机制。     

Monoaminergic interaction in the central nervous system: a morphological analysis in the locus coeruleus of the rat.

The locus coeruleus of the rat is richly innervated by many aminergic neurons varying in amine content and in site of origin. There are adrenergic and noradrenergic neurons originating in the medulla oblongata, dopaminergic from the hypothalamus, serotonergic from the mesencephalon and also intrinsic noradrenergic neurons in the locus coeruleus complex. Of these, adrenergic and dopaminergic inputs appear relatively specific and powerful.     

Beta-adrenergic influences on the firing of raphe dorsalis neurons after neonatal noradrenergic deafferentation in the rat

In Rat, neonatal lesion of the locus coeruleus induces modifications of beta-adrenergic regulations at the level of raphe dorsalis neurons. In normal conditions, the firing of serotoninergic raphe cells is not beta-adrenergic dependent. On the contrary in the lesioned animal, iontophoresis of a beta-blocking agent (DL-propranolol) produces a marked inhibition of the serotoninergic unit firing. Various mechanisms may account for this pharmacological response in the lesioned group: a classical hypersensitivity phenomenon, or the persistence of an immature regulation.     

The synaptic and nonsynaptic glycine transporter type-1 inhibitors Org-24461 and NFPS alter single neuron firing rate in the rat dorsal raphe nucleus. Further evidence for a glutamatergic-serotonergic interaction and its role in antipsychotic action

Single neuron firing rate was recorded from dorsal raphe nucleus of anesthetized rats. The firing rate of raphe neurons varied from 4 to 8 discharge per second before drug administration and this neuronal activity was decreased by L-701,324 (2 mg/kg i.v. injection), a competitive antagonist of glycineB binding site of N-methyl-D-aspartate (NMDA) receptors. The glycine transporter type-1 (GlyT1) antagonists Org-24461 (10 mg/kg i.v.) and NFPS (3 mg/kg i.v.) reversed the inhibitory effect of L-701,324 on single neuron activity recorded from dorsal raphe nucleus of the rat. Org-24461 and NFPS both tended to increase the raphe neuronal firing rate also when given alone but their effect was not significant. This finding serves further evidence that glutamate released from axon terminals of the cortico-striatal projection neurons stimulates serotonergic neurons in the raphe nuclei and this effect is mediated at least in part by postsynaptic NMDA receptors. Thus, GlyT1 inhibitors are able to reverse the hypofunctional state of NMDA receptors, suggesting that these drugs may have beneficial therapeutic effects in neurological and psychiatric disorders characterized with impaired NMDA receptor-mediated transmission.     

Tricyclic antidepressant drugs: Attenuation of excitatory effects of d-lysergic acid diethylamide (LSD) on acoustic startle response

At a dose of 5 mg/kg, the tricyclic antidepressant drugs chlorimipramine (CIMI), desipramine (DMI), imipramine (IMI), and chlordesipramine (C-DMI) all blocked the excitatory effects of a low dose (30 μg/kg) of LSD on the acoustic startle response in the rat. Over a dose range from 1–5 mg/kg, CIMI and DMI were about equally potent in blocking the LSD effect, despite the fact that both drugs actually increased brain levels of LSD. In contrast, α-methyl-p-tyrosine did not block the effect of LSD on startle. By themselves, DMI, IMI and C-DMI increased startle amplitude 20–30% whereas CIMI alone had no effect on startle. The ability of CIMI and IMI to block the excitatory effect of LSD on startle is consistent with the hypothesis that prior cessation of raphe cell firing caused indirectly by these drugs with no resultant change in 5-HT availability should pre-empt the ability of LSD to increase startle by directly inhibiting raphe cell firing and decreasing 5-HT availability. The finding that the other tricyclics also block the effect of LSD is not explained by that hypothesis. Results are discussed in terms of the serotonin hypothesis of the action of hallucinogenic drugs on behavior.     

Increased activity of stress-regulating systems in Alzheimer disease

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.     

Substance P-immunoreactive neurons in the brainstem of the cat related to cardiovascular centers

Summary The distribution of substance P-immunoreactivity (SP-IR) in the brainstem and spinal cord of normal and colchicine-pretreated cats was analysed using the peroxidase-antiperoxidase (PAP) technique. Numerous SP-IR fibers are present in the nucleus solitarius, nucleus dorsalis nervi vagi and nucleus spinalis nervi trigemini, various parts of the formatio reticularis, substantia grisea centralis mesencephali, locus coeruleus and nucleus parabrachialis. SP-IR perikarya occur in the substantiae gelatinosa and intermedia of the spinal cord, the nucleus spinalis nervi trigemini-pars caudalis, the nucleus dorsalis nervi vagi, and the nucleus solitarius, as well as in the adjacent formatio reticularis and the medullary nuclei of the raphe. In addition, SP-IR cell bodies are located in the nuclei raphe magnus and incertus, ventral and dorsal to the nucleus tegmentalis dorsalis (Gudden), nucleus raphe dorsalis, substantia grisea centralis mensencephali, locus coeruleus, nucleus parabrachialis and colliculus superior.The results indicate that SP-IR neurons may be involved in the regulation of cardiovascular functions both at the central and peripheral level. A peripheral afferent portion seems to terminate in the nucleus solitarius and an efferent part is postulated to originate from the nucleus dorsalis nervi vagi and from the area of the nuclei retroambiguus, ambiguus and retrofacialis.     

Selective spread of herpes simplex virus in the central nervous system after ocular inoculation.

The spread of herpes simplex virus (HSV) was studied in the mouse central nervous system (CNS) after ocular inoculation. Sites of active viral replication in the CNS were identified by autoradiographic localization of neuronal uptake of tritiated thymidine. Labeled neurons were first noted in the CNS at 4 days postinoculation in the Edinger-Westphal nucleus, ipsilateral spinal trigeminal nucleus, pars caudalis, pars interpolaris, and ipsilateral dorsal horn of the rostral cervical spinal cord. By 5 days postinoculation, additional sites of labeling included the seventh nerve nucleus, nucleus locus coeruleus, and the nuclei raphe magnus and raphe pallidus. None of these sites are contiguous to nuclei infected at 4 days, but all are synaptically related to these nuclei. By 7 days postinoculation, no new foci of labeled cells were noted in the brain stem, but labeled neurons were noted in the amygdala, hippocampus, and somatosensory cortex. Neurons in both the amygdala and hippocampus receive axonal projections from the locus coeruleus. On the basis of these findings, we conclude that the spread of HSV in the CNS after intracameral inoculation is not diffuse but is restricted to a small number of noncontiguous foci in the brain stem and cortex which become infected in a sequential fashion. Since these regions are synaptically related, the principal route of the spread of HSV in the CNS after ocular infection appears to be along axons, presumably via axonal transport rather than by local spread.