Methylenedioxymethamphetamine-induced hyperthermia and neurotoxicity are independently mediated by 5-HT2 receptors

Methylenedioxymethamphetamine (MDMA) produced a significant hyperthermia in rats which was antagonized in a competitive manner by the selective 5-HT2 antagonist, MDL 11,939. The 5-HT antagonist also blocked MDMA-induced neurotoxicity as assessed by the decline in regional 5-HT concentrations observed 1 week later. These two effects of MDL 11,939 were dissociated at higher doses of MDMA where the antagonist still provided virtually complete protection against the neurochemical deficits but only partially attenuated the hyperthermic response. In contrast to the effect of the 5-HT2 antagonist, haloperidol did not alter MDMA-induced hyperthermia but did antagonize its long-term neurochemical effects. Similarly, coadministration of the selective 5-HT uptake inhibitor, MDL 27,777, did not affect the hyperthermia produced by a high dose of MDMA but completely prevented the depletion of 5-HT. When the MDMA-induced hyperthermia was prevented by temporarily maintaining animals at reduced ambient temperature, the neurochemical changes normally observed 1 week later were also blocked. Although these results demonstrate that the drugs tested do not antagonize MDMA-induced neurotoxicity by interfering with its effect on body temperature, they do indicate that MDMA-induced hyperthermia may contribute to the development of the drug's long-term neurochemical effects.     

Modulation of dopamine release by striatal 5-HT2C receptors

Previous work has demonstrated that dopamine (DA) transmission is regulated by serotonin-2C (5-HT2C) receptors but the site(s) in the brain where these receptors are localized is not known. The present work utilized in vivo microdialysis to investigate the modulation of DA release by 5-HT2C receptors localized in the nerve terminal regions of the mesocortical and nigrostriatal DA pathways. Microdialysis probes implanted in the striatum or the prefrontal cortex (PFC) measured dialysate DA concentrations, while the selective 5-HT2B/2C inverse agonist SB 206553 was given locally by reverse dialysis into these terminal regions. Additionally, the effects of the 5-HT2C agonist mCPP on striatal DA were measured. Local administration of SB 206553 (0.1-100 microM) into the striatum increased DA efflux in a concentration-dependent manner. Systemic administration of mCPP (1.0 mg/kg i.p.) decreased striatal DA and attenuated the SB 206553-induced increase. In contrast, infusion of SB 206553 (0.1-500 microM) by reverse dialysis into the PFC had no significant effect on basal DA efflux in this region. Additionally, high concentrations of SB 206553 had no effect on high potassium (K(+))-stimulated DA release in the PFC. These data contribute to a body of evidence indicating that 5-HT2C receptors inhibit nigrostriatal dopaminergic transmission. In addition, the results suggest that the nigrostriatal system is regulated by 5-HT2C receptors localized in the dorsal striatum. Elucidating the mechanisms by which serotonin (5-HT) modulates striatal and prefrontocortical DA concentrations may lead to improvements in the treatment of diverse syndromes such as schizophrenia, Parkinson's disease, anxiety, drug abuse, and/or depression.     

Direct activation by dopamine of recombinant human 5-HT1A receptors: comparison with human 5-HT2C and 5-HT3 receptors

The effects of dopamine (DA) on the function of human 5-HT1A receptors expressed in Xenopus oocytes and CHO-K1 cells were investigated. In addition, the effect of DA on the activation of three different types of human 5-HT receptors (5-HT1A, 5-HT2C, and 5-HT3) were studied comparatively in Xenopus oocyte expression system. Application of 5-HT or DA in oocytes coexpressing 5-HT1A receptors and G-protein-activated inwardly rectifying potassium channels (GIRK1) induced inward currents with respective EC50 values of 4.2 nM and 11.2 microM. Maximal responses induced by DA were 85 +/- 4% of maximal 5-HT currents and DA responses were blocked by the specific 5-HT1A antagonist, WAY-100635 (50 nM). In CHO-K1 cells expressing 5-HT1A receptors, 5-HT and DA inhibited the specific binding of selective antagonist [3H]-8-OH-DPAT with IC50 values of 10.2 nM and 1.4 microM, and both 5-HT and DA inhibited the forskolin-induced accumulation of cAMP. In oocytes expressing 5-HT2C receptors, 5-HT and DA induced inward currents with respective EC50 values of 6.2 nM and 67.7 microM. Magnitudes of maximal DA induced currents were 42 +/- 3% of maximal 5-HT responses and blocked by the 5-HT2 antagonist, piperazine (1 microM). In oocytes expressing 5-HT3 receptors, 5-HT and DA induced fast inward currents with respective EC50 values of 2.1 microM and 266.3 microM. Maximal DA induced currents were 37 +/- 3% of maximal 5-HT responses and blocked the specific 5-HT3 antagonist LY-278584 (0.1 microM). Comparison of the potencies and efficacies of 5-HT and DA indicated that the relative potency of DA increased in the order of 5-HT3 > 5-HT1A > 5-HT2C, and relative efficacy increased in the order of 5-HT1A > 5-HT2C > 5-HT3. These results suggest that although DA activates different subtypes of human 5-HT receptors directly, the potency and efficacy of the binding site varies significantly among different receptors.     

