Differential effects of two types of antidepressants, amitriptyline and fluoxetine, on anorectal motility and visceral perception

BACKGROUND: Although antidepressants are used for functional gastrointestinal disorders, the mechanisms of their effects on gut are incompletely understood. AIM: To assess the effects of two types of antidepressants (tricyclic, serotoninergic) on anorectal motility and visceral perception. METHODS: A placebo-controlled, randomized, double-blind, crossover study was performed in 12 healthy male volunteers who received a single oral dose of amitriptyline (80 mg), fluoxetine (40 mg) or placebo. Drug effects were assessed using phasic isobaric distensions of the rectum with an electronic barostat (11 levels from 1 to 51 mmHg) 4 h after drug intake. Maximal rectal volume and pressure, mean and residual pressures at upper anal canal, mean pressure at lower anal canal, defecation sensation (5-level scale) and visceral perception (visual analogue scale) were recorded at each level of distending pressure. RESULTS: Ten subjects completed the study. Compared with placebo, neither amitriptyline nor fluoxetine modified rectal compliance or visceral perception. Compared with placebo, antidepressants significantly reduced mean and residual pressures at upper anal canal (-18%, P = 0.0019, and -27%, P = 0.0002, respectively, for amitriptyline; -26%, P = 0.0001, and -33%, P = 0.0001, respectively, for fluoxetine) whereas only amitriptyline significantly reduced mean pressure at lower anal canal (-16%, P = 0.0008). CONCLUSION: Both antidepressants similarly relaxed the internal anal sphincter, probably through a non-specific mechanism, without modifying visceral perception. Only amitriptyline relaxed the external anal sphincter.     

Comparative study of the effects of tianeptine and other antidepressants on the activity of medial septal neurons in rats anesthetized with urethane

Summary Tianeptine is a tricyclic antidepressant which enhances serotonin uptake in certain brain areas. Tianeptine has been reported to improve both working and reference memories in rodents. The effects of tianeptine on the spontaneous activity of medial septal neurons were studied in rats anesthetized with urethane. Systemic administrations (0.2–1 mg/kg i. v.) of tianeptine decreased the spontaneous activity and disorganized or suppressed the rhythmically bursting activity of medial septal neurons, in a dose related manner. Iontophoretic administrations of tianeptine did not modify the spontaneous activity of medial septal neurons. Changes of the bursting activity were inconsistent. However, tianeptine blocked partially or completely the inhibition induced by the serotonin in 68% of the cases. In contrast, other antidepressants (amitriptyline, clomipramine and fluoxetine) potentiated the inhibitory effect of serotonin in 50%–60% of the cases. Our results show that tianeptine, applied by iontophoresis, has an effect on the medial septal neurons which was opposite to that of other antidepressants. On the basis of our findings, it can be tentatively proposed that tianeptine may have a beneficial effect on memory by counteracting the serotonin-induced inhibition of medial septal neurons. Send offprint requests to M. H. Bassant at the above address     

Behavioural analysis of the anorectic effects of fluoxetine and fenfluramine

Two sets of experiments were carried out to compare the effects of fenfluramine and fluoxetine on consummatory and operant behaviour. In food-deprived rats allowed access to a 35% sucrose solution, an initial period of sucrose consumption was followed by a short period of grooming and exploratory behaviour, later superceded by resting. This behavioural satiety sequence was advanced by fluoxetine, but disrupted bydl-fenfluramine, which suppressed post-prandial resting, even at sub-anorectic doses. Fluoxetine also elicited resting behaviour following water drinking. However, this did not appear to be a non-specific sedative effect, since fluoxetine increased post-prandial grooming. In rats performing on random interval schedules of food reinforcement, fluoxetine caused proportionally greater decreases in responding on a reinforcement-lean schedule (RI-300s), as compared to a reinforcement-rich schedule (RI-7.5s); this effect is similar to that of a reduction in level of food deprivation. By contrast, fenfluramine reduced responding equally on both schedules. In both paradigms, the effects of fluoxetine were compatible with an increase in postprandial satiety, but the effects of fenfluramine were not.     

