Aminergic control of neuronal firing rate in thalamic motor nuclei of the rat

The effects induced on neuronal firing by microiontophoretic application of the biological amines noradrenaline (NA) and 5-hydroxytryptamine (5-HT) were studied "in vivo" in ventral-anterior (VA) and ventrolateral (VL) thalamic motor nuclei of anaesthetized rats. In both nuclei the amines had a mostly depressive action on neuronal firing rate, the percentage of units responsive to NA application (88%) being higher than to 5-HT (72%). Short-lasting (less than 2 min) and long lasting (up to 20 min) inhibitory responses were recorded, the former mostly evoked by NA and the latter by 5-HT ejection. In some cases 5-HT application had no effect on the firing rate but modified the firing pattern. NA-evoked responses were significantly more intense in VL than in VA neurons. Short-lasting inhibitory responses similar to NA-induced effects were evoked by the alpha2 adrenergic receptor agonist clonidine and to a lesser extent by the beta adrenergic receptor agonist isoproterenol. Inhibitory responses to 5-HT were partially mimicked by application of the 5-HT(1A) receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) and of the 5-HT2 receptor agonist alpha-methyl-5-hydroxytryptamine (ALPHA-MET-5-HT). The latter evoked excitatory responses in some cases. Both 5-HT agonists were more effective on VA than on VL neurons. The effects evoked by agonists were at least partially blocked by respective antagonists. These results suggest that although both 5-HT and NA depress neuronal firing rate, their effects differ in time course and in the amount of inhibition; besides aminergic modulation is differently exerted on VA and VL.     

Differential regulation of the excitability of prefrontal cortical fast-spiking interneurons and pyramidal neurons by serotonin and fluoxetine

Serotonin exerts a powerful influence on neuronal excitability. In this study, we investigated the effects of serotonin on different neuronal populations in prefrontal cortex (PFC), a major area controlling emotion and cognition. Using whole-cell recordings in PFC slices, we found that bath application of 5-HT dose-dependently increased the firing of FS (fast spiking) interneurons, and decreased the firing of pyramidal neurons. The enhancing effect of 5-HT in FS interneurons was mediated by 5-HT₂ receptors, while the reducing effect of 5-HT in pyramidal neurons was mediated by 5-HT₁ receptors. Fluoxetine, the selective serotonin reuptake inhibitor, also induced a concentration-dependent increase in the excitability of FS interneurons, but had little effect on pyramidal neurons. In rats with chronic fluoxetine treatment, the excitability of FS interneurons was significantly increased, while pyramidal neurons remained unchanged. Fluoxetine injection largely occluded the enhancing effect of 5-HT in FS interneurons, but did not alter the reducing effect of 5-HT in pyramidal neurons. These data suggest that the excitability of PFC interneurons and pyramidal neurons is regulated by exogenous 5-HT in an opposing manner, and FS interneurons are the major target of Fluoxetine. It provides a framework for understanding the action of 5-HT and antidepressants in altering PFC network activity.     

Effects of glutamate on the serotonin-induced responses of vestibular neurons

The aim of this work was to verify whether and how spontaneous or glutamate(GLU)-induced enhancements of the neuronal firing rate modified the responsiveness of the vestibular neurons to microiontophoretic application of serotonin (5-HT). During experiments performed on anaesthetized Wistar rats the responses to 5-HT applications were studied in neurons of the lateral vestibular nucleus identified by the antidromic activation upon stimulation of the vestibulospinal tract. The magnitude (in percent) of the 5-HT induced excitatory responses decreased (hyperbolic correlation, r = 0.91) when the background mean firing rate was enhanced spontaneously or by long-lasting application of GLU. Even in high-discharging units, the response never changed its sign. The trend to a depression of the response to 5-HT in function of the background discharge was observed when either the enhancement of firing occurred spontaneously and it was induced by an application of GLU, no significant difference (F-test) being found between the two cases. It is concluded that serotoninergic afferents can exert a strong control upon the vestibular neurons when the background activity is depressed, and only a weak influence when the neuronal firing is enhanced by other excitatory afferents. It remains to verify whether the type of interference observed between GLU and 5-HT is specific or can be also detected between 5-HT and other excitatory neuromediators.     

