Factors triggering abolishment of benzodiazepines effects in the Four-Plate Test--retest in mice.

Abolishment of anxiolytic-like effects of diazepam occurs during re-exposure to some animal tests of anxiety. We investigated the loss of anxiolytic-like effects of diazepam during Trial 2 on previously undrugged mice, namely one-trial tolerance (OTT). Swiss mice were subjected to 1) Four-Plate Test (FPT) without punishments in Trial 1 or 2) FPT without punishments in both Trials or 3) FPT with spatial modifications in Trial 1 or 4) Elevated Plus Maze (EPM), then 24 h later to FPT, with saline, diazepam (1 mg/kg) or DOI (1 mg/kg). Removing punishments in Trial 1 does not counteract the effect reduction of diazepam in Trial 2, but spatial modifications of the aversive environment. Previous exposure to EPM does not trigger a loss of efficacy of diazepam in FPT. Electric punishments do not trigger OTT to benzodiazepines; whilst knowledge of the environment seems to be responsible for this phenomenon. FPT may be useful to study OTT because punishments potentate OTT in this model of anxiety.

Relationship between cerebral pharmacokinetics and anxiolytic activity of diazepam and its active metabolites after a single intra-peritoneal administration of diazepam in mice.

The relationship between the cerebral pharmacokinetics of diazepam and its active metabolites (desmethyldiazepam, oxazepam) and the anxiolytic effect evaluated by the four-plates test and the light/dark test were investigated after a single intra-peritoneal injection of diazepam (1 mg/kg or 1.5 mg/kg). For up to 30 min after administration, the sedative effect interfered with the anxiolytic effect, thus the results of the anxiolytic effect were not interpretable. From 30 min to 60 min after administration, this interference disappeared, the cerebral level of benzodiazepines was stable (the brain elimination of diazepam was compensated for by the appearance of desmethyldiazepam followed by oxazepam) but the anxiolytic effect decreased dramatically in all the tests with diazepam 1 mg/kg or 1.5 mg/kg. The acute tolerance to benzodiazepines and the difference of affinity for subtypes of GABA(A) receptors between diazepam, desmethyldiazepam, oxazepam could explain this result.

Cyamemazine as an anxiolytic drug on the elevated plus maze and light/dark paradigm in mice.

Several studies have demonstrated that cyamemazine, a classic antipsychotic compound, possesses anxiolytic properties in humans as well as a potent antagonistic effect on 5-HT(2C) and 5-HT(3) receptors. In this study the level of anxiety of mice was assessed in the light/dark exploration test and the elevated plus maze (EPM) following both acute and chronic administration. Spontaneous locomotor activity was measured using a photoelectric actimeter. Acute or chronic administration of cyamemazine dramatically decreases the spontaneous locomotor activity of mice at the dose of 1 mg/kg in comparison with the control group. In the light/dark exploration test, cyamemazine (0.375 mg/kg) only demonstrated anxiolytic-like activity following acute administration. In the elevated plus maze (EPM), cyamemazine did not induce any anxiolytic like effects after acute administration. However, after chronic administration, cyamemazine at doses of 0.25, 0.375, 0.5 and 1 mg/kg significantly increased the time spent in the open arms. The number of open arm entries was also increased at 0.25 and 0.5 mg/kg. Various serotonergic ligands were then used to examine the role of the various receptors in mediating the effects of cyamemazine in the EPM. Concerning the 5-HT(2) ligands DOI and mCPP antagonised the effects of cyamemazine and N-desmethyl clozapine potentiated the effects. For 2-methyl-5-HT and ondansetron, the 5-HT(3) receptor ligands did not seem to have any effect. It appears that the 5-HT(2C) receptors are more implicated in the function of mediating the anxiolytic effect of cyamemazine in the EPM. The discrepancy of results obtained in the tests, following acute or chronic administration could be the result of the combined activity of dopamine D(2) receptor antagonism with antagonism of 5-HT(2C) and 5-HT(3) receptors.

[5-HT1B serotonin receptors and antidepressant effects of selective serotonin reuptake inhibitors ]. / Récepteurs 5-HT1B de la sérotonine et effets antidépresseurs des inhibiteurs de recapture sélectifs de la sérotonine.

