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Z. YARON
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Two types of endocrine tissues are encountered in the teleost testis, the typical interstitial tissue, which is also found in higher vertebrates, and the lobule-boundary cells which may be the only endocrine tissue in the testes of some teleosts (Marshall & Lofts, 1956). The inference that these tissues produce androgens is based on the following grounds: (1) changes in the histological appearance of the interstitial and the boundary cells concomitant with the reproductive state of the fish (Henderson, 1962); (2) development of male secondary sex characters in fishes after the administration of mammalian androgens (Pickford & Atz, 1957; Dodd, 1960); (3) isolation of progesterone, oestriol, oestrone and 11-ketotestosterone from the testis and blood of certain bony fishes (Chieffi, 1962; Schmidt & Idler, 1962).

Histochemistry, apart from enabling morphological allocation, provides a simple means for the determination of tissue constituents while requiring very minute amounts of tissue. However, the histochemical studies

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Z. ILAN
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Z. YARON
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SUMMARY

The effect of ACTH on cortisol concentration in the plasma of the carp has been studied; cortisol was determined using a competitive protein-binding radioassay. Blood was sampled at 12.00 h (the diurnal minimum) by cardiac puncture. The plasma cortisol level of undisturbed carp (blood obtained 1–3 min after netting) was 46 ± 14 (s.e.m.) ng/ml.

One hour after injection of ACTH (1·0 i.u./100 g body wt., i.m.) the level of cortisol increased to 415 ± 62 ng/ml and reached a maximum of 656 ± 62 ng/ml after 2 h. The level of cortisol in saline-injected control carp after 2 h was 72 ± 33 ng/ml. A transient rise of cortisol was noted in both groups 30 min after injection (315 ± 51, 315 ± 62 ng/ml). This was attributed to a surge of endogenous ACTH, presumably due to handling.

Carp head kidneys were superfused in vitro. They released cortisol spontaneously, but the releasing rate declined exponentially and reached a minimum after 135 min. Addition of ACTH to the medium was followed by a prompt increase in cortisol release. The rate of cortisol release was maximal 30–45 min after addition of ACTH and was identical to the rate at the beginning of the superfusion.

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Z. ILAN
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Z. YARON
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A superfusion system was developed in which secretion of cortisol from the interrenal tissue of Sarotherodon aureus could be stimulated by ACTH. Head kidneys from four fish were cut into fragments and superfused with Eagle's basal medium containing 4 mm-NaHCO3 and bovine serum albumin (50 mg/100 ml). The superfused medium was collected every 15 min before stimulation and every 5 min thereafter. Cortisol was measured in the medium by radioimmunoassay. The rate of cortisol secretion increased considerably after a 5 min pulse of 0·1 mu. porcine ACTH/ml, reaching a peak of 11·64 ± 2·40 (s.e.m.) ng/min (n = 5) after 20 min. In the subsequent 35 min the secretion rate decreased to a level of 0·49 ± 0·21 ng/min which was within the range of the baseline (0·2–0·7 ng/min). The amount of cortisol secreted by the superfused tissue in response to the corticotrophin, calculated from the area under the peak, was dose-dependent at the range of 0·06–273 mu. ACTH.

Cortisol secretion in this system could also be stimulated by a crude pituitary extract from the same fish. Using the dose–response line, the adrenocorticotrophic activity in the pituitary gland of S. aureus was estimated as 0·2 i.u./g or 1·87 mu. per gland, in porcine ACTH equivalents.

It was possible to substitute ACTH with dibutyryl cyclic AMP. The response of the interrenal tissue, i.e. the increase in secretion of cortisol, was dose-dependent at the range of 2–20 mmol/l. The response of the superfused interrenal tissue to ACTH could be extended by the addition of the synthetic phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (0·1 mmol/l), to the medium. These results indicated that the stimulation of cortisol secretion from the interrenal tissue of this fish by ACTH is, most probably, mediated by cyclic AMP as a second messenger.

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Z. ILAN
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Z. YARON
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Superfused interrenal tissue of Sarotherodon aureus responded to ACTH with increased release of cortisol. The response to ACTH of interrenal tissue taken from fish treated with the organochlorine insecticide 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane (o,p-DDD; 50 mg/kg) in vivo was almost totally abolished. Lower doses were less effective. The response was also suppressed by exposure in vitro of the interrenal tissue to the organochlorine; there seemed to be a dose–response to o,p-DDD over the range of 0·023 to 1 mg/l. Also 1,1-dichloro-2,2-bis (p-chlorophenyl) ethylene (p,p′-DDE) was effective in suppressing the response to ACTH at concentrations of 50–150 mg/l; 1,1,1-trichloro-2,2-bis (p-chlorophenyl) ethane (p,p′-DDT) or the polychlorinated biphenyl, Aroclor 1254, were ineffective at 50 mg/l.

