Platinum(IV) Prodrugs Incorporating an Indole-Based Derivative, 5-Benzyloxyindole-3-Acetic Acid in the Axial Position Exhibit Prominent Anticancer Activity.

Kinetically inert platinum(IV) complexes are a chemical strategy to overcome the impediments of standard platinum(II) antineoplastic drugs like cisplatin, oxaliplatin and carboplatin. In this study, we reported the syntheses and structural characterisation of three platinum(IV) complexes that incorporate 5-benzyloxyindole-3-acetic acid, a bioactive ligand that integrates an indole pharmacophore. The purity and chemical structures of the resultant complexes, P-5B3A, 5-5B3A and 56-5B3A were confirmed via spectroscopic means. The complexes were evaluated for anticancer activity against multiple human cell lines. All complexes proved to be considerably more active than cisplatin, oxaliplatin and carboplatin in most cell lines tested. Remarkably, 56-5B3A demonstrated the greatest anticancer activity, displaying GI50 values between 1.2 and 150 nM. Enhanced production of reactive oxygen species paired with the decline in mitochondrial activity as well as inhibition of histone deacetylase were also demonstrated by the complexes in HT29 colon cells.

Metabolomic analysis on blood of transgenic mice overexpressing PGC-1α in skeletal muscle.

PGC-1α expression increases in skeletal muscles during exercise and regulates the transcription of many target genes. In this study, we conducted a metabolomic analysis on the blood of transgenic mice overexpressing PGC-1α in its skeletal muscle (PGC-1α-Tg mice) using CE-TOFMS. The blood level of homovanillic acid (dopamine metabolite) and the gene expression of dopamine metabolic enzyme in the skeletal muscle of PGC-1α-Tg mice were high. The blood level of 5-methoxyindoleacetic acid was also high in PGC-1α-Tg mice. The blood levels of branched-chain α-keto acids and ß-alanine were low in PGC-1α-Tg mice. These metabolites in the skeletal muscle were present in low concentration. The changes in these metabolites may reflect the skeletal muscle condition with increasing PGC-1α, such as exercise.

Development and validation of an LC-MS/MS method for the bioanalysis of psilocybin's main metabolites, psilocin and 4-hydroxyindole-3-acetic acid, in human plasma.

Psilocin is the active metabolite of psilocybin, a serotonergic psychedelic substance. It is used recreationally and investigated in substance-assisted psychotherapy. The pharmacokinetic properties of psilocin are only partially characterized. Therefore, we developed and validated a rapid LC-MS/MS method to quantify psilocin and its metabolite 4-hydroxyindole-3-acetic acid (4-HIAA) in human plasma. Plasma samples were processed by protein precipitation using methanol. The injected sample was mixed with water in front of a C18 analytical column to increase retention of the analytes. Psilocin and 4-HIAA were detected by multiple reaction monitoring (MRM) in positive and negative electrospray ionisation mode, respectively. An inter-assay accuracy of 100-109% and precision of ≤8.7% was recorded over three validation runs. The recovery was near to complete (≥94.7%) and importantly, consistent over different concentration levels and plasma batches (CV%: ≤4.1%). The plasma matrix caused negligible ion suppression and endogenous interferences could be separated from the analytes. Psilocin and 4-HIAA plasma samples could be thawed and re-frozen for three cycles, kept at room temperature for 8 h or 1 month at -20 °C without showing degradation (≤10%). The linear range (R ≥ 0.998) of the method covered plasma concentrations observed in humans following a common therapeutic oral dose of 25 mg psilocybin and was therefore able to assess the pharmacokinetics of psilocin and 4-HIAA. The LC-MS/MS method was convenient and reliable for measuring psilocin and 4-HIAA in plasma and will facilitate the clinical development of psilocybin.

Effect of membrane surface potential on the uptake of anionic compounds by liposomes.

The effect of membrane surface potential on the uptake of several anionic compounds by liposomes (large unilamellar vesicles), which contain various amounts of dipalmitoylphosphatidylserine (DPPS), was investigated. The uptake amount of four tested anionic compounds (cefixime, benzyloxyindoleacetic acid (BOIAA), ceftibuten and S-1006) decreased with an increase in the DPPS content of liposomes, and was correlated with the membrane surface potential monitored using a fluorescent dye, 8-anilino-1-naphthalene sulfonate (ANS). Moreover, for all of the tested anionic compounds, a good correlation was observed between the ratio of the uptake value (5 min) by each of the liposomes comprising various amounts of DPPS to the uptake value by liposomes containing 10% DPPS and a relative membrane surface potential monitored by ANS. On the other hand, the uptake of zwitterionic compounds (enoxacin, cephradine and benzyloxytryptophan (BOTP)) was independent of DPPS content. These results suggest that the uptake of tested anionic compounds by large unilamellar lipid vesicles is dependent on the membrane surface potential which originates in the surface negative charge.