We used knockout mice and receptor antagonist strategies to investigate the contribution of the serotonin (5-hydroxytryptamine, 5-HT) 5-HT1B receptor subtype in mediating the effects of selective serotonin reuptake inhibitors (SSRIs). Using in vivo intracerebral microdialysis in awake mice, we show that a single systemic administration of paroxetine (1 or 5 mg/kg, i.p.) increased extracellular serotonin levels [5-HT]ext in the ventral hippocampus and frontal cortex of wild-type and mutant mice. However, in the ventral hippocampus, paroxetine at the two doses studied induced a larger increase in [5-HT]ext in knockout than in wild-type mice. In the frontal cortex, the effect of paroxetine was larger in mutants than in wild-type mice at the 1 mg/kg dose but not at 5 mg/kg. In addition, either the absence of the 5-HT1B receptor or its blockade with the mixed 5-HT1B/1D receptor antagonist, GR 127935, potentiates the effect of a single administration of paroxetine on [5-HT]ext more in the ventral hippocampus than in the frontal cortex. Furthermore, we demonstrate that SSRIs decrease immobility in the forced swimming test; this effect is absent in 5-HT1B knockout mice and blocked by GR 127935 in wild-type suggesting therefore that activation of 5-HT1B receptors mediate the antidepressant-like effects of SSRIs. Taken together these data demonstrate that 5-HT1B autoreceptors appear to limit the effects of SSRI on dialysate 5-HT levels particularly in the hippocampus while presynaptic 5-HT1B heteroreceptors are likely to be required for the antidepressant activity of SSRIs.

The mouse light-dark paradigm: a review.

1. The light/dark paradigm is based on the innate aversion of rodents to brightly illuminated areas and on the spontaneous exploratory behaviour of the animals, applying mild stressors i.e. novel environment and light. The test apparatus consists of a small dark secure compartment (one third) and a large illuminated aversive compartment (two thirds). 2. The test was developed with male mice. The strain, weight and age may be crucial factors. 3. The extent to which an anxiolytic compound can facilitate the exploratory activity depends on the baseline level in the control group. Differences between the type and severity of external stressors might account for variable results reported by different laboratories. 4. In conclusion, the black and white test may be useful to predict anxiolytic-like or anxiogenic-like activity in mice. Transitions have been reported to be an index of activity-exploration because of habituation over time and the time spent in each compartment to be a reflection of aversion. Classic anxiolytics (benzodiazepines) as well as the newer anxiolytic-like compounds (e.g. serotonergic drugs) can be detected using this paradigm. It has the advantages of being quick and easy to use, without requiring the prior training of animals.

Comparison of antidepressant activity in 4- and 40-week-old male mice in the forced swimming test: involvement of 5-HT1A and 5-HT1B receptors in old mice.

RATIONALE: A recent study suggested that selective serotonin reuptake inhibitors were inactive in 40-week-old male mice in the mouse forced swimming test, possibly because of alteration of 5-HT1 receptors. OBJECTIVES: The present study was aimed at investigating the action of various antidepressant drugs in 4- and 40-week-old male mice using the mouse forced swimming test and determining the involvement of 5-HT1A and 5-HT1B receptors mediating the effects. METHODS: Different classes of antidepressants [imipramine (tricyclic), maprotiline (noradrenline reuptake inhibitor), venlafaxine (mixed serotonin and noradrenaline reuptake inhibitors), fluvoxamine and sertraline (selective serotonin reuptake inhibitor)] were tested in the same randomised experimental session, alone and in combination with 5-HT1A and 5-HT1B receptor agonists [buspirone (partial 5-HT1A agonist), anpirtoline (5-HT1B agonist)] in the mouse forced swimming test. RESULTS: All antidepressants were found to be active in the mouse forced swimming test in 4-week-old mice and 40-week-old mice, with the exception of fluvoxamine in the 40-week-old mice. The anti-immobility effect after antidepressant administration was higher in 4-week-old male mice than in 40-week-old male mice. Venlafaxine is the most active antidepressant drug in 40-week-old mice. Prior administration of buspirone (0.06 mg/kg, i.p.) or anpirtoline (1 mg/kg, i.p.) enhanced the antidepressant-like effects in 4-week-old mice (except in the case of sertraline, 8 mg/kg). In elderly mice, only prior administration of buspirone enhanced the antidepressant-like effects of fluvoxamine. A neurochemical study showed that significantly higher serotonin and dopamine concentrations were found in 40-week-old control mice brains than 4-week-old control mice brains but that the noradrenaline concentration is higher in 4-week-old mice. CONCLUSION: Tricyclic, noradrenaline reuptake inhibitors and serotonin reuptake inhibitors are more active in 4-week-old mice than 40-week-old mice. Our results suggested that 5-HT1B receptors may be more altered than 5-HT1A receptors in 40-week-old mice.