Behavioral pharmacology of antagonists at 5-HT2/5-HT1C receptors.

The possible implication of 5-HT2 receptors in CNS disorders such as schizophrenia, anxiety and depression suggests that 5-HT2 antagonists may be useful in the treatment of these disorders. The present review examines behavioral procedures used to characterize 5-HT2 antagonist properties of compounds and behavioral models of clinical activity in which 5-HT2 antagonists have been reported to be active. The pharmacological profile of 5-HT2 receptors in part resembles that of 5-HT1C receptors. Responses that have been proposed to involve the activation of 5-HT1C receptors are examined for their usefulness to detect 5-HT1C antagonist properties of compounds; these responses would help to differentiate 5-HT2 from 5-HT1C antagonist activity.     

Tachyphylaxis to 5-HT3-receptor-mediated activation of vagal afferents is prevented by co-activation of 5-HT2 receptors

Functional studies have provided evidence that 5-HT(3) ion-channel receptors (5-HT(3)Rs) on vagal cardiopulmonary afferents mediating the Bezold-Jarisch reflex (BJR) rapidly desensitize upon repeated exposure to selective 5-HT(3)R agonists. G-protein-coupled 5-HT(2) receptors (5-HT(2)Rs) also exist on vagal afferents, although activation of these receptors does not elicit the BJR. However, there is in vivo evidence that 5-HT(2)Rs may regulate the activity of 5-HT(3)Rs. The aim of this study was to determine whether co-activation of 5-HT(2)Rs prevents desensitization of 5-HT(3)Rs mediating the BJR in conscious rats. The principal findings were that (1) tachyphylaxis rapidly developed to the BJR-mediated hemodynamic responses elicited by successive injections of 5-HT(3)R agonists and (2) co-injection of the selective 5-HT(2)R agonist, alpha-methyl-5-HT, prevented tachyphylaxis to the BJR-mediated hemodynamic responses elicited by the 5-HT(3)R agonists. Additional studies provided evidence that (1) tachyphylaxis to the 5-HT(3)R agonists was not due to impairment of the central or efferent processing of the BJR, and (2) the pressor responses elicited by alpha-methyl-5-HT were not responsible for preventing tachyphylaxis to the BJR reflex responses elicited by 5-HT(3)R agonists. These results suggest that the loss of response to 5-HT(3)R agonists is due to desensitization of 5-HT(3)Rs on vagal afferents mediating the BJR and that co-activation of 5-HT(2)Rs prevents the desensitization of these 5-HT(3)Rs.     

Effect of the activation of central 5-HT2C receptors by the 5-HT2C agonist mCPP on blood pressure and heart rate in rats

In the present study we investigated the role of central 5-HT2C receptors in the control of blood pressure and heart rate in non-stressed and stressed, adult, male, Wistar rats. Third ventricle injections of the 5-HT2C agonist mCPP elicited a significant increase in blood pressure in non-stressed animals. The initial period of this hypertensive response (10-30 min after mCPP administration) was accompanied by baroreflex-mediated bradycardia, while after this period the coexistence of hypertension and tachycardia was observed. These cardiovascular effects promoted by the central administration of mCPP were blocked by pretreatment with the 5-HT2C antagonist, SDZ SER 082. The administration of SDZ SER 082 alone induced no significant changes in blood pressure or heart rate. The pharmacological stimulation of central 5-HT2C receptors by mCPP did not change the hypertensive or tachycardic responses induced by restraint stress. Conversely, the blockade of central 5-HT2C receptors by SDZ SER 082 blunted stress-induced hypertension without modifying stress-induced tachycardia. It is concluded that the activation of central 5-HT2C receptors induces hypertension in non-stressed rats and that the normal function of these receptors is essential for the rise in blood pressure that occurs in the course of restraint stress.     

