BRL 46470A: a highly potent,selective and long acting 5-HT3 receptor antagonist with anxiolytic-like properties

The novel 5-HT₃ antagonist, BRL 46470A (endo-N-(8-methyl-8-azabicyclo [3.2.1]oct-3-yl)2,3-dihydro-3,3 dimethyl-indole-1-carboxamide, hydrochloride), has been investigated in a series of in vitro and in vivo tests, including the effect of the drug in models of anxiolysis. In classical tests for 5-HT₃ receptor antagonism, BRL 46470A was shown to antagonise 5-HT₃ mediated responses in the guinea-pig ileum [pA₂ 8.3±0.5, slope 0.98±0.20, mean±SEM (5)], the rabbit isolated heart (pA₂ 10.1±0.1, slope 1.2±0.2,n=5) and the rat Bezold-Jarisch model (ID₅₀ 0.7 µg/kg IV±0.1,n=8), with a long duration of action (>3 h). BRL 46470A selectively displaced [³H]-BRL 43694 from 5-HT₃ binding sites in rat brain membranes (K_i 0.32 nM±0.04,n=4) without displacing (at concentrations greater than 1 µM) a wide variety of ligands binding to other neurotransmitter receptors, opioid receptors and to neurotransmitter gated ion channel complexes. In vivo, BRL 46470A showed anxiolytic-like activity in two animal models predictive of antianxiety effects-elevated X-maze and social interaction in rats. In both models, BRL 46470A showed significant activity over a wide dose-range following both oral (0.0001–0.1 mg/kg PO) and systemic administration. The unique level of potency of BRL 46470A was apparent in the rat social interaction test and was shown to be 100 fold more potent than the 5-HT₃ receptor antagonist ondansetron, with no evidence of a bell-shaped dose response curve over 4 orders of magnitude. BRL 46470A (0.0001 and 0.01 mg/kg SC) also reduced the anxiogenic effects of m-CPP (1-(3-chlorophenyl) piperazine) in the rat elevated X-maze. BRL 46470A is therefore a chemically novel potent and selective 5-HT₃ receptor antagonist with anxiolytic potential and a long duration of action in animal studies.     

Chronic administration of the 5-HT3 receptor antagonist BRL 43694; effects on reflex epilepsy and social behaviour of the Mongolian gerbil

The 5-HT₃ receptor antagonist BRL 43694 was administered in drinking fluid to Mongolian gerbils, previously selected for their propensity to exhibit seizures on mild stimulation, for 11 days at doses of 1.5 µg/kg, 150 µg/kg and 1 mg/kg daily, while controls received tap water. Effects upon behaviour during encounters under white light with an untreated resident gerbil were assessed using ethological procedures. Effects upon seizure susceptibility and severity were also examined. All doses of BRL 43694 significantly increased the time spent by gerbils in the social activity attend, and acts of social investigation involving physical contact between animals were significantly increased only by the highest dose of 1 mg/kg, as was occurrence of the specific element, groom. The duration of flight was increased in gerbils receiving the drugs at 1.5 µg/kg. The treatment had no effect upon seizure susceptibility or severity. It is suggested that BRL 43694 increases the sensitivity of gerbils to their social environment. At the lower dose this was seen as an increase in flight, at all doses it was associated with increase of the social activity attend and at the high dose it was manifested as an increase in active social interaction. Further investigations are required to assess the relevance of these findings to the purported anxiolytic activity of 5-HT₃ receptor antagonists.     

Inhibition of the 5-HT-induced cardiogenic hypertensive chemoreflex by the selective 5-HT3 receptor antagonist ICS 205-930

Summary We investigated the effect of ICS 205-930 [(3-tropanyl)-1H-indole-3-carboxylic acid ester], a selective antagonist at 5-HT₃ receptors, on the cardiogenic hypertensive chemoreflex in the anaesthetized dog. The reflex was elicited by injection of 5-HT (12.5–1600 g) into the left cardiac ventricle and consisted of a dose-dependent systemic hypertension associated with a decrease in heart rate. ICS 205-930 (10, 30, and 100 g/kg i.v.) caused a displacement to the right of both the dose-response curves of 5-HT-induced blood pressure increase and heart rate reduction. Its blocking effects upon the action of 5-HT could be surmounted by increasing the dose of the agonist. The selective 5-HT₂ receptor antagonist, ketanserin (0.1 mg/kg i.v.) and the combined 5-HT₁ and 5-HT₂ receptor antagonist, methiothepin (0.1 mg/kg i.v.) had no influence on the hypertensive reflex. When the reflex was elicited by the ganglionic stimulant, 1,1-dimethyl-4-phenyl-piperazinium (DMPP; 100–1600 g), ICS 205-930 had no blocking effect. The results suggest that the 5-HT-induced cardiogenic hypertensive chemoreflex is mediated by 5-HT₃ receptors. Send offprint requests to H. Berthold at the above address     