Are there gender differences in the temperature profile of mice after acute antidepressant administration and exposure to two animal models of depression?

Numerous studies have reported gender differences in the rates of depression in humans, but few behavioural observations of antidepressant drug effects have been investigated in female mice. The forced swimming test (FST) is widely used as a predictor of antidepressant activity in rodents, as is the tail suspension test (TST), where immobility is objectively measured and in this last test, no hypothermia is induced by immersion in cold water. The present study investigated gender differences in the temperature profile of mice after acute antidepressant administration (imipramine and paroxetine) and exposure to two animal models of depression. Imipramine and paroxetine were active at 32 mg/kg in male mice in the FST, whereas they were active at 8, 16 and 32 mg/kg in female mice. In the TST, for both antidepressants immobility duration was reduced at a dose of 16 and 32 mg/kg in male mice and at 32 mg/kg in female mice. No significant difference was observed between male and female mice for immobility duration. Imipramine administration, but not paroxetine, decreased the temperature at the higher dose (32 mg/kg) in male and female mice in the FST. The body temperature was reduced in male and female mice for all treatment groups after FST challenge. Imipramine (16 and 32 mg/kg in male and 32 mg/kg in female mice), paroxetine (4, 16 and 32 mg/kg in male and 4 to 32 mg/kg in female mice) attenuated the reduction in temperature due to the FST. In the TST, imipramine tends to decrease the temperature in male and female mice, even though only imipramine at a dose of 32 mg/kg in female mice significantly decreases the temperature. Paroxetine had no effect on temperature. The TST enhanced the body temperature in male and female mice. In mice, there was no difference between the sexes after imipramine or paroxetine administration in the FST and TST. Both tests can be used to predict the activity of antidepressants as the decrease or enhancement of temperature is not correlated with a reduction in immobility duration.

Drug mechanisms in anxiety.

The most common and successful therapyfor the majority of patients suffering from anxiety is treatment with benzodiazepines (BZDs). The problem of drug-induced dependency following treatment with these drugs may be avoided by developing more selective and specific BZD compounds, such as 2,3-substituted BZDs. Alternative approaches to the treatment of anxiety include the following: (i) antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), which are active in treating most anxiety disorders, including GAD; (ii) metabotropic glutamate (mGluR2) receptor agonists, which negatively modulate glutamate neurotransmission, and CRF antagonists, which have been proposed to exhibit anxiolytic properties; (iii) 5-HT1A receptor agonists which have demonstrated anxiolytic effects in clinical studies, although preclinical studies have reported weak or variable effects; (iv) 5-HT moduline antagonists, as well as 5-HT2C receptor antagonists, which may have anxiolytic properties; and, finally, (v) other approaches which are under investigation, including CCK2 antagonists.

Is dopamine implicated in the antidepressant-like effects of selective serotonin reuptake inhibitors in the mouse forced swimming test?

RATIONALE: Microdialysis, binding and behavioural studies have shown that the dopaminergic system plays a role in antidepressant treatment. OBJECTIVES: The present study determined whether the antidepressant-like effects of selective serotonin reuptake inhibitors measured in the mouse forced swimming test are mediated via dopamine receptors. METHODS: Male Swiss mice were randomly assigned to groups of 24 animals and injected IP with citalopram, fluoxetine, fluvoxamine, sertraline, or paroxetine alone or in combination with the dopamine D(1)agonist SKF 38393, the D(1) antagonist SCH 23390, the D(2) agonist bromocriptine, the D(2) antagonist sulpiride, the D(3) agonist PD 128 907, or the D(3) antagonist nafadotride. RESULTS: The anti-immobility effects of paroxetine, fluvoxamine and citalopram were increased by co-administration of SKF 38393 (0.5 and 2 mg/kg), SCH 23390 (0.06 mg/kg), bromocriptine (0.5 and 2 mg/kg) or PD 128 907 (1 and 2 mg/kg), and were attenuated by SCH 23390 (0.5 mg/kg). The anti-immobility effects of paroxetine and fluvoxamine were also increased with sulpiride (0.5 and 2 mg/kg). The anti-immobility effect of fluoxetine was increased by SKF 38393 (2 mg/kg) and PD 128 907(1 and 2 mg/kg) co-administration. The anti-immobility effect of sertraline (16 mg/kg) was increased by SKF 38393 (0.5 mg/kg), bromocriptine (2 mg/kg) and PD 128 907 (2 mg/kg) and the effect of sertraline (2 mg/kg) was increased by bromocriptine (2 mg/kg). The anti-immobility effect of paroxetine (4 mg/kg) was increased by nafadotride (2 mg/kg). CONCLUSIONS: These data indicate that the antidepressant activity of various SSRIs involves different dopamine receptor subtypes and that the serotoninergic and dopaminergic systems interact with each other.