抗抑郁药物对慢性应激抑郁模型大鼠海马神经生长因子表达的影响

目的研究抗抑郁药物氟西汀与噻萘普汀对慢性应激抑郁模型大鼠海马神经生长因子(NGF)表达的影响。方法将大鼠随机分为抑郁模型组、氟西汀组、噻萘普汀组和对照组。模型组、氟西汀组和噻萘普汀组给予21d的应激刺激,此期间对照组正常饲养,刺激期间氟西汀组每天灌胃氟西汀(10mg/kg),噻萘普汀组每天灌胃噻萘普汀(50mg/kg),模型组和对照组每天灌胃等体积的生理盐水。行为学检测应用开场法和液体消耗实验。采用Western Blot法检测各组大鼠海马NGF的表达情况。结果应激后模型组水平穿越格数、竖立次数、修饰次数、糖水消耗百分比均显著低于对照组(P<0.01)。应激后氟西汀组水平穿越格数、竖立次数、修饰次数和糖水消耗百分比均高于模型组(P<0.05)。应激后噻萘普汀组糖水消耗百分比高于模型组(P<0.05),水平穿越格数、竖立次数和修饰次数也高于模型组,但差异无统计学意义。在Western-blotting法检测中,慢性应激后模型组大鼠海马NGF的表达水平显著低于对照组(P<0.01);氟西汀组大鼠海马NGF的表达水平高于模型组(P<0.01),与对照组差异无统计学意义(P>0.05);噻萘普汀组大鼠海马NGF的表达水平高于模型组(P<0.01),略低于对照组和氟西汀组但差异无统计学意义(P>0.05)。结论慢性应激可以导致大鼠海马NGF表达降低,氟西汀和噻奈普汀可以逆转慢性应激抑郁模型大鼠海马中NGF表达的降低。     

Comparative study of the effects of amitriptyline, fluoxetine, and tianeptine on the amplitude of transcallosal evoked potentials

The influence of amitriptyline, fluoxetine and tianeptine upon transcallosal responses has been studied in male albino rats. It is established that amitriptyline does not influence, fluoxetine reduces, and tianeptine increases the amplitude of evoked potentials. These data show evidence that tianeptine facilitates, fluoxetine impairs, and amitriptyline does not affect the interhemispheric transmission.     

抗抑郁药物对慢性应激抑郁模型大鼠海马胱天蛋白酶-9表达的影响

目的研究氟西汀与噻萘普汀对慢性应激抑郁模型大鼠海马胱天蛋白酶-9(Caspase-9)表达的影响。方法将大鼠随机分为抑郁模型组、氟西汀组、噻萘普汀组和对照组。模型组、氟西汀组和噻萘普汀组给予21d的应激刺激,此期间对照组正常饲养,刺激期间氟西汀组每天灌胃氟西汀(10mg/kg),噻萘普汀组每天灌胃噻萘普汀(50mg/kg),模型组和对照组每天灌胃等体积的生理盐水。行为学检测应用开场法和液体消耗实验。采用Western blot法检测各组大鼠海马Caspase-9的表达情况。结果模型组水平穿越格数、竖立次数、修饰次数、糖水消耗百分比均显著低于对照组(P<0.01)。氟西汀组水平穿越格数、竖立次数、修饰次数和糖水消耗百分比均高于模型组(P<0.05)。噻萘普汀组糖水消耗百分比高于模型组(P<0.05),水平穿越格数、竖立次数和修饰次数也高于模型组,但差异无统计学意义。慢性应激后模型组大鼠海马Caspase-9的表达水平显著高于对照组(P<0.01);氟西汀组大鼠海马Caspase-9的表达水平低于模型组(P<0.01),高于对照组(P<0.05);噻萘普汀组大鼠海马Caspase-9的表达水平低于模型组(P<0.01),高于对照组(P<0.01)。结论氟西汀和噻萘普汀2种抗抑郁药物均可以逆转慢性应激抑郁模型大鼠海马中Caspase-9表达的升高。     