A foxy intoxication.

Foxy is the colloquial name for the hallucinogen 5-ethoxy-diisopropyltryptamine (5-MeO-DIPT). A non-fatality involving a 23-year-old Caucasian man who ingested a capsule containing 5-MeO-DIPT is described. He presented to the Emergency Department, not with visual nor auditory hallucinations but with sensory hallucinations, that of formication and paranoia. He was observed and given supportive care for 4 h, then discharged without any known sequelae. Blood and urine were collected for laboratory analyses. Foxy and its metabolites were identified in urine by gas chromatography-mass spectrometry. The concentrations of 5-MeO-DIPT in the serum and urine were 0.14 and 1.6 microg/mL, respectively. The drug undergoes oxidative deamination to form 5-methoxy-indole acetic acid. The urinary concentration of this metabolite was 0.17 microg/mL. Also, the urine contained three other related compounds. Two of them have been described in a previous case of 5-MeO-DIPT ingestion as 5-methoxy-isopropyltryptamine (5-MeO-IPT) and 5-methoxy-diisopropyltryptamine-N'-oxide (5-MeO-DIPT-N'-oxide). The third compound was substantially present in the urine and was tentatively identified as 5-hydroxy-diisopropyltryptamine (5-OH-DIPT). Only the parent drug, 5-MeO-DIPT was detected in the serum sample.

Effect of indole-3-acetic acid derivatives on neuroepithelium in rat embryos.

Indole-3-acetic acid (IAA), a natural auxin, induces microencephaly in rats exposed to IAA during gestation days (Days) 12-14, corresponding to the early stage of cerebral cortex development. The purpose of this study was to examine the effects of 5 IAA derivatives administration in pregnant rats on neuroepithelial cells in the embryos. N-Methylindole-3-acetic acid (1Me-IAA), 2-Methylindole-3-acetic acid (2Me-IAA), 2-Methyl-5-methoxyindole-3-acetic acid (2Me-5MeO-IAA), 5-Methoxyindole-3-acetic acid (5MeO-IAA), Indole butyric acid (IBA), and IAA were administered at 1,000 mg/kg except for 2Me-IAA at 500 mg/kg on Days 12, 13 and 14, and then embryos/fetuses were harvested on Day 14.5 or 21. The dams in the 1Me-IAA and 2Me-IAA groups exhibited rigidity and a decrease in locomotor activity. Although a decrease in the absolute brain weight was observed in the 1Me-IAA, 5MeO-IAA, IBA and IAA groups, a decrease in the relative brain weight was observed in only the IAA group. Histopathologically, apoptotic cells were observed mainly in the medial and dorsal layer of the neuroepithelium in the 5MeO-IAA and IAA groups on Day 14.5. The degree of induced neuroepithelial cell apoptosis was less in the 5MeO-IAA group than in the IAA group. However, it was confirmed that the histopathological changes induced by 5MeO-IAA were quite similar to the lesions induced by IAA and may have resulted from the same mechanisms.

The urinary 5-hydroxyindole acetic acid and plasma nitric oxide levels in irritable bowel syndrome: a preliminary study.