The influence of buspirone, and its metabolite 1-PP, on the activity of paroxetine in the mouse light/dark paradigm and four plates test.

Although numerous animal procedures have been employed in the study of antidepressants (ADs) in anxiety, the results following acute administration remain highly variable. The present study investigated the effect of the SSRI paroxetine (4, 8, and 16 mg/kg, IP) in two tests of anxiety in mice: the light/dark test paradigm, and the four plates test (FPT). In both tests, it was found that paroxetine resulted in an anxiolytic-like effect at doses that did not modify motor performance (at the doses of 4 and 8 mg/kg in the light/dark test and at the doses of 4, 8, and 16 mg/kg in the four plates test). In the light/dark paradigm, both doses of buspirone significantly potentiated paroxetine, while in the four plates only one dose of buspirone (a 5HT(1A) partial agonist) (0.06 mg/kg) increased the anxiolytic-like effect of paroxetine. Prior administration of 1-PP was without effect in the light/dark paradigm but antagonized the effect of paroxetine (at the dose of 0.06 and 0. 5 mg/kg) in the FPT. The results suggested that a balance between pre- and postsynaptic 5-HT(1A) receptor was implicated in the anxiolytic-like effect of paroxetine. Buspirone seemed to emphasize the role of paroxetine in 5-HT(1A) receptor modulation and exerted a biphasic influence in the two tests.

Anxiolytic-like effects of antidepressants after acute administration in a four-plate test in mice.

The four-plate test (FPT) is an animal model of anxiety based on stress caused by unconditioned fear. An increase of spontaneous punished behavior was used as a measure to determine the anxiolytic effects of various antidepressants (ADs). In the present study. ADs with different mechanisms of action, including tricyclics, selective serotonin reuptake inhibitors (SSRIs), a monoamine oxidase inhibitor (MAOI), and atypicals, were studied in the FPT to evaluate their anxiolytic-like effects following acute administration. The number of punished crossings was dramatically increased by the SSRIs citalopram, fluvoxamine, and paroxetine, but not fluoxetine. The mixed 5-HT/NE reuptake inhibitors, milnacipran and venlafaxine, also demonstrated strong antipunishment effects. The specific NE reuptake inhibitors, desipramine and maprotiline, and the atypical AD trazodone, enhanced freezing behavior, suggesting anxiogenic-like behavior. It was concluded that, in the FPT, a model based on spontaneous response, where animals are exposed to an aversive environment from which they can only escape by being motionless, this kind of behavior might be related to anticipatory anxiety. In this situation, ADs acting preferentially on 5-HT transmission possessed clear anxiolytic like effects. The balance between the two transmitters, 5-HT and NE, seemed to be a crucial factor.

Influence of age on behavioural response in the light/dark paradigm.

We have compared the performance of male Swiss mice at different ages (correlated with different body weight; 12-34 g) in the light/dark test of anxiety. Mice received saline only. The best age at which control values were optimum was that of 4 weeks old. Mice at this age spent 58% of the total test duration in the dark compartment. The oldest mice (i.e., 8 weeks old) exhibited an increase in total activity characterised by increase in movements in each compartment, together with an increase in the number of transitions. An age-related effect was found suggesting caution when interpreting the results of mice in the light/dark paradigm, the best period being that of 4 weeks.

A new approach to the light/dark test procedure in mice.

The effect of the known anxiolytic agents diazepam and alprazolam and a putative anxiogenic agent, FG 7142, were assessed in a fully automated and computer-integrated two-compartment light/dark apparatus. In addition, psychostimulant drugs (amphetamine, adrafinil, amineptine, and caffeine) were tested to determinate the influence of increasing locomotor activity on the indices of anxiety. Some modifications, such as using a soiled apparatus, have been made from the initial model to reduce any neophobic response to the test situation. These results have been compared to results obtained after cleaning between trials. In addition, strain differences have been assessed by comparing the effect of Swiss mice with the C57Bl/6J strain. The role of each parameter as an index of anxiety is discussed. The time spent in the lit area and exploratory behaviors seemed to be the most reliable parameter for assessing anxiolytic-like activity. Diazepam and alprazolam were found to have an anxiolytic profile. FG 7142 did not demonstrate any intrinsic effect. Amphetamine was reported to be anxiogenic, and amineptine, adrafinil, and caffeine only had a psychostimulant profile. We conclude that the light/dark test may be useful for identifying putative anxiolytic and anxiogenic agents, but an additional test such as an open field or an actimeter test must be performed as a control with regard to the problem of sedation and change in exploration. The Swiss strain of mice has been found a suitable strain to be used in the test.