Brain 5-HT synthesis in the Flinders Sensitive Line rat model of depression: an autoradiographic study

Alterations of serotonin (5-HT) levels and serotonergic transmission have been associated with depression. 5-HT synthesis is an important factor of serotonergic neurotransmission that may also be altered in depression. Many studies of the relationships between brain serotonergic functions and affective disorders have been performed in different animal models. In this study, brain regional 5-HT synthesis was examined using the alpha-[(14)C]methyl-L-tryptophan (alpha-MTrp) autoradiographic method in a genetic rat model of depression, Flinders Sensitive Line (FSL) rats, and was compared to both the Flinders Resistant Line (FRL) rats and the control Sprague-Dawley (SD) rats. The plasma concentration of free tryptophan in the FSL rats was not significantly different (p > 0.05; ANOVA and post-hoc Bonferroni correction) when compared to that of the FRL and SD rats. The FSL rats had significantly lower 5-HT synthesis (one sample two-tailed t-test on the ratio) than both the FRL and SD rats (the mean ratios were 0.78 +/- 0.12 and 0.73 +/- 0.15, respectively). Overall, the 5-HT synthesis in the FRL rats was not significantly different (p > 0.05) from that in the SD rats (one sample two-tailed t-test on the ratio and the mean ratio was 0.93 +/- 0.13). Studies of individual brain structures, such as the raphe nuclei and their many terminal areas, including the nucleus accumbens, cingulate and frontal cortex, hippocampus, amygdala, and thalamus revealed significant reductions (typically 25-50%) in 5-HT synthesis in the FSL rats compared to the non-depressive FRL and SD rats. These results suggest that significantly reduced 5-HT synthesis in the raphe nuclei and limbic areas in FSL rats may contribute to their depressive features.     

Venlafaxine enhances the effect of bupropion on extracellular dopamine in rat frontal cortex

Venlafaxine is recognised as an effective treatment for depression and is known to inhibit the reuptake of serotonin (5-HT) and noradrenaline (NA). Another antidepressant, bupropion, acts to inhibit dopamine (DA) and NA reuptake and is commonly co-administered with other antidepressants to improve the efficacy of the antidepressant effect. The present study was designed to investigate the acute effect of combining the 2 drugs on extracellular levels of 5-HT, DA, and NA in rat frontal cortex using brain microdialysis, with the drugs being administered by intraperitoneal injection (i.p). Bupropion (10 mg/kg body mass, i.p.) alone had no effect on extracellular 5-HT levels, whereas venlafaxine (10 mg/kg, i.p.) alone significantly elevated extracellular 5-HT over basal values. As expected, bupropion alone elevated extracellular dopamine above basal values at 40 min post-drug administration, and this effect lasted for a further 2 h. Venlafaxine alone did not statistically elevate extracellular dopamine. The co-administration of venlafaxine with bupropion resulted in a dramatic increase in extracellular dopamine, and this effect was significantly greater than that seen with bupropion alone. In the frontal cortex, NA was elevated by bupropion alone and venlafaxine alone, relative to the control animals. The combination of bupropion and venlafaxine resulted in a marked elevation of NA.     

Tandospirone potentiates the fluoxetine-induced increases in extracellular dopamine via 5-HT(1A) receptors in the rat medial frontal cortex.

Recent clinical studies suggest that 5-HT(1A) receptor agonists, including buspirone, may have an antidepressant effect and potentiate the efficacy of selective serotonin reuptake inhibitors (SSRI) in major depressive disorders. In the present study, we investigated the effect of tandospirone, a highly potent and selective 5-HT(1A) receptor agonist, on dopamine release and potentiation of fluoxetine-induced dopamine outflow in the medial frontal cortex using microdialysis in freely moving rats. Intraperitoneal injection of tandospirone (5 mg/kg) increased dopamine release to about 190% of basal levels. Pretreatment with the selective 5-HT(1A) receptor antagonist, WAY 100635 (1mg/kg), blocked the effect of tandospirone. Local application of WAY 100635 (10 microM) via microdialysis probe antagonized the increase in dopamine release in the medial frontal cortex induced by systemic injection of tandospirone. Fluoxetine (10 mg/kg) also increased dopamine release in the medial frontal cortex, to 200% of basal levels, and the simultaneous administration of tandospirone and fluoxetine increased the release to 380%. These results indicate that tandospirone potentiates the fluoxetine-induced increase in dopamine release via 5-HT(1A) receptors in the rat medial frontal cortex, and suggest that tandospirone may have therapeutic potential for the treatment of depression.     