BACKGROUND AND AIMS: Postprandial increase of 5-hydroxytryptamine (5-HT) has been implicated in irritable bowel syndrome (IBS). There is evidence that nitric oxide (NO) may act as a mediator of 5-HT-evoked secretions in the colon. Our aim is to investigate the role of urinary 5-hydroxyindole acetic acid (5-HIAA) and plasma NO levels (with diarrhoea) in IBS patients. METHODS: Nineteen (with constipation) IBS patients (group 1), 22 IBS patients (group 2) and 18 healthy controls (group 3) were included in the study. The diagnosis of IBS was made according to the Rome I Criteria. The urine was collected for determination of 5-HIAA and venous blood was collected from each subject for the measurement of plasma NO levels. RESULTS: The levels of urinary 5-HIAA mmol/day and plasma NO mmol/l of group 1 (22.4 +/- 2.2 and 29.4 +/- 2 respectively) were significantly higher than group 3 (14.2 +/- 2.3 and 21.3 +/- 2.1 respectively) (p = 0.036 and p = 0.019 respectively). The NO level of group 1 was also significantly higher than group 2 (21.8 +/- 1.9) (p = 0.021). The 5-HIAA level of group 1 was higher than group 2 (15.2 +/- 2.1) and the difference was marginally significant (p = 0.055). There was no difference between group 2 and group 3 with respect to 5-HIAA and NO levels. CONCLUSIONS: The results of this preliminary study lend support to the involvement of 5-HT in some symptomatology of diarrhoea predominant IBS. Furthermore, NO may be one of the effector mediators of the 5-HT-induced symptoms in these patients.

Photoperiod affects amplitude but not duration of in vitro melatonin production in the ruin lizard (Podarcis sicula).

The pineal gland and its major output signal melatonin have been demonstrated to play a central role in the seasonal organization of the ruin lizard Podarcis sicula. Seasonal variations in the amplitude of the nocturnal melatonin signal, with high values in spring as compared to low values in summer and autumn, have been found in vivo. The authors examined whether the pineal gland of the ruin lizard contains autonomous circadian oscillators controlling melatonin synthesis and whether previously described seasonal variations of in vivo melatonin production can also be found in isolated cultured pineal glands obtained from ruin lizards in summer and winter. In vitro melatonin release from isolated pineal glands of the ruin lizard persisted for 4 days in constant conditions. Cultured explanted pineal glands obtained from animals in winter and summer showed similar circadian rhythms of melatonin release, characterized by damping of the amplitude of the melatonin rhythm. Although different photoperiodic conditions were imposed on ruin lizards before explantation of pineal glands, the authors did not find any indication for corresponding differences in the duration of elevated melatonin in vitro. Differences were found in the amplitude of in vitro melatonin production in light/dark conditions and, to a lesser degree, in constant conditions. The presence of a circadian melatonin rhythm in vitro in winter, although such a rhythm is absent in vivo in winter, suggests that pineal melatonin production is influenced by an extrapineal oscillator in the intact animal that may either positively or negatively modulate melatonin production in summer and winter, respectively.

The serotonin aldehyde, 5-HIAL, oligomerizes alpha-synuclein.

In Parkinson's disease (PD) alpha-synuclein oligomers are thought to be pathogenic, and 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate aldehyde intermediate in neuronal dopamine metabolism, potently oligomerizes alpha-synuclein. PD involves alpha-synuclein deposition in brainstem raphe nuclei; however, whether 5-hydroxyindoleacetaldehyde (5-HIAL), the aldehyde of serotonin, oligomerizes alpha-synuclein has been unknown. In this study we tested whether 5-HIAL oligomerizes alpha-synuclein in vitro and in PC12 cells conditionally over-expressing alpha-synuclein. Alpha-synuclein oligomers were quantified by western blotting after incubation of alpha-synuclein with serotonin and monoamine oxidase-A (MAO-A) to generate 5-HIAL or dopamine to generate DOPAL. Oligomerization of alpha-synuclein in PC12 cells over-expressing the protein was compared between vehicle-treated cells and cells incubated with levodopa to generate DOPAL or 5-hydroxytryptophan to generate 5-HIAL. Monoamine aldehyde mediation of the oligomerization was assessed using the MAO inhibitor, pargyline. Dopamine and serotonin incubated with MAO-A both strongly oligomerized alpha-synuclein (more than 10 times control); pargyline blocked the oligomerization. In synuclein overexpressing PC12 cells, levodopa and 5-hydroxytryptophan elicited pargyline-sensitive alpha-synuclein oligomerization. 5-HIAL oligomerizes alpha-synuclein both in vitro and in synuclein-overexpressing PC12 cells, in a manner similar to DOPAL. The findings may help explain loss of serotonergic neurons in PD.

Reciprocal day/night relationship between serotonin oxidation and N-acetylation products in the rat pineal gland.

