Altered Neuronal Intrinsic Properties and Reduced Synaptic Transmission of the Rat's Medial Geniculate Body in Salicylate-Induced Tinnitus

Sodium salicylate (NaSal), an aspirin metabolite, can cause tinnitus in animals and human subjects. To explore neural mechanisms underlying salicylate-induced tinnitus, we examined effects of NaSal on neural activities of the medial geniculate body (MGB), an auditory thalamic nucleus that provides the primary and immediate inputs to the auditory cortex, by using the whole-cell patch-clamp recording technique in MGB slices. Rats treated with NaSal (350 mg/kg) showed tinnitus-like behavior as revealed by the gap prepulse inhibition of acoustic startle (GPIAS) paradigm. NaSal (1.4 mM) decreased the membrane input resistance, hyperpolarized the resting membrane potential, suppressed current-evoked firing, changed the action potential, and depressed rebound depolarization in MGB neurons. NaSal also reduced the excitatory and inhibitory postsynaptic response in the MGB evoked by stimulating the brachium of the inferior colliculus. Our results demonstrate that NaSal alters neuronal intrinsic properties and reduces the synaptic transmission of the MGB, which may cause abnormal thalamic outputs to the auditory cortex and contribute to NaSal-induced tinnitus.     

Pre & postsynaptic tuning of action potential timing by spontaneous GABAergic activity

Frequency and timing of action potential discharge are key elements for coding and transfer of information between neurons. The nature and location of the synaptic contacts, the biophysical parameters of the receptor-operated channels and their kinetics of activation are major determinants of the firing behaviour of each individual neuron. Ultimately the intrinsic excitability of each neuron determines the input-output function. Here we evaluate the influence of spontaneous GABAergic synaptic activity on the timing of action potentials in Layer 2/3 pyramidal neurones in acute brain slices from the somatosensory cortex of young rats. Somatic dynamic current injection to mimic synaptic input events was employed, together with a simple computational model that reproduce subthreshold membrane properties. Besides the well-documented control of neuronal excitability, spontaneous background GABAergic activity has a major detrimental effect on spike timing. In fact, GABA(A) receptors tune the relationship between the excitability and fidelity of pyramidal neurons via a postsynaptic (the reversal potential for GABA(A) activity) and a presynaptic (the frequency of spontaneous activity) mechanism. GABAergic activity can decrease or increase the excitability of pyramidal neurones, depending on the difference between the reversal potential for GABA(A) receptors and the threshold for action potential. In contrast, spike time jitter can only be increased proportionally to the difference between these two membrane potentials. Changes in excitability by background GABAergic activity can therefore only be associated with deterioration of the reliability of spike timing.     

Synaptic and intrinsic activation of GABAergic neurons in the cardiorespiratory brainstem network

GABAergic pathways in the brainstem play an essential role in respiratory rhythmogenesis and interactions between the respiratory and cardiovascular neuronal control networks. However, little is known about the identity and function of these GABAergic inhibitory neurons and what determines their activity. In this study we have identified a population of GABAergic neurons in the ventrolateral medulla that receive increased excitatory post-synaptic potentials during inspiration, but also have spontaneous firing in the absence of synaptic input. Using transgenic mice that express GFP under the control of the Gad1 (GAD67) gene promoter, we determined that this population of GABAergic neurons is in close apposition to cardioinhibitory parasympathetic cardiac neurons in the nucleus ambiguus (NA). These neurons fire in synchronization with inspiratory activity. Although they receive excitatory glutamatergic synaptic inputs during inspiration, this excitatory neurotransmission was not altered by blocking nicotinic receptors, and many of these GABAergic neurons continue to fire after synaptic blockade. The spontaneous firing in these GABAergic neurons was not altered by the voltage-gated calcium channel blocker cadmium chloride that blocks both neurotransmission to these neurons and voltage-gated Ca(2+) currents, but spontaneous firing was diminished by riluzole, demonstrating a role of persistent sodium channels in the spontaneous firing in these cardiorespiratory GABAergic neurons that possess a pacemaker phenotype. The spontaneously firing GABAergic neurons identified in this study that increase their activity during inspiration would support respiratory rhythm generation if they acted primarily to inhibit post-inspiratory neurons and thereby release inspiration neurons to increase their activity. This population of inspiratory-modulated GABAergic neurons could also play a role in inhibiting neurons that are most active during expiration and provide a framework for respiratory sinus arrhythmia as there is an increase in heart rate during inspiration that occurs via inhibition of premotor parasympathetic cardioinhibitory neurons in the NA during inspiration.     