5-HT_3受体拮抗剂抑制化疗致吐的研究进展

目的通过对5-HT3受体特点的研究和5-HT3受体参与的化疗致吐机制的剖析,阐明5-HT3受体拮抗剂对抗化疗致吐方面的作用机制和临床应用。方法综述国内外相关文献19篇,对相关研究的进展和成果进行总结。结果5-HT3受体拮抗剂通过在外周和中枢选择性拮抗5-HT3受体,有效控制化疗致吐的发生。因其效果显著、不良反应小而得到了较好的临床应用。结论5-HT3受体拮抗剂可选择性阻断5-HT3受体,从而有效控制化疗导致的呕吐。     

The 5-HT3 receptor ligand, [3H]BRL 43694, binds to presynaptic sites in the nucleus tractus solitarius of the rat

This study has employed receptor autoradiography to localise the distribution of binding sites for the 5-HT₃ receptor ligand [³H]BRL 43694 in sections of the brain of the rat (using a concentration of 10 nM [³H]BRL 43694 with 100 μM GR38032F to define non-specific binding). The highest density of binding sites for [³H]BRL 43694 was observed in the nucleus tractus solitarius and amounted to 652 fmol/mg tissue. The binding of [³H]BRL 43694 was also examined in sections prepared 10 days after unilateral nodose ganglionectomy, in an attempt to determine the neuronal location of these binding sites. Denervation reduced the binding of [³H]BRL 43694 by around 50% in the ipsilateral side of the nucleus tractus solitarius, relative to the contralateral side. This would indicate that the 5-HT₂ binding sites may have a presynaptic location on vagal afferent terminals.     

The effect of acute and chronic LY 277359, a selective 5-HT3 receptor antagonist, on the number of spontaneously active midbrain dopamine neurons.

In this study, we have examined the effect of acute and chronic administration of LY 277359, a putative 5-HT3 receptor antagonist, on the number of spontaneously active dopamine cells in the substantia nigra pars compacta (SNC or A9) and ventral tegmental area (VTA or A10). This was accomplished using the standard extracellular single unit recording techniques. The acute administration of LY 277359 (0.1 or 1.0 mg/kg i.p.) produced a significant increase in the number of spontaneously active A10, but not A9, dopamine cells compared to saline controls. The acute administration of 10 mg/kg of LY 277359 did not significantly alter the number of spontaneously active dopamine cells in either area. In contrast to its acute effects, the administration of 0.1 mg/kg per day of LY 277359 for 21 days decreased the number of spontaneously active A9 and A10 dopamine cells. However, the i.v. administration of (+/-)-apomorphine (50 micrograms/kg) did not reverse LY 277359's action, suggesting that the chronic LY 277359-induced reduction of dopamine cells was not the result of depolarization block. To test whether chronic administration of LY 277359 at a high dose would induce depolarization block of dopamine cells, rats were treated with 1.0 or 10 mg/kg LY 277359. Interestingly, the chronic administration of 1.0 mg/kg LY 277359 increased the number of A10, but not A9 dopamine cells. In contrast, chronic treatment with 10 mg/kg selectively decreased the number of spontaneously active A10 dopamine cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

5-HT3受体阻滞剂帕洛诺司琼

帕洛诺司琼（palonosetron）是新型5-HT3受体阻滞剂,适用于中～重度呕吐化疗所引起的恶心、呕吐,其与传统5-HT3受体阻滞剂相比,具有疗效高、作用时间长、用量小、不良反应少的优点.现对帕洛诺司琼的作用机制、药动学、安全性以及临床应用等做一简单综述.     

Reversal of neuroleptic-induced orofacial dyskinesia by 5-HT3 receptor antagonists.