Sodium Salicylate Suppresses GABAergic Inhibitory Activity in Neurons of Rodent Dorsal Raphe Nucleus

Sodium salicylate (NaSal), a tinnitus inducing agent, can activate serotonergic (5-HTergic) neurons in the dorsal raphe nucleus (DRN) and can increase serotonin (5-HT) level in the inferior colliculus and the auditory cortex in rodents. To explore the underlying neural mechanisms, we first examined effects of NaSal on neuronal intrinsic properties and the inhibitory synaptic transmissions in DRN slices of rats by using whole-cell patch-clamp technique. We found that NaSal hyperpolarized the resting membrane potential, decreased the input resistance, and suppressed spontaneous and current-evoked firing in GABAergic neurons, but not in 5-HTergic neurons. In addition, NaSal reduced GABAergic spontaneous and miniature inhibitory postsynaptic currents in 5-HTergic neurons. We next examined whether the observed depression of GABAergic activity would cause an increase in the excitability of 5-HTergic neurons using optogenetic technique in DRN slices of the transgenic mouse with channelrhodopsin-2 expressed in GABAergic neurons. When the GABAergic inhibition was enhanced by optical stimulation to GABAergic neurons in mouse DRN, NaSal significantly depolarized the resting membrane potential, increased the input resistance and increased current-evoked firing of 5-HTergic neurons. However, NaSal would fail to increase the excitability of 5-HTergic neurons when the GABAergic synaptic transmission was blocked by picrotoxin, a GABA receptor antagonist. Our results indicate that NaSal suppresses the GABAergic activities to raise the excitability of local 5-HTergic neural circuits in the DRN, which may contribute to the elevated 5-HT level by NaSal in the brain.     

选择性5-HT1A受体拮抗剂WAY-100635增加6-羟多巴胺损毁大鼠杏仁基底外侧核的神经活动

本文采用玻璃微电极细胞外记录法,观察正常大鼠和6-羟多巴胺(6-hydroxydopamine,6-OHDA)损毁黑质致密部大鼠杏仁基底外侧核(basolateral nucleus,BL)神经元电活动的变化,以及体循环给予选择性5-HT1A受体拮抗剂WAY-100635对神经元电活动的影响.结果显示,正常大鼠BL投射神经元和中间神经元的放电频率分别足(O.39±0.04)Hz和(0.83±0.16)Hz,6-OHDA损毁大鼠BL投射神经元和中间神经元的放电频率分别足(0.32±0.04)Hz和(0.53±0.12)Hz,与正常大鼠相比无显著差异.在正常大鼠,所有投射神经元呈现爆发式放电;94%的中间神经元为爆发式放电,6%为不规则放电.在6.OHDA损毁大鼠,85%的投射神经元呈现爆发式放电,15%为不规则放电;86%的中间神经元为爆发式放电,14%为不规则放电,与正常大鼠相比无显著差别.静脉给予0.1 mg/kg体重的WAY-100635不改变正常大鼠和6-OHDA损毁人鼠BL投射神经元和中间神经元的放电频率.然而,0.5 mg/kg体重的WAY-100635却显著降低正常大鼠BL投射神经元的平均放电频率(P<0.01),明显增加6-OHDA损毁大鼠BL投射神经元的平均放电频率(P<0.004).高剂量WAY-100635不影响正常大鼠和6-OHDA损毁大鼠BL中间神经元的平均放电频率.结果表明,黑质多巴胺能损毁后内在和外在的传入调节BL神经元的活动,在正常大鼠和6-OHDA损毁大鼠5-HT1A 受体调节投射神经元的活动,并且在6-OHDA损毁大鼠WAY-100635诱发投射神经元平均放电频率增加.结果提示,5-HT1A 受体在帕金森病情感性症状的产生中起重要作用.     