5-HT7 receptors modulate GABAergic transmission in rat hippocampal CA1 area

The effects of the activation of serotonin-7 (5-HT(7)) receptors were investigated in the CA1 area pyramidal cells and stratum radiatum fast spiking GABAergic interneurons of rat hippocampal slices. To activate 5-HT(7) receptors, 5-carboxamidotryptamine (5-CT), a nonselective 5-HT(1A)/5-HT(7) agonist, was applied in the presence of N-[2-[4-(2-methoxyphenyl)-1piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY 100635), a selective 5-HT(1A) receptor antagonist. The activation of 5-HT(7) receptors resulted in a dose-dependent increase in the mean frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from pyramidal neurons while the mean amplitude of sIPSCs remained unaltered. A nonselective glutamate receptor antagonist, kynurenic acid, and voltage-gated sodium channel blocker, tetrodotoxin (TTX), attenuated but did not prevent the 5-HT(7) receptor-mediated increase of sIPSCs frequency in pyramidal cells. 5-CT application did not influence the excitability of stratum radiatum interneurons but it dose-dependently increased the mean frequency of spontaneous excitatory postsynaptic currents (sEPSCs) recorded from interneurons while the mean amplitude of sEPSCs remained unaltered. These data suggest that the activation of 5-HT(7) receptors results in an enhancement of the GABAergic transmission in the hippocampal CA1 area via two mechanisms. The first one involves an enhancement of excitatory glutamatergic input to GABAergic interneurons and is likely to be mediated by presynaptic 5-HT(7) receptors. The second effect, most likely related to the activation of 5-HT(7) receptors located on interneurons, results in an enhancement of the release of GABA.     

Long-lasting increases in intrinsic excitability triggered by inhibition

Although experience-dependent changes in neural circuits are commonly assumed to be mediated by synaptic plasticity, modifications of intrinsic excitability may serve as a complementary mechanism. In whole-cell recordings from spontaneously firing vestibular nucleus neurons, brief periods of inhibitory synaptic stimulation or direct membrane hyperpolarization triggered long-lasting increases in spontaneous firing rates and firing responses to intracellular depolarization. These increases in excitability, termed firing rate potentiation, were induced by decreases in intracellular calcium and expressed as reductions in the sensitivity to the BK-type calcium-activated potassium channel blocker iberiotoxin. Firing rate potentiation is a novel form of cellular plasticity that could contribute to motor learning in the vestibulo-ocular reflex.     

中枢阿片神经系统对焦虑情绪的调控作用及其机制探讨

吗啡依赖大鼠自发戒断后其主动接触时间和突期舔水次数均显著减少,并可被５－ＨＴ１Ａ受体激动丁螺环酮和色氨酸羟化酸抑制剂对氯苯丙氨酸所对抗。纳曲酮也可使上述两指标降低,并可被吗啡和ＰＣＰＡ所拮抗、被５－羟色氨酸所增强。     

Effect of serotonin on the activity of the neurons involved in the realization of the avoidance reflex of the snail

Bath application of 10(-5) mol/l of serotonin (5-HT) elicited a 50% increase of summary EPSPs recorded in command neurones for avoidance behaviour. No significant changes of rest potential and input resistance were seen in these cells. 5-HT evoked an increase of spontaneous level of firing in motoneurones involved in the same reflex, as well as an increase in the number of spikes which paralleled increase of EPSPs to the same stimulus in command neurones. In sensory cells, presynaptic to the command neurones, application of 5-HT evoked a significant increase of excitability and of input resistance. Monosynaptic EPSPs recorded in the command neurones showed a 40% increase after serotonin application. It is concluded that the major locus of plastic changes evoked by 5-HT application in the neuronal chain underlying avoidance reflex is the synaptic contact between sensory and command neurones.     