Pineal tryptophan, serotonin [5-hydroxytryptamine (5-HT)], N-acetylserotonin, melatonin, 5-hydroxyindoleacetic acid, 5-hydroxytryptophol, 5-methoxytryptophol, and 5-methoxyindoleacetic acid were measured by high pressure liquid chromatography with electrochemical detection. A complete analysis required less than the equivalent of two rat pineal glands. Samples were obtained at eight time points. A reciprocal physiological relationship was found between oxidation and N-acetylation products of 5-HT. 5-HT and the oxidation products 5-hydroxyindoleacetic acid, 5-hydroxytryptophol, 5-methoxytryptophol, and 5-methoxyindoleacetic acid decreased at night, when the N-acetylation products N-acetylserotonin and melatonin increased. These observations are consistent with the hypothesis that circadian changes in the N-acetylation of 5-HT by indoleamine N-acetyltransferase is the major factor controlling circadian changes in the amounts of 5-HT, and 5-HT oxidation and N-acetylation products in the rat pineal gland.

Melatonin deacetylase activity in the pineal gland and brain of the lizards Anolis carolinensis and Sceloporus jarrovi.

Melatonin modulates a variety of rhythmic processes in vertebrates, and is synthesized in both the retina and pineal gland. We have shown previously that retinal melatonin is deacetylated generating 5-methoxytryptamine, which is then deaminated by monoamine oxidase, producing 5-methoxyindoleacetic acid and 5-methoxytryptophol. This process occurs within the eyes of a variety of vertebrates including the iguanid lizard Anolis carolinensis. To determine whether melatonin deacetylase activity also occurs in the pineal organ or in other parts of the lizard brain, pineals and brains of Anolis carolinensis and Sceloporus jarrovi were cultured in the presence of [3H-methoxy]-melatonin. High-performance liquid chromatography of the resulting culture media and tissues revealed the generation of radiolabeled 5-methoxytryptamine and 5-methoxyindoleacetic acid. These two methoxyindoles were the only radiolabeled metabolites detectable, and together accounted for all melatonin lost. Both the loss of melatonin and the production of melatonin metabolites were inhibited by inclusion of 100 microM eserine, an inhibitor of the melatonin deacetylase. Pargyline, a monoamine oxidase inhibitor, reduced the production of 5-methoxyindoleacetic acid and increased the production of 5-methoxytryptamine relative to control incubations. Similar effects of eserine and pargyline were seen in eyecup, brain and pineal gland, but the specific activity of melatonin deacetylation in cultured pineal glands was much greater than in either brains or eyecups. These results indicate that pineal glands of both Anolis carolinensis and Sceloporus jarrovi can rapidly catabolize melatonin by a mechanism very similar to that in the eye, that the melatonin deacetylation pathway exists elsewhere in the iguanid brain, and also extend our previous observations of ocular melatonin deacetylation to an additional species.

Day-night rhythm of 5-methoxytryptamine biosynthesis in the pineal gland of the golden hamster (Mesocricetus auratus).

5-Methoxytryptamine is a potent agonist of presynaptic 5-hydroxytryptamine autoreceptors modulating serotonin release in the central nervous system. This methoxyindole can be synthesized in the pineal gland, but its presence in vivo is still controversial, probably because of rapid catabolism by monoamine oxidase. An improved high-pressure liquid chromatography method, with coulometric detection, has been developed for the simultaneous measurement of melatonin, 5-methoxytryptamine, 5-methoxytryptophol and 5-methoxyindolacetic acid. We have demonstrated a day-night rhythmicity in the amount of 5-methoxytryptamine in the pineal gland of golden hamsters (Mesocricetus auratus) maintained under a long photoperiod (14 h light: 10 h darkness) and pretreated with the monoamine oxidase inhibitor pargyline. Levels of 5-methoxytryptamine were highest at 16.30 h and lowest at 00.30 h. The rhythm for 5-methoxytryptamine appears to be the same as for serotonin (opposite in phase to that of melatonin). The identification of 5-methoxytryptamine has been confirmed by analysis with gas chromatography-mass spectrometry.

Methoxyindole production by the pineal gland appears to be dependent on the concentration of hydroxy precursors and their affinity for hydroxyindole-O-methyltransferase.

Various pineal gland indole metabolites were separated by thin-layer chromatography after organ culture with tritiated serotonin. The amounts of methoxyindoles produced were remarkably constant and female rats in oestrus appeared to produce greater amounts than male rats. The results show a correlation between methylation and the concentration and affinity of the various hydroxyindoles for hydroxyindole-O-methyltransferase.

Metabolism of biogenic aldehydes in isolated human blood cells, platelets and in plasma.