Nonexocytotic serotonin release tonically suppresses serotonergic neuron activity

The firing activity of serotonergic neurons in raphe nuclei is regulated by negative feedback exerted by extracellular serotonin (5-HT)_o acting through somatodendritic 5-HT1A autoreceptors. The steady-state [5-HT]_o, sensed by 5-HT1A autoreceptors, is determined by the balance between the rates of 5-HT release and reuptake. Although it is well established that reuptake of 5-HT_o is mediated by 5-HT transporters (SERT), the release mechanism has remained unclear. It is also unclear how selective 5-HT reuptake inhibitor (SSRI) antidepressants increase the [5-HT]_o in raphe nuclei and suppress serotonergic neuron activity, thereby potentially diminishing their own therapeutic effect. Using an electrophysiological approach in a slice preparation, we show that, in the dorsal raphe nucleus (DRN), continuous nonexocytotic 5-HT release is responsible for suppression of phenylephrine-facilitated serotonergic neuron firing under basal conditions as well as for autoinhibition induced by SSRI application. By using 5-HT1A autoreceptor-activated G protein–gated inwardly rectifying potassium channels of patched serotonergic neurons as 5-HT_o sensors, we show substantial nonexocytotic 5-HT release under conditions of abolished firing activity, Ca²⁺ influx, vesicular monoamine transporter 2–mediated vesicular accumulation of 5-HT, and SERT-mediated 5-HT transport. Our results reveal a cytosolic origin of 5-HT_o in the DRN and suggest that 5-HT_o may be supplied by simple diffusion across the plasma membrane, primarily from the dense network of neurites of serotonergic neurons surrounding the cell bodies. These findings indicate that the serotonergic system does not function as a sum of independently acting neurons but as a highly interdependent neuronal network, characterized by a shared neurotransmitter pool and the regulation of firing activity by an interneuronal, yet activity-independent, nonexocytotic mechanism.     

Effect of pentobarbital on neurones in the reticular formation of the brain stem: ionophoretic study in the rat

The effect of ionophoretically applied pentobarbital (PB) upon neurones in the nucleus reticularis gigantocellularis of the rat was studied. PB applied through a micropipette depressed the spontaneous activity of 81% of the neurones tested; the remaining neurones did not change their firing rates. Regardless of current intensities used for PB ejection (5-60 nA) there was no increase in the firing rate during PB administration. The depression was dependent upon both the control firing rate and the PB dose; a total depression of activity was observed at currents between 40 and 60 nA. EC50 (15.5 nA, about 5 X 10(-5) mol.l-1--the drug concentration was approximated theoretically) was assessed from the dose-response curve. Repeated application resulted in a shift of EC50 towards higher current values (desensitization). The Hill coefficient was calculated in conformity with the classical theory. From its value (1.4), it may be assumed that the occupation of only one subunit of the binding site is enough to give a response. Possible mechanisms of action of PB upon neurones are discussed.     

Brain Region-Specific Effects of Short-Term Treatment with Duloxetine,Venlafaxine, Milnacipran and Sertraline on Monoamine Metabolism in Rats

We examined brain region-specific changes in monoamines and metabolites, and their ratios, after short-term administration of antidepressants to rats. Serotonin noradrenaline reuptake inhibitors (SNRIs; duloxetine, venlafaxine, milnacipran) and a serotonin-selective reuptake inhibitor (SSRI; sertraline) elevated serotonin (5-HT) levels in the midbrain (MB). Duloxetine and venlafaxine increased 5-HT levels in the brainstem and 5-HT terminal areas, whereas milnacipran and sertraline increased levels in the brainstem only. Significant reductions in 5-HT turnover were observed in various forebrain regions, including the hippocampus and hypothalamus, after treatment with all of the tested drugs except for milnacipran. In addition, there was reduced 5-HT turnover in the dorsolateral frontal cortex (dlFC), the medial prefrontal cortex (mPFC), and both the dlFC and the mPFC after treatment with duloxetine, sertraline, and venlafaxine, respectively. Venlafaxine significantly increased dopamine (DA) levels in the nucleus accumbens (NAc) and the substantia nigra and decreased DA turnover in the NAc. Similar changes were observed after treatment with duloxetine and sertraline in the NAc, whereas milnacipran increased DA levels in the mPFC. Limited increases in noradrenaline levels were detected after treatment with duloxetine, venlafaxine, or sertraline, but not after treatment with milnacipran. These results show that SNRIs and SSRIs induced region-specific monoaminergic changes after short-term treatment.     