Developmental changes in intrinsic excitability of principal neurons in the rat medial nucleus of the trapezoid body

The calyx of Held synapse is a giant axosomatic synapse that has a fast relay function within the sound localization circuit of the brainstem. In the adult, each principal neuron of the medial nucleus of the trapezoid body (MNTB) is contacted by a single calyx terminal. In rodents, the calyx of Held synapse forms around the third postnatal day (P3). Here, we studied the developmental changes in the intrinsic excitability of the principal neurons during the first postnatal week by making whole-cell recordings from brainstem slices. In slices from P0-1 rats, about 20% of the principal neurons were spontaneously active, whereas after P3, no spontaneously active cells were observed. Already at P0, principal neurons received both glutamatergic and GABAergic/glycinergic inputs. The occurrence of spontaneous action potentials depended upon the presence of spontaneous glutamatergic inputs; summation of only a few quanta was enough to reach action potential threshold. The main cause for this high excitability was a high resting membrane resistance, which decreased at least four-fold during the first postnatal week. A relatively slow decay of synaptic currents and a relatively depolarized membrane potential may have contributed as well. We conclude that the decrease in the excitability of principal neurons in the MNTB matches the increase of the strength of the synaptic inputs resulting from the formation and maturation of the calyx of Held synapse during the first postnatal week. This decrease in excitability will make it progressively more difficult for non-calyceal inputs to trigger action potentials.     

Homeostatic Plasticity of Striatal Neurons Intrinsic Excitability following Dopamine Depletion

The striatum is the major input structure of basal ganglia and is involved in adaptive control of behaviour through the selection of relevant informations. Dopaminergic neurons that innervate striatum die in Parkinson disease, leading to inefficient adaptive behaviour. Neuronal activity of striatal medium spiny neurons (MSN) is modulated by dopamine receptors. Although dopamine signalling had received substantial attention, consequences of dopamine depletion on MSN intrinsic excitability remain unclear. Here we show, by performing perforated patch clamp recordings on brain slices, that dopamine depletion leads to an increase in MSN intrinsic excitability through the decrease of an inactivating A-type potassium current, I _A. Despite the large decrease in their excitatory synaptic inputs determined by the decreased dendritic spines density and the increase in minimal current to evoke the first EPSP, this increase in intrinsic excitability resulted in an enhanced responsiveness to their remaining synapses, allowing them to fire similarly or more efficiently following input stimulation than in control condition. Therefore, this increase in intrinsic excitability through the regulation of I _A represents a form of homeostatic plasticity allowing neurons to compensate for perturbations in synaptic transmission and to promote stability in firing. The present observations show that this homeostatic ability to maintain firing rates within functional range also occurs in pathological conditions, allowing stabilizing neural computation within affected neuronal networks.     

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.     

Presynaptic serotonergic modulation of spontaneous and miniature synaptic activity in frog lumbar motoneurons

The effects of serotonin (5-HT, 30 μM) on spontaneous and miniature synaptic activity in lumbar motoneurons from the isolated Rana ridibunda spinal cord were investigated using intracellular recording. 5-HT increased the frequency of spontaneous (sPSPs) and miniature postsynaptic potentials (mPSPs). The effect of 5-HT on different subpopulations of mPSPs was multidirectional: it increased the frequency of glutamatergic excitatory mPSPs by 18% and decreased the frequency of glycinergic inhibitory mPSPs by 28%, but had no effect on the frequency of GABAergic inhibitory mPSPs. The amplitude and kinetic parameters of any subpopulation of mPSPs did not change. The data obtained show that 5-HT regulates the probability of glutamate and glycine release from the presynaptic terminals ending at frog spinal motoneurons. 5-HT shifts the balance between synaptic excitation and inhibition in the spinal neural network toward excitation. Thus, 5-HT participates in control of motor output and provides its facilitation.     

