Modafinil does not affect serotonin efflux from rat frontal cortex synaptosomes: comparison with known serotonergic drugs

Modafinil did not affect spontaneous and K(+)-evoked [3H]5-HT efflux from cortical synaptosomes while it increased K(+)-evoked tritium efflux from cortical slices, an action that became stronger in the presence of paroxetine. In contrast, DL-fenfluramine and fluoxetine were able to enhance spontaneous and/or K(+)-evoked tritium efflux from synaptosomes and slices. These results suggest that modafinil does not affect 5-HT transmission from cortical synaptosomes and that its 5-HT releasing action is different from that of DL-fenfluramine and fluoxetine.     

Potentiation of morphine hyperthermia in cats by pimozide and fluoxetine hydrochloride

Administration of morphine sulfate (1--4 mg/kg i.v.) to cats produces changes in body temperature, with hyperthermia appearing with larger doses. Since the central neurotransmitters dopamine and serotonin have been implicated in thermoregulation, studies were done to determine whether morphine's action could be mediated via these transmitters. Temperature responses were measured in freely moving cats by means of rectal thermometer probes. Either pimozide, 0.5 mg/kg i.p., a specific DA receptor blocker, or fluoxetine HCl, 10 mg/kg i.p., a specific inhibitor of 5-HT uptake, was administered 2--3 h prior to morphine injection. Temperatures were monitored for 3.5 h after morphine administration. Both agents were found to enhance the hyperthermic response to morphine with the maximum morphine effect occurring in most cases by 2 h. The results indicate that a balance in the ratio of 5-HT : DA may be involved in cat thermoregulation and that the hyperthermic response in the cat to morphine may be effected by shifting this 5-HT : DA ratio.     

Chronic fluoxetine-induced desensitization of 5-HT1A and 5-HT1B autoreceptors: regional differences and effects of WAY-100635

Desensitization of 5-HT(1A) and 5-HT(1B) autoreceptors is thought to be the mechanism underlying the therapeutic effects of fluoxetine and other selective serotonin reuptake inhibitors when these are administered chronically. The blockade of 5-HT(1A) autoreceptors occurring on administration of a selective serotonin reuptake inhibitor together with a 5-HT(1A) autoreceptor antagonist is responsible for the acute increase in 5-hydroxytryptamine (serotonin, 5-HT) levels observed under these circumstances. The effects of repeated administration of selective serotonin reuptake inhibitors together with 5-HT(1A) receptor antagonists have not been widely studied. In this work, we found that the effects of fluoxetine (5 mg/kg, i.p., daily for 12 days) to desensitize 5-HT(1B) autoreceptors in the frontal cortex, as measured by the effect of the locally administered 5-HT(1B) receptor agonist, 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (CP 93129), and to desensitize 5-HT(1A) autoreceptors as measured by the action of the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 50 microg/kg, s.c.) to reduce 5-HT levels in cortex, were prevented by concomitant administration of the 5-HT(1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY-100635; 0.3 mg/kg, s.c.). 5-HT(1B) receptor activity in the hypothalamus, as measured by the effects of locally administered CP 93129, and 5-HT(1A) autoreceptor activity, as determined by the effects of subcutaneous 8-OH-DPAT to reduce 5-HT levels in hypothalamus, were not altered either by fluoxetine alone or by fluoxetine in the presence of WAY-100635. The data suggest that the regulation of extracellular levels of 5-HT in the cortex and hypothalamus is subject to different autoregulatory mechanisms.     

Fluoxetine attenuates thermal hyperalgesia through 5-HT1/2 receptors in streptozotocin-induced diabetic mice

Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, is recognised as one of the most difficult types of pain to treat. A lack of understanding of its aetiology, inadequate relief, development of tolerance and potential toxicity of classical antinociceptives warrant the investigation of newer agents to relieve this pain. The aim of the present study was to explore the antinociceptive effect and possible mechanism of action of a serotonin reuptake inhibitor, fluoxetine, in streptozotocin-induced diabetic mice. Four weeks after a single intraperitoneal injection of streptozotocin (200 mg/kg), mice were tested in the tail-immersion and hot-plate assays. Diabetic mice exhibited significant hyperalgesia compared with control mice. Fluoxetine (10 and 20, but not 5 mg/kg, i.p.) injected into diabetic mice produced an antinociceptive effect in both the tail-immersion and hot-plate assays. The percentage maximum possible effect (% MPE) produced by fluoxetine (20 mg/kg, i.p.) was significantly lower in diabetic mice than in control mice. The antinociceptive effect of fluoxetine (20 mg/kg) in diabetic mice was dose-dependently potentiated by pindolol (5 and 10 mg/kg, i.p., a selective 5-HT(1A/1B) receptor antagonist), attenuated by ritanserin (1 and 2 mg/kg, i.p., a selective 5-HT(2A/2C) receptor antagonist) and remained unaffected by ondansetron (1 and 2 mg/kg, i.p., a selective 5-HT(3) receptor antagonist) in both test systems. These results suggest that fluoxetine-induced antinociception primarily involves serotonin pathway modulation through 5-HT(1) and 5-HT(2) receptors, but not through 5-HT(3) receptors, in the chronic pain associated with streptozotocin-induced diabetic neuropathy. Further, the potentiation of the antinociceptive effect of fluoxetine by pindolol indicates the usefulness of a combination of an antidepressant and a 5-HT(1A/1B) receptor antagonist in the treatment of diabetic neuropathic pain in humans.     

Effects of fluoxetine on ethanol withdrawal syndrome in rats

The present study was designed to investigate the effects of fluoxetine, a selective serotonin reuptake inhibitor, on ethanol withdrawal syndrome in rats. Adult male Wistar rats (218-255 g) were subjects. Ethanol (7.2%, v/v) was given to rats by a liquid diet for 21 days. Control rats were pair fed an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. Fluoxetine (2.5, 5 and 10 mg/kg) and saline were injected to rats intraperitoneally just before ethanol withdrawal. After 2nd, 4th and 6th hour of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs that included locomotor hyperactivity, agitation, stereotyped behavior, wet dog shakes and tremor were recorded or rated. A second series of injections was given at 6 h after the first one, and subjects were then tested for audiogenic seizures. Fluoxetine produced some dose-dependent and significant inhibitory effects on all the signs of ethanol withdrawal during ethanol withdrawal period. Our results suggest that acute fluoxetine treatment has some beneficial effects on ethanol withdrawal in rats. Thus, this drug may be useful for treatment of ethanol withdrawal syndrome.     

The serotonergic system may be involved in the sleep-inducing action of oleamide in rats

The mechanism underlying the sleep-inducing effect of oleamide, an endogenous fatty acid amide, was studied in rats. Animals implanted with cerebrocortical and dorsal neck muscle electrodes were monitored continuously by electroencephalograph (EEG) and electromyograph (EMG) for 4 h after i.p. or s.c. injection of drugs. Oleamide induced a dose-dependent increase in slow-wave sleep (SWS), a decrease in wakefulness (W) and sleep latency, but had no effect on rapid-eye-movement sleep (REMS). The oleamide-induced increase in SWS was prevented by 5-HT reuptake inhibitors such as fluoxetine or fenfluramine and by agonists at 5-HT_1A receptors such as buspirone or 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT). Moreover, the selective 5-HT_1A receptor antagonist WAY100635 markedly antagonized the suppression of the oleamide-induced increase in SWS by 8-OH-DPAT. These data provide the first behavioural evidence that the serotonergic system may be involved in the sleep-inducing action of oleamide in rats.     