Stimulation of 5-HT1A, 5-HT1B, 5-HT2A/2C, 5-HT3 and 5-HT4 receptors or 5-HT uptake inhibition: short- and long-term memory

In order to determine whether short- (STM) and long-term memory (LTM) function in serial or parallel manner, serotonin (5-hydroxtryptamine, 5-HT) receptor agonists were tested in autoshaping task. Results show that control-vehicle animals were modestly but significantly mastering the autoshaping task as illustrated by memory scores between STM and LTM. Thus, post-training administration of 8-OHDPAT (agonist for 5-HT(1A/7) receptors) only at 0.250 and 0.500 mg/kg impaired both STM and LTM. CGS12066 (agonist for 5-HT(1B)) produced biphasic affects, at 5.0 mg/kg impaired STM but at 1.0 and 10.0 mg/kg, respectively, improved or impaired LTM. DOI (agonist for 5-HT(2A/2C) receptors) dose-dependently impaired STM and, at 10.0 mg/kg only impaired LTM. Both, STM and LTM were impaired by either mCPP (mainly agonist for 5-HT(2C) receptors) or mesulergine (mainly antagonist for 5-HT(2C) receptors) lower dose. The 5-HT(3) agonist mCPBG at 1.0 impaired STM and its higher dose impaired both STM and LTM. RS67333 (partial agonist for 5-HT(4) receptors), at 5.0 and 10.0 mg/kg facilitated both STM and LTM. The higher dose of fluoxetine (a 5-HT uptake inhibitor) improved both STM and LTM. Using as head-pokes during CS as an indirect measure of food-intake showed that of 30 memory changes, 21 of these were unrelated to the former. While some STM or LTM impairments can be attributed to decrements in food-intake, but not memory changes (either increase or decreases) produced by 8-OHDPAT, CGS12066, RS67333 or fluoxetine. Except for animals treated with DOI, mCPBG or fluoxetine, other groups treated with 5-HT agonists 6 h following autoshaping training showed similar LTM and unmodified CS-head-pokes scores.     

5-HT2C受体在癫患者脑组织的表达

目的研究5-羟色胺2C受体(5-HT2C受体)在癫患者脑组织的表达,探索其临床意义。方法用免疫组化方法检测46例癫患者术后脑组织5-HT2C受体的表达,研究比较不同部位不同病程脑组织表达。结果癫患者额叶脑组织5-HT2C受体的含量较颞叶海马明显增高,长病程组表达低于短病程组。结论 5-HT2C受体可能参与了癫的发病机制,改变5-HT2C受体的表达有望成为癫新的治疗靶点。     

Inhibition of rat nucleus tractus solitarius neurones by activation of 5-HT2C receptors

In vivo, nucleus tractus solitarius (NTS) neurones receiving monosynaptic vagal input and inactive intermediate neurones were inhibited by both DOI and a selective 5-HT2C receptor agonist, MK-212. Cells receiving a more polysynaptic input were excited by DOI and although MK-212 also excited a few of these cells, the majority of cells in these groups were unaffected by MK-212. The inhibitory, but not the excitatory actions of both MK-212 and DOI were prevented by a selective 5-HT2C receptor antagonist, RS-102221. In contrast, most dorsal vagal preganglionic neurones were unaffected by application of either DOI or MK-212, the few remaining cells being excited by both agonists. These data demonstrate that DOI-evoked inhibition of NTS cells activated by vagal afferent input and DOI-evoked excitation of vagal preganglionic neurones is mediated by 5-HT2C receptors.     

Different roles of 5-HT2A and 5-HT2C receptors in regulation of female rat paced mating behaviour

Serotonin (5-HT) receptor 2A (5-HT2A) and 2C (5-HT2C) agonists have been reported to facilitate female rat lordosis behaviour. This study investigated the acute effects of the 5-HT2A receptor agonist DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) and the 5-HT2C receptor agonist MK-212 (2-chloro-6-(1-piperazinyl) pyrazine) on paced mating behaviour in a population of sexually receptive female rats in order to explore the role of 5-HT2A and 5-HT2C receptors in the mediation of female rat sexual motivation. DOI (0.5 and 1.0 mg/kg) increased female rat sexual motivation during the first of two consecutive copulatory series seen as a tendency towards a decrease in return latencies following ejaculation and decreased inter-intromission intervals. MK-212 generally increased approach latencies. 0.5 mg/kg MK-212 increased post-ejaculatory exit latency, while 1.0 and 2.0 mg/kg MK-212 increased both post-ejaculatory exit latencies and post-ejaculatory return latencies. The possibility that an increased level of anxiety confounded the effects of MK-212 on sexual motivation behaviour is discussed. The results may support the hypothesis that both 5-HT2A and 5-HT2C receptors are important in regulation of female sexual behaviour.     