GABA(B) receptors in 5-HT transporter- and 5-HT1A receptor-knock-out mice: further evidence of a transduction pathway shared with 5-HT1A receptors

The functional properties of GABA(B) receptors were examined in the dorsal raphe nucleus (DRN) and the hippocampus of knock-out mice devoid of the 5-HT transporter (5-HTT-/-) or the 5-HT(1A) receptor (5-HT(1A)-/-). Electrophysiological recordings in brain slices showed that the GABA(B) receptor agonist baclofen caused a lower hyperpolarization and neuronal firing inhibition of DRN 5-HT cells in 5-HTT-/- versus 5-HTT+/+ mice. In addition, [(35)S]GTP-gamma-S binding induced by GABA(B) receptor stimulation in the DRN was approximately 40% less in these mutants compared with wild-type mice. In contrast, GABA(B) receptors appeared functionally intact in the hippocampus of 5-HTT-/-, and in both this area and the DRN of 5-HT(1A)-knock-out mice. The unique functional changes of DRN GABA(B) receptors closely resembled those of 5-HT(1A) autoreceptors in 5-HTT-/- mice, further supporting the idea that both receptor types are coupled to a common pool of G-proteins in serotoninergic neurons.     

Mechanism of activation of human c-KIT kinase by internal tandem duplications of the juxtamembrane domain and point mutations at aspartic acid 816

The patients suffering from acidosis usually sign psychological deficits. The cerebral dysfunction is reportedly caused by an acid-induced functional impairment of GABAergic neurons; however, the role of pyramidal neurons in this process remains unclear. By using electrophysiological method and changing extracellular pH, we investigated the influence of acidic environment on pyramidal neurons in the cortical slices, such as their ability of firing spikes and response to synaptic inputs. A low pH of artificial cerebral spinal fluid elevates the responses of pyramidal neurons to excitatory synaptic inputs and their ability of encoding digital spikes, as well as reduces the signal transmission at GABAergic synapses. The elevated ability of neuronal spiking is associated with the decreases of refractory periods and threshold potentials. Therefore, acidosis deteriorates brain functions through making the activities between cortical pyramidal neurons and GABAergic neurons imbalanced toward the overexcitation of neural networks, a process similar to neural excitotoxicity.     

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。     

5-HT对弓状核神经元的直接兴奋作用和通过GABA能局部神经元实现的抑制作用

用大鼠离体灌流脑片的细胞外单一神经元电生理记录技术,观察了5－HT对弓状核神经元自发放电的影响。结果表明：（1）在随机选取的149个神经元中,有33个（22．2％）可被5－HT兴奋,82个（55．0％）被抑制,其余34个（22．8％）出现双相反应或不出现反应;（2）用低Ca^2 -高Mg^2 人工脑脊液替换正常人工脑脊液后,5－HT引起的兴奋效应仍可出现,但5－HT引起的抑制效应不再出现;（3）5－HT受体的非选择性拮抗剂cyproheptadine对5－HT引起的兴奋或抑制都有阻断作用;（4）用GABA受体拮抗剂bicuculline(Bic)可以阻断5－HT引起的抑制作用。据此推测：（1）5－HT的兴奋效应对低Ca^2 环境不敏感,因而是5－HT直接作用于所记录细胞的结果;（2）5－HT的抑制效应对低C a^2 敏感,并可被Bic所阻断,因而－HT可能是兴奋了局部GABA能中间神经元,后者再通过释放GABA抑制了所记录的神经元。     

Role of dorsal raphe nucleus serotonin 5-HT1A receptor in the regulation of REM sleep