Behavioural effects of etiracetam in rats

The effects of etiracetam, a structural analogue of piracetam, were investigated in rats on Y-maze discrimination acquisition, on open field behaviour, on one-trial passive avoidance learning and on shuttlebox acquisition and extinction. The results indicate that this drug significantly enhances acquisition and may improve retention without having any detectable effects on spontaneous behaviour, not even in very high doses (500 mg/kg IP). Sensitivity to footshock, measured as “flinch” thresholds, was not altered by etiracetam in doses of 25 or 100 mg/kg IP. For a shuttlebox task the effective dose-range lies between 20–30 mg/kg IP, provided pretreatment during 4 days is given. Without pretreatment, i.e. when the drug is only administered during the relatively fast acquisition in the shuttlebox, it was found that acquisition was not enhanced, but extinction of the acquired behaviour was significantly inhibited. The effects of etiracetam can be found at lower dose-levels than with piracetam and also in tests (passive avoidance, shuttlebox) in which piracetam has no or only marginal effects.     

Behavioural effects of d-amphetamine alone and in combination with antidepressants,antihistamines or other psychotropic drugs in young chicks

Antidepressants, antihistamines or other psychotropic drugs were administered before injection of d-amphetamine in 3–5 day old chicks. This pretreatment completely protected some animals against the characteristic behavioural changes seen after d-amphetamine 6 mg/kg i.p. In addition chlorpheniramine, chlorimipramine, imipramine, cocaine and diphenhydramine were also able to antagonize a dose of 10 mg/kg i.p. It was further noticed that well developed d-amphetamine symptoms were interrupted by subsequent treatment with imipramine.     

Behavioural effects of deltorphins in rats.

When given i.c.v. in rats deltorphins induced a syndrome of behavioural stimulation consisting of increased locomotion rearing and sniffing. The increased locomotor activity and rearing were dose-related over the range of 0.13 to 3.8 nmol/rat for [D-Ala2]deltorphin II (DADELT II) and 1.04 to 20.8 nmol/rat for deltorphin. The delta-selective antagonist, naltrindole (10 mg/kg i.p.), completely abolished the behavioural stimulation induced by 1.3 nmol/rat of DADELT II and shifted the dose-response curve to the right, without decreasing the maximum effect. The mu-preferring antagonist, naloxone, was able to antagonize the DADELT II-induced locomotor activity but only at very high doses (10 and 20 mg/kg i.p.). The i.v. administration of a large dose (10 mg/kg) of the mu 1-selective antagonist, naloxonazine, did not affect the DADELT II response. At doses up to 38 nmol/rat, the i.c.v. injection of DADELT II never induced analgesia. At doses over 20.8 nmol/rat, deltorphin always induced spontaneous controlateral barrel rotations and circling, responses which were not blocked by prior administration of naloxone or haloperidol. In studies performed on the social behaviour of rats, i.c.v. administration of 0.38 nmol/rat of DADELT II was ineffective, while 1.3 nmol/rat increased the number of social contacts. Regression analysis showed that the increase in social contacts was a primary effect of the peptide, not correlated with the increased locomotor activity.     

Comparative study of the antidepressant and anxiolytic activity of fluoxetine and tianeptine

The activity of fluoxetine (prozac) and tianeptine (coaxil) was studied in outbred male rats under Porsolt and S. Nomura modified forced swim tests. The antidepressant effect of tianeptine was much more pronounced that that of fluoxetine. In the conflict situation test, fluoxetine produced anxiogenic action. In contrast, tianeptine decreased (albeit not reliably) the anxiety. In combination with bicuculline (GABAA receptor blocker), the anxiolytic action was more pronounced for both antidepressants, which was manifested by a significant increase in the number of punished water takes. A neural network explaining the observed behavior is proposed, which includes GABA-ergic intemeurons inhibiting serotonin release from serotoninergic terminals.     