5-HT2A/C receptors mediate the antipsychotic-like effects of alstonine

The purpose of this study was to determine the effects of alstonine, an indole alkaloid with putative antipsychotic effects, on working memory by using the step-down inhibitory avoidance paradigm and MK801-induced working memory deficits in mice. Additionally, the role of serotonin 5-HT_2A/C receptors in the effects of alstonine on mouse models associated with positive (MK801-induced hyperlocomotion), negative (MK801-induced social interaction deficit), and cognitive (MK801-induced working memory deficit) schizophrenia symptoms was examined. Treatment with alstonine was able to prevent MK801-induced working memory deficit, indicating its potential benefit for cognitive deficits now seen as a core symptom in the disease. Corroborating previously reported data, alstonine was also effective in counteracting MK801-induced hyperlocomotion and social interaction deficit. Ritanserin, a 5-HT_2A/C receptor antagonist, prevented alstonine's effects on these three behavioral parameters. This study presents additional evidence that 5-HT_2A/C receptors are central to the antipsychotic-like effects of alstonine, consistently seen in mouse models relevant to the three dimensions of schizophrenia symptoms.     

Anti-serotonergic effects of urethane and chloral hydrate may not be mediated by a blockade of 5-HT2 receptors

Summary The general anesthetics urethane and chloral hydrate have profound anti-serotonergic effects both in the rat cortex in vivo and the rat aortic ring in vitro. The suggestion that these effects may be due to an action on 5-HT₂ receptors was tested using ex vivo and in vitro [³H]ketanserin binding assays with membrane-enriched fractions from rat brain. Urethane did not alter [³H]ketanserin binding in the ex vivo assay. In the in vitro assay, urethane, chloral hydrate, and its active metabolite 2,2,2-trichloroethanol produced slight reductions (of 16%, 9%, and 18%, respectively) of [³H]ketanserin binding. These studies suggest that anti-serotonergic effects of urethane and chloral hydrate may not be mediated by a blockade of 5-HT₂ receptors.     

Regulation of striatal dopamine release through 5-HT1 and 5-HT2 receptors

Dopamine (DA) release in the striatum is regulated by 5-hydroxytryptamine (5-HT, serotonin) through putative heteroreceptors. However, the effect of 5-HT is controversial. The present study investigated the effects of different 5-HT receptor ligands on DA release in the rat striatum by using in vivo microdialysis in conscious and freely moving rats. Perfusion with 5-carboxamidotryptamine, anpirtoline, pindobind-5-HT1A, and isamoltane demonstrated the involvement of 5-HT1A and 5-HT1B receptors in facilitating DA release. In contrast, 5-HT2 receptors mediated inhibition of DA efflux, as shown by experiments with DOI [R-(-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] and ketanserin. A 5-HT3 agonist (1-(m-chlorophenyl)-biguanide hydrochloride) did not have any effect. None of the agonists used affected DA uptake into striatal synaptosomes. Unilateral 6-hydroxydopamine lesioning of the nigrostriatal DA pathway led to a selective decrease in 5-HT2 receptors. It is concluded that there are 5-HT2 heteroreceptors at the dopaminergic terminals that mediate inhibition of DA release. Further investigation is required to clarify the localization of the 5-HT1 receptors in the striatum.     

Excitatory responses to serotonin (5-HT) in neurons of the rat piriform cortex: evidence for mediation by 5-HT1C receptors in pyramidal cells and 5-HT2 receptors in interneurons.