Cholinergic neurons in the laterodorsal (LDT) and the pedunculopontine (PPT) tegmental nuclei act to promote REM sleep (REMS). The predominantly glutamatergic neurons of the REMS-induction region of the medial pontine reticular formation are in turn activated by cholinergic cells, which results in the occurrence of tonic and phasic components of REMS. All these neurons are inhibited by serotonergic (5-HT), noradrenergic, and presumably histaminergic (H2 receptor) and dopaminergic (D2 and D3 receptor) cells. 5-Hydroxytryptamine-containing neurons in the dorsal raphe nucleus (DRN) virtually cease firing when an animal starts REMS, consequently decreasing the release of 5-HT during this state. The activation of GABA(A) receptors is apparently responsible for this phenomenon. Systemic administration of the selective 5-HT1A receptor agonist 8-OHDPAT induces dose-dependent effects; i.e. low doses increase slow wave sleep and reduce waking, whereas large doses increase waking and reduce slow wave sleep and REM sleep. Direct injection of 8-OHDPAT or flesinoxan, another 5-HT1A agonist into the DRN, or microdialysis perfusion of 8-OHDPAT into the DRN significantly increases REMS. On the other hand, infusion of 8-OHDPAT into the LDT selectively inhibits REMS, as does direct administration into the DRN of the 5-HT1A receptor antagonists pindolol or WAY 100635. Thus, presently available evidence indicates that selective activation of the somatodendritic 5-HT1A receptor in the DRN induces an increase of REMS. On the other hand, activation of the postsynaptic 5-HT1A receptor at the level of the PPT/LDT nuclei decreases REMS occurrence.     

Sustained pharmacological blockade of NK1 substance P receptors causes functional desensitization of dorsal raphe 5-HT 1A autoreceptors in mice

Antagonists at NK1 substance P receptors have demonstrated similar antidepressant properties in both animal paradigms and in human as selective serotonin reuptake inhibitors (SSRIs) that induce desensitization of 5-HT 1A autoreceptors within the dorsal raphe nucleus (DRN). We investigated whether this receptor adaptation also occurs upon NK1 receptor blockade. C57B/L6J mice were treated for 21 days with the selective NK1 receptor antagonist GR 205171 (10 mg/kg daily) through subcutaneously implanted osmotic mini pumps, and DRN 5-HT 1A autoreceptor functioning was assessed using various approaches. Recording of DRN serotonergic neurons in brainstem slices showed that GR 205171 treatment reduced (by approximately 1.5 fold) the potency of the 5-HT 1A receptor agonist, ipsapirone, to inhibit cell firing. In parallel, the 5-HT 1A autoreceptor-mediated [35S]GTP-gamma-S binding induced by 5-carboxamidotryptamine onto the DRN in brainstem sections was significantly decreased in GR 205171-treated mice. In vivo microdialysis showed that the cortical 5-HT overflow caused by acute injection of the SSRI paroxetine (1 mg/kg) was twice as high in GR 205171-treated as in vehicle-treated controls. In the DRN, basal 5-HT outflow was significantly enhanced by GR 205171 treatment. These data supported the hypothesis that chronic NK1 receptor blockade induces a functional desensitization of 5-HT 1A autoreceptors similar to that observed with SSRIs.     

Cav1.2 calcium channels modulate the spiking pattern of hippocampal pyramidal cells

Ca(v)1.2 L-type calcium channels support hippocampal synaptic plasticity, likely by facilitating dendritic Ca2+ influx evoked by action potentials (AP) back-propagated from the soma. Ca2+ influx into hippocampal neurons during somatic APs is sufficient to activate signalling pathways associated with late phase LTP. Thus, mechanisms controlling AP firing of hippocampal neurons are of major functional relevance. We examined the excitability of CA1 pyramidal cells using somatic current-clamp recordings in brain slices from control type mice and mice with the Ca(v)1.2 gene inactivated in principal hippocampal neurons. Lack of the Ca(v)1.2 protein did not affect either affect basic characteristics, such as resting membrane potential and input resistance, or parameters of single action potentials (AP) induced by 5 ms depolarising current pulses. However, CA1 hippocampal neurons from control and mutant mice differed in their patterns of AP firing during 500 ms depolarising current pulses: threshold voltage for repetitive firing was shifted significantly by about 5 mV to more depolarised potentials in the mutant mice (p<0.01), and the latency until firing of the first AP was prolonged (73.2+/-6.6 ms versus 48.1+/- 7.8 ms in control; p<0.05). CA1 pyramidal cells from the mutant mice also showed a lowered initial spiking frequency within an AP train. In control cells, isradipine had matching effects, while BayK 8644 facilitated spiking. Our data demonstrate that Ca(v)1.2 channels are involved in regulating the intrinsic excitability of CA1 pyramidal neurons. This cellular mechanism may contribute to the known function of Ca(v)1.2 channels in supporting synaptic plasticity and memory.     