A Generalised Increase in Protein Carbonyls in the Brain in Parkinson''s but Not Incidental Lewy Body Disease

Abstract: A serotonin (5-HT)_1A receptor partial agonist, buspirone, potentiates the clinical antidepressant properties of 5-HT reuptake inhibitors (SSRIs). Herein, we examined the interaction of buspirone with two SSRIs, duloxetine and fluoxetine, on extra-cellular levels of 5-HT, dopamine (DA), and noradrenaline (NAD) in single dialysate samples of freely moving rats. Duloxetine (5.0 mg/kg, s.c.) and fluoxetine (10.0 mg/kg, s.c.) increased dialysate levels of DA (65 and 60% vs. basal values, respectively), NAD (400 and 90%, respectively), and 5-HT (130 and 110%, respectively) in the frontal cortex (FCX). Buspirone (2.5 mg/kg, s.c.) similarly elevated levels of DA (100%) and NAD (160%) but reduced those of 5-HT (−50%). Administered with buspirone, the ability of duloxetine and fluoxetine to increase 5-HT levels was transiently inhibited (over 60 min), although by the end of sampling (180 min) their actions were fully expressed. In contrast, buspirone markedly and synergistically facilitated the elevation in DA levels elicited by duloxetine (550%) and fluoxetine (240%). Furthermore, buspirone potentiated the induction of NAD levels by duloxetine (750%) and fluoxetine (350%). These data suggest that a reinforcement in the influence of SSRIs on DA and, possibly, NAD but not 5-HT release in FCX may contribute to their increased antidepressant activity in the presence of buspirone. More generally, they support the hypothesis that a reinforcement in dopaminergic transmission in the FCX contributes to the actions of SSRIs and other antidepressant drugs.     

Advances toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5-HT1A receptor antagonism/SSRI activities. Part 5

A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT1A receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinities at the 5-HT1A receptor and serotonin reuptake site in vitro. In vivo evaluation of this series of compounds demonstrated elevated extracellular serotonin levels from the basal and quick recovery of neuron firing that was presumably suppressed by the initial acute activation of 5-HT1A somatodendritic autoreceptors.     

Inhibition of Purkinje cell firing by systemic administration of phenylisopropyl adenosine: effect of central noradrenaline depletion by DSP4

The effect of the metabolically stable adenosine analog (-)-N6(R-phenyl-isopropyl)-adenosine (PIA) on the rate of spontaneous Purkinje cell firing was studied in anesthetized rats. In control animals, systemically administered PIA elicited only small and inconsistent changes in firing rate. However, in animals previously treated with DSP4 (50 mg/kg i.p.), which selectively lesions central noradrenergic afferents, or with the adrenergic antagonist sotalol (15 mg/kg), PIA elicited consistent decreases in firing rate. These effects were antagonized by the systemic administration of the adenosine receptor antagonist aminophylline (50-150 mumol/kg). Local administration of adenosine by pressure ejection caused a dose-dependent depression of Purkinje cell firing that was likewise inhibited by the methylxanthine. In DSP4 treated rats the depression of synaptic transmission by adenosine in rat hippocampus in vitro was unaltered, and theophylline did not cause any marked rise in Purkinje cell firing, suggesting that DSP4 does not sensitize neurons to the depressant effects of adenosine derivatives. PIA also caused a dose-dependent decrease in arterial blood pressure and a decrease in heart rate that was of equal magnitude in control and DSP4 treated rats. The results show that the central effects of systemically administered adenosine analogs are altered by procedures that disrupt the normal depressant effect of tonic noradrenergic input.     

Cortical and septal responses to dorsal raphe nucleus stimulation in the rat: long-term clomipramine actions.

In cerebral cortex and lateral septal nuclei different serotonergic receptor subtypes coexist, thus a different action on neuronal firing may be expected depending on the receptor activated. Dorsal raphe nucleus stimulation produced an increased rate of firing in cortical layer V, and in lateral septal nuclei. However, firing rate in cortical layer VI remained unchanged after stimulating the dorsal raphe nucleus. Clomipramine is a tricyclic which exerts its main actions on serotonergic receptors, and long-term treatment with this antidepressant produced a selective increased firing rate in lateral septal neurons, but not in cortical neurons. From an electrophysiological point of view, it is concluded that the excitatory actions on firing rate elicited by dorsal raphe nucleus stimulation or clomipramine treatment are mediated by 5-HT2 receptor subtype activation which is likely to be acting as a 5-HT1A modulator in such places where both receptor subtypes coexist.     