Tardive dyskinesia, a syndrome of abnormal, involuntary hyperkinetic movements that occurs during long-term neuroleptic therapy is a major limitation of chronic neuroleptic therapy. The pathophysiology of tardive dyskinesia is still an enigma. The objective of the present study was to elucidate the role of 5-HT₃ receptor involvement in neuroleptic-induced vacuous chewing movements in rats. Rats chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) significantly developed vacuous chewing movements, as compared to vehicle-treated controls. Both ondansetron and tropisetron dose-dependently (0.25, 0.5 and 1.0 mg/kg, i.p.) reversed the haloperidol-induced vacuous chewing movements. Serotonin acting through 5-HT₃ receptors might play a significant role in the pathophysiology of tardive dyskinesia, and 5-HT₃ receptor ligands can be exploited as novel therapeutic agents for the treatment of tardive dyskinesia.     

The anxiolytic-like effect of the selective 5-HT6 receptor antagonist SB-399885: the impact of benzodiazepine receptors

The effect of lesion of 5-hydroxytryptamine (5-HT) neurons, produced by p-chloroamphetamine (p-CA; 2 × 10 mg/kg), and the influence of the benzodiazepine receptor antagonist flumazenil (10 mg/kg) on the anticonflict action of N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB-399885), a selective 5-HT₆ receptor antagonist, were investigated in the Vogel conflict drinking test in rats. In addition, the interaction between SB-399885 (0.3 mg/kg) and diazepam (2.5 mg/kg) was evaluated in that test. All the compounds tested were administered intraperitoneally. The anticonflict activity produced by SB-399885 (3 mg/kg) was not modified in p-CA-pretreated rats, but it was totally blocked by flumazenil. Combined administration of non-active doses of SB-399885 (0.3 mg/kg) and diazepam (2.5 mg/kg) produced a pronounced anticonflict effect in rats. The present results suggest that the anticonflict activity of SB-399885 is not conditioned by the integrity of 5-HT neurons, and that benzodiazepine receptors are indirectly involved in its effect, possibly due to a functional interaction between 5-HT₆ receptors and the γ-aminobutyric acid (GABA)/benzodiazepine system.     

Comparative 5-HT4 receptor antagonist activity of LY353433 and its active hydroxylated metabolites

LY353433 is a selective, potent, and orally active 5-HT₄ receptor antagonist with a long duration of pharmacological activity following its oral administration to rats. After oral administration of LY353433 (100 mg/kg) to rats, peak plasma concentration of the parent material was approximately 25 ng/ml and rapidly declined such that 4 h after administration, plasma concentration of the parent material was barely detectable. However, two additional peaks (LY343031 and LY343032) were observed in plasma via HPLC and subsequently identified as hydroxylated metabolites of LY353433. Peak plasma concentrations of LY343031 (approximately 50 ng/ml) and of LY343032 (approximately 150 ng/ml) were achieved within 1 h after the oral administration of LY353433. Furthermore, plasma concentrations of these metabolites were maintained for several hours and declined more slowly than plasma concentrations of the parent material. Both metabolites inhibited esophageal 5-HT₄ receptors in a concentration range similar to that observed with LY353433. In addition, the receptor selectivity profiles for LY343031 and LY343032 were similar to that of LY353433 at α₁, α₂, β, Dopamine D₁, Dopamine D₂, benzodiazapine, histamine H₁, GABA_A, 5-HT₂, and muscarinic receptors. Thus, these hydroxylated derivatives of LY353433 were potent and selective 5-HT₄ receptor antagonists in vitro. Lastly, using ex vivo esophageal relaxation to serotonin to assess 5-HT₄ receptor antagonism, these compounds were less active after oral administration to rats than LY353433. Thus, the long duration of pharmacological activity observed after oral administration of LY353433 is likely related not only to the 5-HT₄ receptor antagonist activity of the parent molecule, but also to the 5-HT₄ receptor antagonist activity associated with its two hydroxylated metabolites. Drug Dev. Res. 43:193–199, 1998. © 1998 Wiley-Liss, Inc.     