Behavioural effects in rats of morphine and amphetamine and of a combination of the two drugs

Summary Small single doses of morphine (1 mg/kg s.c.) and of amphetamine (1 mg/kg s. c.) induce excitation in rats. Locomotion and rearing are selectively stimulated by amphetamine, and grooming by morphine. Higher doses of morphine (5 mg/kg s. c.) cause sedation or catalepsy (20 mg/kg s. c.) but no stereotypies are seen as after amphetamine (10 mg/kg s. c.). Repeated doses of morphine induce stereotyped behaviour, which is inhibited by nalorphine. An antagonism between morphine and amphetamine is demonstrated but the anti-amphetamine effect of morphine is different from that of the neuroleptic drugs. Catecholamines in the basal ganglia may play a role in these behavioural effects of morphine.     

Efficacy and safety of tianeptine in the treatment of depressive disorders in comparison with fluoxetine*

Depression is treated by a great variety of antidepressant treatments. SSRIs (such as fluoxetine) are well known: it is, however, sure that further progress is needed and the search for antidepressants with other mechanisms of action (such as tianeptine) or different efficacy is still of interest. A multinational study compared tianeptine with fluoxetine in 387 patients with Depressive Episode, or Recurrent Depressive Disorder, or Bipolar Affective Disorder (ICD-10), in a double-blind parallel group design. They were treated for six weeks. At inclusion, no significant difference between groups was shown. Final MADRS scores were 15.7 and 15.8 with tianeptine and fluoxetine, respectively (ITT population) (p = 0.944). MADRS responders were 58% and 56% with tianeptine and fluoxetine, respectively (p = 0.710). No statistical difference was observed for the other efficacy parameters. Thirty-six withdrawals occurred in each group, without any difference for the reasons of discontinuation. There was no major difference between groups for the other safety parameters. In this study, both tianeptine and fluoxetine exhibited a good efficacy and safety. Copyright 1999 Elsevier Science B. V. All rights reserved.     

Cardiovascular effects of omega-conopeptides in conscious rats: mechanisms of action.

We examined the effects of omega-conopeptides, a novel class of neuronal voltage-gated calcium channel antagonists, on hemodynamic responses in rats. Intravenous (i.v.) injections of SNX-111 (omega-conopeptide MVIIA) dose-dependently decreased arterial blood pressure (BP) in conscious rats. Intracerebroventricular (i.c.v.) SNX-111 injections (580 pmol) tended to increase BP and, after an initial decrease, to increase heart rate (HR). The dose-response curve for SNX-111 administered i.v. in conscious rats was biphasic. Beginning at subdepressor doses, SNX-111 caused a long-lasting blockade of pressor responses elicited by sympathetic nerve stimulation in pithed animals but did not prevent increases in BP evoked by exogenously administered norepinephrine (NE). Pretreatment of rats with histamine antagonists partially blocked the hypotensive effects of the higher (870 and 2,900 nmol/kg) doses of SNX-111. Substitution of alanine for arginine at position 10 ([Ala10]-MVIIA) markedly attenuated the histamine-mediated component of the vasodepressor response. Together, these findings indicate that SNX-111 administered i.v. decreases systemic BP by a combination of blockade of sympathetic neurotransmission and mast cell degranulation; the latter function appears to be dependent on the arginine residue in position 10 of the amino acid sequence of SNX-111.     

Behavioural and biochemical effects of 6-hydroxydopa in rats

The influence of 6-hydroxydopa (6-HDP) injected into the lateral ventricles of rat brain on the behaviour of animals was examined. The level of noradrenaline (NA), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in discrete areas of the brain was also measured.6-HDP was injected in a dose of 100 or 150 g into both lateral ventricles, or in a dose of 200 g into the right lateral ventricle. Immediately after 6-HDP injection, circling movements, convulsions, aggressive behaviour, and Stereotypic activity were seen. These components of behaviour were most obvious during the first hour after injection of 6-HDP. During one month after 6-HDP administration the behaviour of rats did not differ significantly from the behaviour of control animals, only very subtle differences in behaviour being seen. The dose of 150 g of 6-HDP caused aphagia and loss of body weigth during the first 5 days after treatment. 6-HDP also caused hypothermia. 20 min after administration of 200 g of 6-HDP a decrease of the NA level but no changes in the 5-HT level in the brain cortex were seen. The same changes were observed 1 month after 6-HDP treatment. The dose of 150 g of 6-HDP decreased the NA level in the brain cortex, cerebellum, mesencephalon and brain stem 5 days after treatment. 5-HT content was not changed and the 5-HIAA level was increased in the same brain areas. The dose of 100 g of 6-HDP, 2 weeks after the treatment decreased the content of NA in the brain cortex, cerebellum, hypothalamus and brain stem without changes in 5-HT content. 5-HIAA level was elevated only in the brain stem.It is concluded that 6-HDP is a long-acting potent depletor of NA in rat brain. There is a different sensitivity of brain areas to the depleting effect of 6-HDP. 6-HDP does not deplete the 5-HT content of discrete areas of brain but increases the level of 5-HIAA. 6-HDP causes distinct behavioural changes shortly after the treatment. It does not change the behaviour of rats between 1 and 30 days after its administration.     