Evaluation of efficacies of different classes of antidepressants in the forced swimming test in mice at different ages.

1. The efficacies of different classes of antidepressants were investigated using the forced swimming test with mice at different ages. 2. Imipramine (4-32 mg/kg), desipramine (2-16 mg/kg) and bupropion (32, 64 mg/kg) showed activity in all age groups. 3. The selective serotonin reuptake inhibitors (SSRIs) citalopram (16 and 32 mg) and paroxetine (4 and 8 mg) were inactive in the oldest (40 weeks) group of mice, despite showing activity at the same doses in mice ranging in age from 4-24 weeks old. 4. Both SSRIs showed anti-immobility effects at low doses, (paroxetine: 1 and 2 mg/kg; citalopram: 4 and 8 mg/kg) in the 40-week old mice. These effects were not evident in the three younger groups of mice. 5. Moclobemide, a reversible selective inhibitor of monoamine oxidase-A, showed activity only at a high dose (128 mg/kg) and only in 12-week old animals. 6. Since SSRIs have been reported to have relatively selective effects on 5-HT1B receptors, the present results suggest that further studies comparing the effectiveness of SSRIs and other antidepressants in elderly patients should be done. Studies of the effects of aging on the density and/or affinity of 5-HT1A and 5-HT1B/1D receptors are also warranted.

Anticonflict effect of alpidem as compared with the benzodiazepine alprazolam in rats.

A comparative study between two drugs acting on the GABAA receptor, alprazolam and alpidem was undertaken, using simple tests such as measurement of spontaneous locomotor activity, four plates test and rotarod in mice. Additional conflict test was further performed using a new conflict paradigm where the opportunity existed for rats to choose during punished periods between immediate, punished reinforcement and delayed non-punished reinforcement. The benzodiazepine alprazolam, demonstrated, as expected, strong anxiolytic effects in mice and increased punished response in rats at non sedative doses (0.5, 1 mg/kg). High doses of alprazolam decreased spontaneous locomotor activity and induced myorelaxant effects in mice. Alpidem, an imidazopyridine derivative, induced motor impairment in mice and only very weak anxiolytic effects in the four plates test in mice (4 mg/kg) and in punished procedure in rats (32 mg/kg). As alprazolam is a full agonist for the GABAA receptor complex and alpidem is a partial agonist acting with specificity on omega 1 GABAA receptor subtypes, the results are discussed. Activity on omega 1 receptor subtypes is perhaps not sufficient in order to obtain a true anti-conflict effect and compounds such as alpidem only relieve some of the symptoms of anxiety disorders.

Influence of prior experience on mice behavior using the four-plate test.

A single prior undrugged exposure to the four-plate test reduces punished responding on retest at intervals ranging from 24 h to 42 days. Furthermore, prior experience attenuates the anxiolytic response to the benzodiazepines diazepam (0.25 to 2 mg/kg) and lorazepam (0.5 to 4 mg/kg). The result was first discussed in term of "one trial tolerance." The anxiety baseline was increased during the retest, which counteracted the anxiolytic action of benzodiazepines. To ascertain if memory processes are also implicated, the cholinergic drugs scopolamine and oxotremorine were used. Additional experiments with the GABAergic inverse agonist FG7142 and with the 5-HT1A receptor agonist 8-OH-DPAT were also performed. Administration of scopolamine and 8-OH-DPAT-induced weak impairment of memory, when administered before the second trial, but no effect was seen with cognition enhancing agents.

A schematic representation of the psychopharmacological profile of antidepressants.