5-HT_(2B)受体阻断剂对心肌肥厚大鼠心肌5-HT含量及5-HT_(2B)受体表达的影响

目的观察5-HT2B受体阻断剂对去甲肾上腺素(norepinephrine,NE)诱导的心肌肥厚大鼠心肌中5-羟色胺(5-hydrotriptamine,5-HT)含量及5-HT2B受体表达的影响。方法雄性SD大鼠24只,随机分为3组,8只/组,分别为对照组、肥厚组、实验组。采用腹腔注射NE(1.5 mg/kg,2次/d,28 d)的方法建立心肌肥厚模型,自第15天起实验组腹腔注射SB204741(5-HT2B受体阻断剂;2 mg/kg,2次/d),连续注射14 d。对照组腹腔注射相同体积的生理盐水(2次/d,28 d)。检测各组左心室重量与体重之比(LVW/BW)、心肌组织中5-HT的含量及5-HT2B受体的表达情况。结果在NE诱导心肌肥厚过程中,应用SB204741干预可显著减轻心肌肥厚的程度,降低心肌组织中5-HT的含量,并抑制5-HT2B受体表达的上调。结论应用5-HT2B受体阻断剂可减轻NE诱导心肌肥厚的程度,降低心肌组织中5-HT的含量,并抑制5-HT2B受体表达的上调。     

Palonosetron: a unique 5-HT3-receptor antagonist for the prevention of chemotherapy-induced emesis

Palonosetron (Aloxi^?) is a 5-HT₃-receptor antagonist antiemetic indicated for the prevention of acute and delayed nausea and vomiting following moderately emetogenic chemotherapy and for acute nausea and vomiting following highly emetogenic chemotherapy. Although it is the fourth member of this class to enter the US market, palonosetron is distinguished by distinct pharmacological characteristics. It has a higher binding affinity for the 5-HT₃receptor and a terminal serum half-life at least four times greater than any other available agent of this class (～ 40 h). The high affinity and long half-life may explain the persistence of antiemetic effect throughout the delayed emesis risk period. The indications for palonosetron are supported by one dose-ranging study and three large, randomised, Phase III studies that all demonstrated at least equivalent activity (and in some cases, superior activity) compared to other 5-HT₃-receptor antagonists. In spite of the pharmacological differences, the side effect profile of palonosetron is comparable to that of other 5-HT₃-receptor antagonists. Palonosetron may prove valuable in combination therapy for delayed emesis and may be an appropriate agent for clinical settings, such as multiple-day chemotherapy, where acute emesis is repeatedly induced. Palonosetron provides a convenience advantage if multiple-day 5-HT₃-receptor antagonist therapy is anticipated and is a unique addition to the antiemetic armamentarium.     

L-683,877: Pharmacological profile of a novel 5-HT3 receptor antagonist

The 5-HT₃ receptor antagonist properties of the novel compound L-683,877 (?) (2′-(1-methyl-1H-indol-3-yl)-)spiro(1-azabicyclo[2.2.2]octane-3,5′(4′H)-oxazole) have been characterised in vitro and in vivo. In radioligand binding studies, L-683,877 displaced [³H]quaternized ICS 205–930 binding to membranes of rat cortex with a pK_i of 8.71. L-683,877 was essentially inactive (pK_i<5) at 5-HT_1A, 5-HT_1B, 5-HT_1C, 5-HT_1D, 5-HT₂, and dopamine D₁ and D₂ binding sites. In the rat isolated vagus nerve and superior cervical ganglion (SCG) preparations, L-683,877 antagonized 5-HT₃ agonist-induced depolarizations with apparent pK_B values of 9.30 and 8.25, respectively. Similarly L-683,877 antagonized the positive chronotropic effects of 5-HT in the isolated rabbit heart preparation (apparent pK_B 10.10). In the anaesthetized rat, L-683,877 (10–100 μg kg^?1 i.v.) antagonized the Bezold Jarisch reflex evoked by 5-HT; at a dose of 10 μg kg^?1 i.v. L-683,877 caused a twofold shift in the dose response curve. The retching and vomiting response induced in the ferret by cisplatin (10 mg kg^?1 i.v.), was markedly attenuated by L-683,877 (0.1 mg kg^?1 i.v. and p.o.) and completely prevented by higher doses (10 mg kg^?1 i.v. and p.o.). These data indicate that L-683,877 is a potent and selective 5-HT₃ receptor antagonist.     