No suppressive effect of o,p-DDD on output of cortisol could be detected in superfusion when N6,O2′-dibutyryl cyclic AMP (20 mmol/l) was substituted for ACTH. This may indicate that the interference of o,p-DDD with the interrenal response to ACTH results from an interruption in the generation of cyclic AMP.

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M. Laudon
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Z. Yaron
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N. Zisapel
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ABSTRACT

N-(3,5-dinitrophenyl)-5-methoxytryptamine (ML-23) has recently been synthesized and shown to antagonize the inhibitory effect of melatonin on the release of dopamine in vitro from the hypothalamus of female rats. In the present study the ability of ML-23 to inhibit in vivo the following melatonin-mediated effects was investigated: (1) delayed sexual maturation of young male rats, (2) delayed sexual maturation of young female rats, (3) inhibition of ovulation in mature female rats and (4) re-establishment of oestrous cycles in adult female rats maintained in continuous light.

The inhibitory effect of daily melatonin injections, given in the afternoon, on the growth of the prostate gland and seminal vesicles and on serum testosterone concentrations in young male rats was prevented by daily injections of ML-23. Daily injections of ML-23 alone did not affect sexual maturation of young rats.

In young male rats treated through the drinking water with melatonin, the growth of the accessory sex organs, but not that of the testes, was delayed and serum concentrations of testosterone were lower than in untreated rats. Administration of ML-23 through the drinking water increased serum concentrations of testosterone but did not significantly affect the weights of the accessory sex organs. Simultaneous administration of ML-23 and melatonin through the drinking water prevented completely, in a dose-dependent manner, the melatonin-mediated decrease in epididymal weights and in serum concentrations of testosterone and partially inhibited the delayed growth of the prostate glands and seminal vesicles.

In young female rats treated with melatonin through the drinking water for 30 days, the growth of the ovaries was inhibited and serum concentrations of oestradiol were lower than in untreated rats. The growth of the uterus was not significantly affected. Administration of ML-23 through the drinking water did not significantly affect uterine and ovarian weights or oestradiol concentrations. Simultaneous administration of melatonin and ML-23 through the drinking water prevented completely the melatonin-mediated decrease in ovarian weights and in serum oestradiol concentrations.

Ovulation during presumptive oestrus was prevented in adult female rats treated through the drinking water for 7 days with melatonin. Administration of ML-23 alone did not significantly affect the average numbers of ova shed and corpora lutea present. Simultaneous administration of ML-23 and melatonin prevented completely the melatonin-mediated inhibition of ovulation; the average number of ova shed was the same as in controls.

Suppression of reproductive cycles occurred in adult female rats after long-term exposure to continuous light. This suppression was prevented by daily injections of melatonin in the afternoon; the incidence of constant oestrus decreased by 80%. Simultaneous injection of ML-23 and melatonin into rats maintained under continuous illumination prevented the effect of melatonin, and all the animals remained in constant oestrus. Administration of ML-23 alone did not alter the incidence of constant oestrus.

A tritium-labelled derivative of ML-23 was prepared and administered orally to male rats. Peak concentrations of ML-23 occurred in the blood within 30 min after feeding and disappeared subsequently with a half-life of about 42 min. Intraperitoneal injection of [3H]ML-23 resulted in the appearance of peak concentrations of the drug in the brain within 20 min.

The effects of ML-23 on serotonin S1 and S2 receptors, dopamine D2 receptors and melatonin receptors in the brain of the male rat were investigated using [3H]serotonin, [3H]spiperone and 2-[125I]iodomelatonin respectively. The binding of [3H]serotonin to brain synaptosomes and of [3H]spiperone to synaptosomes prepared from the cortical and caudate regions of the cerebrum was unaffected by ML-23 (10 μmol/l), whereas the binding of 2-[125I]iodomelatonin to brain synaptosomes was entirely inhibited.

The results demonstrate the potency of ML-23 in antagonizing melatonin-mediated effects in the male and female rat in vivo. The drug may be administered to the animals simply through the drinking water, for relatively long periods without apparent deleterious effects on survival and welfare. ML-23 is accessible to both central and peripheral sites and acts specifically on melatonin but not on serotonin or dopamine receptors in the brain. The availability of a melatonin antagonist offers new opportunities for exploring the physiological role of melatonin in the neuroendocrine system.

J. Endocr. (1988) 116, 43–53

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