1. Using simple animal tests, "behavioural" and "biochemical" aspects of depression, anxiolysis, disinhibition, psychostimulation and sedation were investigated in mice using a variety of antidepressant drugs. 2. Dothiepin and mianserin (16 and 32 mg/kg), fluoxetine (32 and 64 mg/kg), maprotiline and imipramine (16, 32 and 64 mg/kg) and viloxazine (16 mg/kg) significantly potentiated mortality following acute administration with yohimbine. 3. Dothiepin and imipramine (32 mg/kg), fluoxetine (16 and 32 mg/kg), viloxazine (8 and 16 mg/kg), maprotiline (32 mg/kg) and mianserin (32 mg/kg) reduced immobility time in the forced swimming test. 4. In the black and white box, dothiepin (32 mg/kg) significantly increased the time spent in the bright compartment: Fluoxetine (8 and 16 mg/kg) significantly increased the number of crossings between compartments, an effect indicative of desinhibition. 5. It can be concluded that dothiepin possesses both antidepressant and anxiolytic properties in these animal models. The present procedure is useful not only for the screening of compounds that may possess antidepressant properties, but is also of value in determining other properties that may contribute to the overall clinical efficacy of the drugs.

Additive effects of glyburide and antidepressants in the forced swimming test: evidence for the involvement of potassium channel blockade.

Evidence in the literature suggests that the modulatory effects of antidepressant drugs (ADS) on neuronal excitability, via the inhibition of K+ channels, may be the final common pathway of pharmacological action. Therefore, we tested the hypothesis that combining the ATP-sensitive K+ channel blocker glyburide with a variety of ADS would produce an additive effect and decrease the immobility time of mice in the forced swimming test (FST). Glyburide (GLY, IP, 30 and 50 mg/kg) and subactive doses of ADS were administered 45 and 30 min, respectively, prior to behavioral testing. Results showed that when combined with GLY, ADS whose main pharmacological effect is one of 5-HT uptake blockade (imipramine, amitriptyline, citalopram, paroxetine, fluoxetine, and fluvoxamine) were more effective in decreasing the amount of time mice were immobile, than when these drugs were administered alone. Some noradrenaline uptake inhibiting ADS (desipramine and viloxazine, but not maprotiline) were also significantly more effective in decreasing immobility time when combined with GLY than when administered alone. Pretreatment with GLY was found to have no effect on the dopamine uptake inhibitor bupropion, and out of the atypical ADS tested (trazodone, mianserine and iprindole), only coadministration with iprindole decreased the immobility time. Only the specific MAO-A inhibitor moclobemide was observed to have an antiimmobility effect when combined with GLY. Neither MAO-B specific (RO 16 6491) nor mixed MAO inhibitors (nialamide and pargyline) interacted with GLY to produce antiimmobility effects. These results corroborate and extend our previous report of the ADS enhancing effects of quinine in the same behavioral model, and suggest that the additive effects of quinine and GLY on ADS in FST are a result of K+ channel blockade.

Differential effects of clonidine, lithium and quinine in the forced swimming test in mice for antidepressants: possible roles of serotoninergic systems.

The forced swimming test (FST) is a behavioral test used to predict the efficacy of antidepressant (AD) treatments. In the present study, it was found that, when combined with clonidine, lithium or quinine, subactive doses of several types of ADs (tricyclics, 5-HT uptake inhibitors and atypical ADs) produced anti-immobility effects in mice. Clonidine (0.06 mg/kg) was found to potentiate the AD-like effects of all the drugs tested in the FST. More interesting is the additivity of gepirone with lithium (1 mEq/l), and ondansetron with quinine (0.5 mg/kg). The results of the present study are in favour of the potentiation of AD activity by clonidine via 5-HT2 receptors, lithium through 5-HT1A receptors, and quinine through 5-HT3 receptors. Further studies to examine in detail which of these three 5-HT receptors or their subtypes is the most important in the actions of individual ADs are warranted.

5-HTP induced diarrhea as a carcinoid syndrome model in mice?

Serotonin (5-HT) is present in the gastrointestinal tract and is probably one of the compounds responsible for diarrhea in patients presenting with carcinoid syndrome. Intraperitoneal administration of L-5-hydroxytryptophan (L-5-HTP) at doses of 25 to 100 mg/kg dramatically increase defecation in mice. In this new paradigm, counting fecal boli deposited is simple and the appraised or inhibition of diarrhea induced by ip 25 mg/kg of L-5-HIP is very clear, with a good reproducibility of scores. L-5-HTP needs to be metabolized into 5-HT to be active; benserazide, an inhibitor of decarboxylase, antagonized the diarrhea induced by 5-HT. Among the 5-HT antagonists used in interaction with 5-HT, only these of the 5-HT3 type (ondansetron, granisetron, tropisetron) and, to a lesser extent 5-HT2 type (ritanserin), decreased the diarrhea induced by 5-HTP. The 5-HT4 receptor agonists from the benzamide family (metoclopramide and zacopride) increased defecation in mice but the effect failed to reach statistical significance.