Effect of the selective 5-HT1A receptor antagonist WAY 100635 on the inhibition of e.p.s.ps produced by 5-HT in the CA1 region of rat hippocampal slices

1. The actions of N-(2-(-4(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635), a novel and selective 5-hydroxytryptamine_1A (5-HT_1A) antagonist, on excitatory postsynaptic potentials (e.p.s.ps) were investigated by use of intracellular recordings in pyramidal cells of the CA1 region of rat hippocampal slices.
2. WAY 100635 (10 nM) did not affect any of the investigated parameters of cell excitability such as membrane potential, total input resistance (R_in), firing threshold, action potential amplitude, action potential frequency adaptation, and slow afterhyperpolarization (sAHP) which follows repetitive firing of action potentials. WAY 100635 did not have any effect on either the slope or the amplitude of e.p.s.ps evoked by stimulation of the CA1 stratum radiatum.
3. Bath application of either 5-hydroxytryptamine (5-HT, 10–30 μM) or 5-carboxamidotryptamine (5-CT, 300 nM) hyperpolarized the membrane potential (ΔV_m=−4.1±0.9 and −6.0±0.9 mV, respectively), and reduced R_in (−25±8% and −18±1%, respectively). 5-HT blocked the action potential frequency adaptation and significantly reduced the amplitude of the sAHP that follows repetitive firing of action potentials.
4. 5-HT significantly decreased the amplitude of evoked e.p.s.ps (−14±6%). This effect was greater in the presence of the GABA_A receptor antagonist bicuculline (10 μM, −45±12%) and was mimicked by 5-CT (−49±5%). Both AMPA and NMDA components of e.p.s.ps were significantly reduced in amplitude by 5–HT (−38±8%, n=6, and −29±12%, n=3, respectively; P<0.05).
5. WAY 100635 fully antagonized the hyperpolarization, the reduction of R_in, and the decrease in amplitude of e.p.s.ps elicited by 5-HT, while it did not affect the action of 5-HT on the action potential frequency adaptation. In the presence of WAY 100635, 5-HT elicited a depolarization which was blocked by 10–30 μM RS 23597-190, a selective 5-HT₄ receptor antagonist.
6. Our data demonstrate that WAY 100635 is devoid of direct effects on CA1 pyramidal cell excitability and on evoked e.p.s.ps, while it fully antagonizes the effects of 5-HT on excitatory synaptic transmission and on hyperpolarization, without affecting the 5-HT₄ receptor-mediated response. Since WAY 100635 selectively antagonizes 5-HT_1A receptor-mediated actions of 5-HT, our data also demonstrate that the inhibitory action of 5-HT on excitatory synaptic transmission in CA1 is mediated by 5-HT_1A receptors.

     

5-HT4受体拮抗剂哌波色罗的合成

目的合成5-HT4受体拮抗剂哌波色罗。方法以吲哚-3-羧酸甲酯为原料,在NBS、三乙胺作用下,与3-氯-1-丙醇反应,再经环合、胺解、成盐等反应,合成哌波色罗。结果与结论实验总收率为43%,其结构经熔点、氢谱、质谱测试确证。该方法合成工艺简单,易操作,收率高,成本低。     

5 HT3受体拮抗剂相关便秘的研究进展

5- HT3受体拮抗剂是恶性肿瘤患者在化疗过程中常用的止吐药,其大大缓解了中高致吐性的化疗药物所致呕吐的发生率,对化疗的疗效的提高和不良反应的减少起到重要作用。但是5- HT3受体拮抗剂所引起的便秘也不可忽视,便秘极大地影响了患者对化疗的依从性,给患者精神、躯体造成损害,是肿瘤患者额外的负担。目前,尚缺乏特异性防治5- HT3受体拮抗剂所致便秘的药物,而中医药防治5- HT3受体拮抗剂所致便秘是一种有效的治疗手段,值得进一步研究及推广。本文从5- HT3受体拮抗剂相关便秘的研究进展着手,为更好地防治5- HT3受体拮抗剂所致便秘提供参考。     