The effects of two antidepressants,imipramine and viloxazine,upon driving performance

Forty male volunteers were randomly assigned to one of four treatment groups on a doubleblind basis: (1) Imipramine-25 mg t.d.s., (2) Viloxazine-50 mg t.d.s., (3) Placebo, and (4) Control-no tablets. Tests were carried out (1) before treatment, (2) 2 h after the first dose, (3) on Day 3 after 7 doses, and (4) on Day 7 after 21 doses. The driving tasks consisted of (1) weaving around a series of bollards while simultaneously responding to an auditory logic task and (2) a gap acceptance task. Using an analysis of covariance repeated measures design, it was found that imipramine tended to increase the level of risk acceptable to the subject as compared to either placebo or control. Imipramine also impaired performance on other tasks. Viloxazine appeared to be little different from either placebo or control on any of the tasks.     

Neurofunctional effects in rats prenatally exposed to fluoxetine

In the treatment of depression fluoxetine [a selective serotonine reuptake inhibitor (SSRIs)] is a widely used drug in humans. The selectivity, efficacy, side effects and simplicity of dosage contributed to fluoxetine's clinical acceptance. Several psychiatric disorders (many of them responsive to SSRIs) are present during pregnancy; up to 10% of pregnant women fulfill diagnostic criteria for major or minor depression with an even higher percentage developing postpartum depression. Therefore, significant numbers of women may be taking SSRIs while pregnant. Since fluoxetine's safe use during pregnancy is not yet established and experimental studies inconclusive, we performed the present research in order to investigate the neurobehavioral effects produced in rats by prenatal exposure to fluoxetine (5 and 10 mg/kg/sc from day 13 to 20 of gestation) on cognitive functions, emotional reactivity and sexual performance.     

Sex-specific antidepressant effects of dietary creatine with and without sub-acute fluoxetine in rats

The potential role of metabolic impairments in the pathophysiology of depression is motivating researchers to evaluate the treatment efficacy of creatine, a naturally occurring energetic and neuroprotective compound found in brain and muscle tissues. Growing evidence is demonstrating the benefit of oral creatine supplements for reducing depressive symptoms in humans and animals. A novel question is whether dietary creatine, when combined with antidepressant drug therapy, would be more effective than either compound alone. To answer this question, four studies were conducted to investigate the behavioral effects of combined creatine and low-dose fluoxetine treatment using the forced swim test in male and female rats. Sprague-Dawley rats were fed powdered rodent chow supplemented with 0%, 2% or 4% w/w creatine monohydrate for 5 weeks. Rats were injected with fluoxetine (5.0 or 10.0 mg/kg) or saline according to a sub-acute dosing schedule. Female rats maintained on a 4% creatine diet displayed antidepressant-like effects compared to non-supplemented females prior to fluoxetine treatment. In contrast, creatine did not alter behavior reliably in males. Following drug treatment and a second forced swim trial, the antidepressant-like profile of creatine remained significant only in females co-administered 5.0 mg/kg fluoxetine. Moreover, in females only, supplementation with 4% creatine produced a more robust antidepressant-like behavioral profile compared to either dose of fluoxetine alone. Estrous cycle data indicated that ovarian hormones influenced the antidepressant-like effects of creatine. Addressing the issue of sex differences in response to treatment may affect our understanding of creatine, its relationship with depressive behavior, and may lead to sex-specific therapeutic strategies.