The role of 5-HT1B receptors in the regulation of serotonin cell firing and release in the rat brain

The release of 5-HT in terminal areas of the rodent brain is regulated by 5-HT1B receptors. Here we examined the role of 5-HT1B receptors in the control of 5-HT output and firing in the dorsal raphe nucleus (DR), median raphe nucleus (MnR) and forebrain of the rat in vivo. The local perfusion (30-300 microM) of the selective 5-HT1B receptor agonist CP-93,129 to freely moving rats decreased 5-HT release in the DR and more markedly in the MnR. Likewise, 300 microM CP-93,129 reduced 5-HT output in substantia nigra pars reticulata, ventral pallidum, lateral habenula and the suprachiasmatic nucleus. The effect of CP-93,129 was prevented by SB-224289, but not by WAY-100635, selective 5-HT1B and 5-HT1A receptor antagonists, respectively. SB-224289 did not alter dialysate 5-HT in any raphe nuclei. The intravenous administration of the brain-penetrant selective 5-HT1B receptor agonist CP-94,253 (0.5-2.0 mg/kg) to anesthetized rats decreased dialysate 5-HT in dorsal hippocampus and globus pallidus, increased it in MnR and left it unaltered in the DR and medial prefrontal cortex. SB-224289, at a dose known to block 5-HT1B autoreceptor-mediated effects (5 mg/kg), did not prevent the effect of CP-94,253 on MnR 5-HT. The intravenous administration of CP-94,253 (0.05-1.6 mg/kg) to anesthetized rats increased the firing rate of MnR, but not DR-5-HT neurons. The local perfusion of CP-94,253 in the MnR showed a biphasic effect, with 5-HT reductions at 0.3-3 microM and increase at 300 microM. These results suggest that 5-HT cell firing and release in midbrain raphe nuclei (particularly in the MnR) are under control of 5-HT1B receptors. The activation of 5-HT1B autoreceptors (possibly located on 5-HT nerve endings and/or varicosities within DR and MnR) reduces 5-HT release. The effects of higher concentrations of 5-HT1B receptor agonists seem more compatible with the activation of 5-HT1B heteroreceptors on inhibitory neurons.     

The effects of asphyxia on 5-hydroxytryptamine metabolism in the immature rat brain

Five-day-old rats subjected to prolonged asphyxia at 37 degrees C show a slower rate of synthesis of 5-HT as measured by the accumulation of the amine after inhibition of monoamine oxidase. During recovery from asphyxia 5-HT synthesis is markedly stimulated when measured over a 50 or 90 min period. No change in 5-HT synthesis was observed in 5-day-old rats during recovery from cold exposure or immobilization. The results indicate that the persistent increase in synthesis that follows resuscitation may be related to asphyxia per se rather than to the stress component of the treatment.     

Selective blockade of neurokinin (NK)(1) receptors facilitates the activity of adrenergic pathways projecting to frontal cortex and dorsal hippocampus in rats

The selective NK(1) receptor antagonist, GR205,171 (2.5-40.0 mg/kg, i.p.), dose-dependently elevated dialysate levels of noradrenaline (NA), but not serotonin (5-HT), in the frontal cortex of freely moving rats. This action was exerted stereospecifically inasmuch as its less active isomer, GR226,206, was ineffective. In the dorsal hippocampus, GR205,171 (but not GR226,206) also significantly increased dialysate levels of NA, whereas levels of 5-HT were unaffected. Further, in anaesthetized rats, GR205,171 dose-dependently (1.0-4.0 mg/kg, i.v.) increased the firing rate of adrenergic perikarya in the locus coeruleus. In contrast, their activity was not modified by GR226,206. These findings indicate that selective blockade of NK(1) receptors enhances the activity of ascending adrenergic pathways in rats. Adrenergic mechanisms may, thus, be involved in the potential antidepressant and other functional properties of NK(1) receptor antagonists.     

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。