某院5-HT3受体拮抗剂防治CINV的合理性评价

目的：对我院5-HT3受体拮抗剂用于防治化疗引起的恶心呕吐的使用情况进行合理性评价,进一步提高临床化疗止吐药的合理使用。方法：从我院用药决策系统随机抽取2016年6-11月住院静脉化疗患者中使用5-HT3受体拮抗剂止吐的电子病历200例。从适应症、药品遴选、用法用量、综合止吐方案、药物相互作用、用药时机、给药途径等多方面进行处方点评。结果：不合理用药病历111例,占55.5%。药品遴选不合理13例,占6.5%,以肺癌和乳腺癌为著;用法用量不合理75份,占37.5%;联合用药不合理19例,占9.5%。9例存在2种以上不合理用药情况,占4.5%。14例高致吐风险级别综合止吐方案单用5-HT3受体拮抗剂不合理,占7.0%。结论：我院止吐药5-HT3受体拮抗剂的应用存在较多不合理使用情况,有必要规范临床合理使用5-HT3受体拮抗剂,促进临床合理用药。     

Interactions of GR127935, a 5-HT1B/D receptor ligand, with functional 5-HT receptors

GR127935 (N-[methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2’-methyl-4’-(5-methyl-1,2,4-oxadiazol-3-yl) [1, 1-biphenyl]-4-carboxamide hydrochloride) has been recently introduced as an experimental tool to antagonize 5-HT_1B/D receptor-mediated functional responses. The compound indeed exhibits a very high affinity and selectivity for 5-HT_1B/D binding sites and it antagonizes a number of 5-HT_1B/D receptor-mediated responses. The present experiments were performed to investigate the selectivity of GR127935 against functional responses mediated by 5-HT₁-like, ‘orphan’ 5-HT₁-like (5-ht₇?), 5-HT₂, 5-HT₃ or 5-HT₄ receptors in several invivo preparations. Intravenous (i.v.) treatment with GR127935 (300μg?kg^-1) potently antagonized decreases in total carotid blood flow as well as hypotensive responses induced by the 5-HT₁-like receptor agonist sumatriptan in rabbits. I.v. bolus injections of GR127935 (up to 500 and/or 1500μg?kg^-1) did not significantly modify 5-HT-induced: (i) tachycardia in the pig (5-HT₄ receptor-mediated) and cat (‘orphan’ 5-HT₁-like or, perhaps, 5-ht₇ receptor-mediated); (ii) depressor effects in the rat and cat (‘orphan’ 5-HT₁-like or 5-ht₇ receptor-mediated); (iii) vonBezold-Jarisch reflex in the rat or the early phase of the urinary bladder contraction in the cat (both 5-HT₃ receptor-mediated). In contrast, high doses (500-1500μg?kg^-1) of GR127935 suppressed 5-HT-induced pressor responses in the rat and cat and urinary bladder contractions (secondary phase) in the cat as well as the DOI ((±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride)-induced pressor responses in the rat, which are all mediated by 5-HT_2A receptors. In conclusion, the present study demonstrates that GR127935 is a selective 5-HT_1B/D receptor antagonist devoid of interactions at ‘orphan’ 5-HT₁-like (5-ht₇?), 5-HT₃ and 5-HT₄ receptors. However, GR127935 possesses a moderate 5-HT_2A receptor blocking property, which is consistent with its binding profile (pK_i: 7.4). Lastly, in view of the potent antagonist action of GR127935, the sumatriptan-induced hypotension in rabbits seems to be mediated by 5-HT_1B/D receptors.     

5-HT3 receptor over-expression decreases ethanol self administration in transgenic mice

 The 5-HT₃ receptor is thought to play a role in the reward pathway and the phenomena of drug abuse by modulating dopamine release in the mesolimbic pathway. Studies involving this receptor have been hampered due to the low level of 5-HT₃ receptors in the CNS. A 5-HT₃ receptor over-expressing mouse was produced to study the role of this receptor in the rewarding properties of drugs of abuse. Over-expression was restricted to the forebrain by controlling gene expression with the Ca²⁺ calmodulin (CAM) kinase IIα promoter. No over-expression was detected in other body organs nor the cerebellum, as measured by ligand binding and Northern analysis. 5-HT₃ receptor over-expressing mice drank less alcohol than non-transgenic mice in a two-bottle free choice test. Over-expression of the 5-HT₃ receptor in these mice resulted in a decrease in ethanol consumption. These mice should prove useful in testing hypothesis regarding a common reward pathway for drugs of abuse and the role 5-HT₃ receptors play in this pathway. Received: 17 June 1998 / Final version: 14 August 1998