The metabolism of biogenic aldehydes was measured in different human blood fractions. Isolated erythrocytes, leukocytes, platelets and plasma were incubated with 3,4-dihydroxyphenyl-acetaldehyde (DOPAL) or 5-hydroxyindole-3-acetaldehyde (5-HIAL), the aldehydes derived from dopamine and 5-hydroxytryptamine, respectively. The disappearance of the aldehydes and the formation of acid and alcohol metabolites were analysed using high-performance liquid chromatography with electrochemical detection. The aldehydes were unstable in phosphate-buffered saline, but this nonenzymatic oxidation was prevented in the presence of EDTA, pyrophosphate or blood tissue. When DOPAL or 5-HIAL were incubated with erythrocytes, only acid metabolites were formed, whereas both acid and alcohol metabolites were formed in incubations with leukocytes or platelets. The amount of the acid metabolite exceeded that of the alcohol metabolite, both with leukocytes and platelets. No metabolites were formed when the aldehydes were incubated in plasma. The oxidation of the aldehydes in incubations with erythrocytes or platelets was totally inhibited in the presence of 50 microM of the aldehyde dehydrogenase inhibitor disulfiram. However, disulfiram did not inhibit the metabolism of DOPAL and 5-HIAL in incubations with leukocytes, suggesting that different isozymes of aldehyde dehydrogenase are present in leukocytes as compared to erythrocytes and platelets.

Studies on the interaction between ethanol and serotonin metabolism in rat, using deuterated ethanol and 4-methylpyrazole.

The metabolic interaction between ethanol and serotonin (5-hydroxytryptamine) via alcohol dehydrogenase (ADH; EC 1.1.1.1) was studied in tissue homogenates of Sprague-Dawley rats by following the transfer of deuterium from deuterated ethanol over endogenous NADH to 5-hydroxytryptophol (5HTOL). Homogenates of whole brain, lung, spleen, kidney, liver, stomach, jejunum, ileum, colon, and caecum were incubated in the presence of [2H2]ethanol and 5-hydroxyindole-3-acetaldehyde (5HIAL), and the [2H]5HTOL formed was identified and quantified using gas chromatography-mass spectrometry. ADH activity was most abundant in liver, kidney, and within the gastrointestinal tract. The highest incorporation of deuterium was obtained in homogenates of kidney, lung, and colon, whereas in brain, which contains very low ADH activity, no incorporation could be demonstrated. Addition of extra NAD+ (2.4 mM) increased the formation of [2H]5HTOL 2.6-fold in liver homogenates, but only 1.2-fold in kidney homogenates. 4-Methylpyrazole, a potent inhibitor of class I ADH, inhibited the 5HIAL reduction in homogenates of lung, kidney, jejunum, ileum, and colon, and caused a marked drop in 5HTOL oxidation in all tissues except stomach and spleen. These results demonstrate that in the rat a metabolic interaction between ethanol and serotonin via the ADH pathway may take place in several tissues besides the liver, which is the main tissue for ethanol detoxification.

Effects of ethanol, acetaldehyde and disulfiram on the metabolism of biogenic aldehydes in isolated human blood cells and platelets.

The effects of ethanol, acetaldehyde and disulfiram on the metabolism of biogenic aldehydes were measured in different human blood fractions. Intact erythrocytes, leukocytes and platelets were incubated in phosphate-buffered saline with 3,4-dihydroxyphenylacetaldehyde (DOPAL) or 5-hydroxy-indole-3-acetaldehyde (5-HIAL), the aldehydes derived from dopamine and serotonin, respectively. The disappearance of the aldehyde and the formation of acid and alcohol metabolites were analysed in the presence of different concentrations of ethanol, acetaldehyde or disulfiram using high-performance liquid chromatography with electrochemical detection. Ethanol at a concentration of 20 mM did not affect the biogenic aldehyde metabolism. High concentrations of acetaldehyde caused a dose-dependent inhibition of the disappearance rate of the biogenic aldehydes and of the formation rate of acid metabolites. In incubations with leukocytes or platelets, the inhibition of the acid formation was associated with a slight increase in the formation of the alcohol metabolites. Disulfiram at a concentration of 50 microM totally inhibited the metabolism of DOPAL and 5-HIAL in incubations with erythrocytes or platelets, whereas much less inhibition was observed in incubations with leukocytes.

Secretion of methoxyindoles from trout pineal organs in vitro: indication for a paracrine melatonin feedback.