As a prerequisite to pharmacological analysis of the excitatory effects of serotonin (5-HT) on piriform pyramidal cells and interneurons, this study first examined the physiological characteristics of these two cell types. Intracellular recordings confirmed that the subpopulation of 5-HT-activated cells located at the border of layers II and III are indeed interneurons. Voltage clamp recordings in pyramidal cells showed that the increase in excitability produced by 5-HT in these cells was the result of voltage- and Ca(2+)-dependent outward currents with the characteristics of IM and IAHP. Pharmacological studies were designed to discriminate 5-HT2 from 5-HT1C responses in interneurons and pyramidal cells of piriform cortex. The 5-HT antagonist spiperone, which has a much higher affinity for 5-HT2 receptors than for 5-HT1C receptors, blocked the excitatory effect of 5-HT at lower concentrations in interneurons (IC50 = 31 nM) than in pyramidal cells (IC50 = 2.1 microM). Similarly, ritanserin, a drug which also has a higher affinity for 5-HT2 than 5-HT1C receptors, blocked the effect of 5-HT at lower concentrations in interneurons (IC50 = 400 nM) than in pyramidal cells (IC50 = 8.1 microM). In contrast, LY 53857, an antagonist with higher affinity for 5-HT1C than for 5-HT2 receptors, blocked the effect of 5-HT at lower concentrations in pyramidal cells (IC50 = 26 nM) than in interneurons (IC50 = 364 nM). The 5-HT1C partial agonist/5-HT2 antagonist mCPP produced agonist-like effects in only 66% of pyramidal cells tested indicating that not all pyramidal cells may express 5-HT1C receptors. In that both spiperone and ritanserin have higher affinity for 5-HT2 receptors than for 5-HT1C receptors and LY 53857 has a higher affinity for 5-HT1C receptors than for 5-HT2 receptors, these data suggest that in piriform cortex excitatory effects of 5-HT are mediated by 5-HT1C receptors in pyramidal cells an by 5-HT2 receptors in interneurons.     

5-HT2C receptors inhibit and 5-HT1A receptors activate the generation of spike-wave discharges in a genetic rat model of absence epilepsy

The present study was conducted to investigate the role of 5-HT(2C) and 5-HT(1A) receptors in the generation of spike-wave discharges (SWD) in the genetic absence epilepsy model Wistar Albino Glaxo rats from Rijswijk, Netherlands (WAG/Rij rats). We have determined the effects of the 5-HT(2C) receptor preferring agonist m-chlorophenyl-piperazine (m-CPP), the selective 5-HT(2C) receptor antagonist SB-242084, the selective 5-HT(1A) receptor antagonist WAY-100635, two selective serotonin re-uptake inhibitors (SSRI, fluoxetine and citalopram) and their combinations in this model. The 5-HT(2C) agonist m-CPP caused marked, dose-dependent decreases in the cumulative duration and number of SWD administered either intraperitoneally (0.9 and 2.5 mg/kg) or intracerebroventricularly (0.05 and 0.1 mg/kg). Treatment with SB-242084 (0.2 mg/kg, ip) alone failed to cause any significant change in SWD compared to vehicle. Pretreatment with SB-242084 (0.2 mg/kg, ip) eliminated the effects of m-CPP on SWD. Fluoxetine (5.0 mg/kg, ip) alone caused moderate increase in SWD. After pretreatment with SB-242084, the effect of fluoxetine was significantly enhanced. The combination of SB-242084 and citalopram (2.5 mg/kg, ip) caused a similar effect, namely an increase in SWD. In contrast, pretreatment with WAY-100635 significantly attenuated the effect of fluoxetine. In conclusion, these results indicate that the increase in endogenous 5-HT produces a dual effect on SWD; the inhibition of epileptiform activity is mediated by 5-HT(2C), the activation by 5-HT(1A) receptors.     

Hypothermia induced by m-trifluoromethylphenylpiperazine or m-chlorophenylpiperazine: an effect mediated by 5-HT1B receptors?

Summary In the present study we examined the effect of different drugs on the m-trifluoromethylphenylpiperazine (TFMPP)- and m-chlorophenylpiperazine (m-CPP)-induced hypothermia in mice. Both the hypothermias studied are blocked or reversed by pindolol, cyanopindolol and compound 21-009, but not by atenolol. Neither hypothermia is antagonized by 5-HT_1A antagonists (ipsapirone, spiperone), a 5-HT_1C antagonist (mesulergine), 5-HT₂ antagonists (cyproheptadine, mianserin, methysergide), 5-HT₃ antagonists (ICS 205930, metoclopramide). The examined hypothermias are not antagonized by other antihypothermic agents (pimozide, idazoxan, atropine). The 8-OH-DPAT-induced hypothermia is not affected by cyanopindolol or compound 21009. The obtained results indicate that the TFMPP- and m-CPP-induced hypothermias in mice are mediated by 5-HT_1B. These hypothermias may be a good screening test for evaluation of the 5-HT_1B-agonistic and 5-HT_1B-antagonistic activity.     