Clozapine enhances breakpoint in common marmosets responding on a progressive ratio schedule

RATIONALE: Motivational effects of psychotropic drugs may contribute to their therapeutic profile and progressive ratio (PR) schedules provide a method of measuring these effects in animals. OBJECTIVE: Determine effects of selected antipsychotic, psychotomimetic, anxiolytic and antidepressant drugs on PR performance in common marmosets. METHOD: Marmosets were trained to lever press for banana milkshake reinforcement using a PR schedule, in which the number of lever presses to achieve successive reinforcements increased by one until responding ceased (breakpoint). RESULTS: Clozapine administered intramuscularly (0.01-2 mg/kg IM; 30 min pretreatment time (ptt) or by oral gavage (0.1-4 mg/kg PO; 60 min ptt) significantly increased the breakpoint. Independent tests of fluid consumption failed to show enhanced fluid intake after clozapine pretreatment, suggesting this effect was not due to drug induced polydipsia. Neither haloperidol (0.005-0.1 mg/kg PO; 60 min ptt) nor risperidone (0.0025-0.05 mg/kg PO; 60 min ptt) altered breakpoint. Olanzapine (0.01-1 mg/kg PO; 60 min ptt) significantly enhanced the breakpoint at 0.05 mg/kg PO, but the effect was not robust. Amphetamine (0.2-2 mg/kg SC; 30 min ptt) significantly reduced the breakpoint at 2 mg/kg and fluoxetine (0.1-1 mg/kg PO; 60 min ptt) was without effect. Diazepam significantly increased the breakpoint at 0.5 mg/kg PO. Drug-induced polydipsia might play a role in this response as independent tests showed increased fluid consumption following diazepam. CONCLUSIONS: These results demonstrate that, unlike other antipsychotics, clozapine over a wide dose range increased the motivational state of marmosets to respond for banana milkshake. This motivational aspect of clozapine's actions may contribute to its unique clinical profile and the PR procedure may provide a method for detecting novel antipsychotics with a clozapine-like profile.     

氟西汀与马来酸曲美布汀联合治疗功能性消化不良的临床观察

目的:探讨氟西汀与马来酸曲美布汀联合治疗功能性消化不良(FD)的疗效。方法:将门诊160例FD患者随机分成甲、乙两组,甲组80例予以马来酸曲美布汀治疗,乙组80例予以马来酸曲美汀与氟西汀联合治疗,治疗时间均为8周,以自制FD症状评定量表评定疗效。结果:甲、乙两组有效率分别为62.5%(50例),91.25%(73例),疗效差异有显著性(P<0.01)。结论:氟西汀与马来酸曲美布汀联合使用可显著提高治疗FD的疗效,值得推广。     

颐脑解郁方改善抑郁症肾虚肝郁型患者中医证候的临床观察

目的观察颐脑解郁方对抑郁症肾虚肝郁型患者中医证候的影响。方法将60例抑郁症肾虚肝郁型患者随机分为颐脑解郁组30例和氟西汀组30例。颐脑解郁组给予颐脑解郁方治疗,氟西汀组给予氟西汀治疗,用药疗程均为6周。在治疗2周、4周、6周时,观察两组患者主要中医证候的改善情况。结果颐脑解郁方对性欲减退、时有太息的疗效在2周、4周、6周时均优于氟西汀(P<0.05或0.01);对腰酸背痛的疗效在2周、4周时优于氟西汀(P<0.01),在6周时组间比较无明显差异(P>0.05);对胁肋胀痛的疗效在2周时优于氟西汀(P<0.01),在4周、6周时组间比较无明显差异(P>0.05);对神思不聚的疗效在2周、4周时组间比较无明显差异(P>0.05),在6周时优于氟西汀(P<0.01);对忧愁善感、兴趣索然、精神委靡的疗效与氟西汀相当(P>0.05)。结论颐脑解郁方能有效改善抑郁症肾虚肝郁型患者的主要中医证候。     

针刺联合氟西汀对卒中后抑郁症疗效及HPA轴功能的影响

目的:观察针刺联合氟西汀治疗卒中后抑郁症(PSD)的疗效并探讨其神经内分泌机制。方法:40例PSD患者随机分为两组,对照组20例单纯使用氟西汀治疗6周,研究组20例采用针刺结合氟西汀治疗6周。观察两组疗效和治疗前后血浆ACTH、CORT的含量变化。结果:治疗后两组临床疗效和ACTH、CORT值均有明显改善,研究组尤甚(P<0.05或0.01)。结论:针刺联合药物治疗PSD和单纯使用药物治疗相比,能够更好地改善患者的抑郁状态,其机理可能与抑制下丘脑-垂体-肾上腺(HPA)轴功能亢进有关。