The effects of 5-HT on sensory, central and motor neurons driving the abdominal superficial flexor muscles in the crayfish

Serotonin (5-HT) induces a variety of physiological and behavioral effects in crustaceans. However, the mechanisms employed by 5-HT to effect behavorial changes are not fully understood. Among the mechanisms by which these changes might occur are alterations in synaptic drive and efficacy of sensory, interneurons and motor neurons, as well as direct effects on muscles. We investigated these aspects with the use of a defined sensory-motor system, which is entirely contained within a single abdominal segment and consists of a ‘cuticular sensory neurons–segmental ganglia–abdominal superficial flexor motor neurons–muscles’ circuit. Our studies address the role of 5-HT in altering (1) the activity of motor neurons induced by sensory stimulation; (2) the inherent excitability of superficial flexor motor neurons; (3) transmitter release properties of the motor nerve terminal and (4) input resistance of the muscle. Using en passant recordings from the motor nerve, with and without sensory stimulation, and intracellular recordings from the muscle, we show that 5-HT enhances sensory drive and output from the ventral nerve cord resulting in an increase in the firing frequency of the motor neurons. Also, 5-HT increases transmitter release at the neuromuscular junction, and alters input resistance of the muscle fibers     

Identification of 5-HT receptor subtypes enhancing inhibitory transmission in the rat spinal dorsal horn in vitro

ABSTRACT: BACKGROUND: 5-hydroxytryptamine (5-HT) is one of the major neurotransmitters widely distributed in the CNS. Several 5-HT receptor subtypes have been identified in the spinal dorsal horn which act on both pre- and postsynaptic sites of excitatory and inhibitory neurons. However, the receptor subtypes and sites of actions as well as underlying mechanism are not clarified rigorously. Several electrophysiological studies have been performed to investigate the effects of 5-HT on excitatory transmission in substantia gelatinosa (SG) of the spinal cord. In the present study, to understand the effects of 5-HT on the inhibitory synaptic transmission and to identify receptor subtypes, the blind whole cell recordings were performed from SG neurons of rat spinal cord slices. RESULTS: Bath applied 5-HT (50 microM) increased the frequency but not amplitudes of spontaneous inhibitory postsynaptic currents (sIPSCs) in 58% of neurons, and both amplitude and frequency in 23 % of neurons. The frequencies of GABAergic and glycinergic mIPSCs were both enhanced. TTX (0.5 microM) had no effect on the increasing frequency, while the enhancement of amplitude of IPSCs was eliminated. Evoked-IPSCs (eIPSCs) induced by focal stimulation near the recording neurons in the presence of CNQX and APV were enhanced in both amplitude by 5-HT. In the presence of Ba2+ (1 mM), a potassium channel blocker, 5-HT had no effect on both frequency and amplitude. A 5-HT2Areceptor agonist, TCB-2 mimicked the 5-HT effect, and ketanserin, an antagonist of 5-HT2A receptor, inhibited the effect of 5-HT partially and TCB-2 almost completely. A 5-HT2C receptor agonist WAY 161503 mimicked the 5-HT effect and this effect was blocked by a 5-HT2C receptor antagonist, N-desmethylclozapine. The amplitude of sIPSCs were unaffected by both agonists. A 5-HT3 receptor agonist mCPBG enhanced both amplitude and frequency of sIPSCs. This effect was blocked by a 5-HT3 receptor antagonist ICS-205,930. The perfusion of 5-HT2B receptor agonist had no effect on sIPSCs. CONCLUSIONS: Our results demonstrated that 5-HT modulated the inhibitory transmission in SG by the activation of 5-HT2A and 5-HT2C receptors subtypes located predominantly at inhibitory interneuron terminals, and 5-HT3 receptors located at inhibitory interneuron terminals and soma-dendrites, consequently enhanced both frequency and amplitude.