Combined treatment with citalopram and buspirone: effects on serotonin 5-HT2A and 5-HT2C receptors in the rat brain

INTRODUCTION: We wanted to elucidate whether the proposed advantages of citalopram-buspirone combination treatment are related to changes in 5-HT(2A/C) receptor-mediated neurotransmission. METHODS: The affinity of buspirone to 5-HT2A and 5-HT2C receptors was measured in vitro, and the influence of buspirone on 5-HT2C receptor-mediated phosphoinositide hydrolysis was estimated. Four groups of rats received citalopram (10 mg/kg), buspirone (6 mg/kg), citalopram-buspirone combination, or saline once a day s.c. for 14 days. Treatment effects on 5-HT2A and 5-HT2C receptors were investigated by receptor autoradiography with antagonist and agonist radioligands. RESULTS: Buspirone was found to be a weak 5-HT2C receptor antagonist, with a low affinity for 5-HT2A and 5-HT2C receptors. Repeated buspirone-citalopram combination treatment markedly decreased [3H]ketanserin and [125I]DOI binding to 5-HT2A receptors. Repeated administration of buspirone and buspirone-citalopram combination increased the affinity of [3H]mesulergine toward 5-HT2C receptors, and buspirone-citalopram combination also decreased [125I]DOI binding to 5-HT2C receptors. DISCUSSION: We suggest that downregulation of brain 5-HT2A receptors and possibly of 5-HT2C receptor agonist sites is involved in the beneficial clinical effects of buspirone-SSRI augmentation treatment. Furthermore, a conversion of brain 5-HT2C receptors from high- to low-affinity state may provide an additional mechanism for the anti-anxiety effects of buspirone.     

Anxiolytic effect of estradiol in the median raphe nucleus mediated by 5-HT1A receptors

Estrogen deficiency has been associated with stress, anxiety and depression. Estrogen receptors have been identified in the median raphe nucleus (MRN). This structure is the main source of serotonergic projections to the hippocampus, a forebrain area implicated in the regulation of defensive responses and in the resistance to chronic stress. There is evidence showing that estrogen modulates 5-HT1A receptor functions. In the MRN, somatodendritic 5-HT1A receptors control the activity of serotonergic neurones by negative feedback. The present study evaluated the effect of intra-MRN injection of estradiol benzoate (EB) (600 or 1200ng/0.2microl) on the performance of ovariectomised rats submitted to the elevated plus-maze test of anxiety and to the open-field test. Additionally, the same effect was evaluated with a previous intra-MRN injection of WAY 100635(100ng/0.2microl), an antagonist of 5-HT1A receptors. The results showed that both doses of EB increased the percentage of entries and the percentage of time spent into the open arms, suggestive of an anxiolytic effect. The highest dose of the drug also increased the number of entries into the enclosed arm and locomotion in the open field, indicating a stimulatory motor effect. WAY 100635 antagonised the effect of estradiol in the elevated plus-maze and in the open-field. The results show that estrogen receptors of the MRN are implicated in the regulation of anxiety-related behaviour. The results also support claims that the effect of estrogen involves a change in 5-HT1A receptor function.     

Excitability of pontine startle processing neurones is regulated by the two-pore-domain K+ channel TASK-3 coupled to 5-HT2C receptors

The mammalian startle reflex is a fast response to sudden intense sensory stimuli that can be increased by anxiety or decreased by reward. The cellular integration of sensory and modulatory information takes place in giant neurones of the caudal pontine reticular formation (PnC). The startle reflex is known to be enhanced by 5-hydroxytryptamine (5-HT); however, signalling mechanisms that change the excitability of the PnC giant neurones are poorly understood. Possible molecular candidates are two-pore-domain K⁺ (K₂P) channels that generate a variable K⁺ background conductance and control neuronal excitability upon activation of G-protein-coupled receptors. We demonstrate by in situ hybridization that the K₂P channel TASK-3 is substantially expressed in PnC giant neurones. Brain slice recordings revealed a corresponding background K⁺ current in these cells that forms about 30% of the outward current at −30 mV. Inactivation of TASK-3 at pH 6.4 and by ruthenium red depolarized the cells by about 7 mV and increased the action potential frequency as well as duration. Specific activation of Gα_q-coupled 5-HT₂ receptors with α-methyl 5-HT evoked a similar increase of neuronal excitability. Consistently, we measured afferent synaptic inputs from serotonergic raphe neurones and detected 5-HT_2C receptors in PnC giant neurones by immunohistochemistry. Thus, neuronal excitability of PnC giant neurones in vivo is most likely increased by serotonergic projections via the K₂P channel TASK-3.