Synthesis and release of the pineal hormone melatonin is in all vertebrates primarily regulated by the light/dark cycle. In pineal organs of teleost fish, like in other non-mammalian vertebrates, melatonin formation is regulated by a direct photoreception of the pineal organ. We performed measurements in explanted, perifused pineal organs of the rainbow trout, Oncorhynchus mykiss, to examine whether melatonin can influence its own production. For this purpose we have continuously perifused isolated pineal organs under light- and dark-adapted conditions and measured the release of melatonin and other methoxy-indoles by HPLC with electrochemical detection. Addition of 2-iodomelatonin to the perifusate in a concentration of 2 ng/ml significantly inhibited melatonin release in light-, as well as in dark-adapted organs. The release of 5-methoxytryptamine and 5-methoxytryptophol was also significantly reduced in light-adapted organs. These results indicate that extracellular melatonin may act as a paracrine or autocrine feedback signal and may be important for the illumination-dependent melatonin production.

Evaluation of fluorinated indole derivatives for electron-capture negative ionization mass spectrometry: application to the measurement of endogenous 5-methoxyindole-3-acetic acid in rat.

A series of N-trifluoroacetyl/pentafluoropropionyl-O-trifluoroethyl/ pentafluoropropyl/heptafluorobutyl ester derivatives of 5-methoxyindole-3-acetic acid (5MIAA) were synthesized. Under electron-capture negative ionization conditions, the N-trifluoroacetyl derivatives were found to yield relatively abundant, analyte-specific M-. molecular ions and [M-HF]-., [M-HF-CF2CO]-. and [M-CF3CO]- fragment ions, while the N-pentafluoropropionyl derivatives yielded predominantly the reagent-specific pentafluoroacylium C2F5CO- ion. 5-[2H3]Methoxyindole-3-acetic acid was prepared in high yield by a new synthetic procedure and used as the internal standard in subsequent gas chromatographic/mass spectrometric analysis. Using the N-trifluoroacetyl-O-pentafluoropropyl ester derivative, femtomole to low picomole per gland/organ per g ml-1 levels of endogenous 5MIAA were identified and determined in the rat pineal gland, retina, whole brain and serum.

Effects of biogenic aldehydes and aldehyde dehydrogenase inhibitors on rat brain tryptophan hydroxylase activity in vitro.

The effect of indole-3-acetaldehyde, 5-hydroxyindole-3-acetaldehyde, disulfiram, diethyldithiocarbamate, coprine, and 1-amino-cyclopropanol on tryptophan hydroxylase activity was studied in vitro using high performance liquid chromatography with electro-chemical detection. With the analytical method developed, 5-hydroxytryptophan, serotonin, and 5-hydroxyindole-3-acetic acid could be measured simultaneously. Indole-3-acetaldehyde (12-1200 microM) was found to cause a 6-33% inhibition of the enzyme. Dependent upon the nature of the sulfhydryl- or reducing-agent (dithiotreitol, glutathione, or ascorbate) present in the incubates, the degree of inhibition by disulfiram varied, probably due to the formation of various mixed disulfides. Also the presence of diethyldithiocarbamate (160-1600 microM) was found to inhibit tryptophan hydroxylase (28-91%), while 5-hydroxyindole-3-acetaldehyde, coprine, or 1-aminocyclopropanol appeared to have no effect on the enzyme activity.

Effect of a pineal indolamine, 5-methoxyindole-3-acetic acid, on the estrous cycle and reproductive organs of female Wistar albino rats.

It has been suggested that the pineal gland has a specific role in the control of cyclic sexual activity in rats. One or more of the compounds isolated from this gland have been considered to be possible anti-fertility agents. In this study, the effect of different doses of 5-methoxyindole-3-acetic acid (5-MIAA) on the estrous cycle and the reproductive organs of female rats was studied. Daily injections of either 100 or 200 micrograms of 5-MIAA significantly prolonged the estrous cycles of mature female rats. After injections of 5-MIAA, an increase in diestrous smears was observed; in addition, the animals had estrous cycles without proestrous phase. Following the injections of 200 micrograms of 5-MIAA, a significant increase in uterine weight, plasma 17 beta-estradiol level and in the number of follicles were observed, and after injections of 5-MIAA (50, 100, 200 micrograms) a medium level of plasma progesterone was obtained. Thus it is concluded that 5-MIAA has an effect on the ovulation process of female rats.