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The hormonally and behaviorally active nonapeptide oxytocin (OXT), its behaviorally active N-terminal octapeptide desglycinamide9-OXT and Z-prolyl-D-leucine, a synthetic analog of the C-terminal prolyl7-leucine8 sequence, inhibited the development both of a moderate and of a strong tolerance to morphine. N-alpha-Acetyl-(2-0-methyltyrosine)-OXT and (penicillamine1-2-0-methyltyrosine)- lysine8-vasopressin, both OXT receptor antagonists, facilitated the development of a moderate morphine tolerance. The i.c.v. injection of either antagonist prevented the effects of i.c.v. and s.c. OXT treatment on the development of tolerance. The effect of desglycinamide9-OXT, but not that of Z-prolyl-D-leucine was also prevented by N-alpha-acetyl-(2-0-methyltyrosine)-OXT. It is concluded that OXT and desglycinamide9-OXT, but not Z-prolyl-D-leucine, attenuate morphine tolerance by affecting putative oxytocinergic binding sites in the mouse brain. The fact that i.c.v. injection of the receptor antagonist also blocked the effect of s.c. OXT treatment argues in favor of the possibility that a minor proportion of s.c. OXT (or behaviorally active fragments thereof) may reach central nervous system target sites.

Immunoreactive oxytocin (OXT) and arginine8-vasopressin (AVP) levels were measured in limbic areas of the mouse brain (hippocampus, amygdala and basal forebrain). Peptides were measured by radioimmunoassay (RIA). Acute morphine treatment caused a naloxone-reversible increase in OXT content in all three brain regions. The AVP contents of the same brain areas, on the other hand, were not affected by acute morphine treatment. In mice rendered tolerant to/dependent on morphine with subcutaneous morphine pellets, the OXT levels in the limbic brain structures were in the control range (basal forebrain and amygdala) or even decreased (hippocampus). In the latter brain structure of the tolerant animals, the AVP content was also decreased. Naloxone-precipitated withdrawal syndrome in the tolerant/dependent animals resulted in abrupt increases in the OXT and AVP levels of the hippocampus and in the OXT content of the basal forebrain structures.

The effects of desglycinamide9-arginine8-vasopressin (DG-AVP) on memory processes have been studied in patients with central diabetes insipidus (DI) and in non-diabetic control patients. Acute im injection of DG-AVP improved some aspects of short-term memory. Subchronic intranasal administration of DG-AVP facilitated short-term memory more consistently and in addition improved long-term memory. DG-AVP increased the attention, but only in the non-diabetic subjects. The effects of DG-AVP on memory processes persisted after discontinuation of treatment. DG-AVP did not affect the parameters for water and electrolyte metabolism, blood pressure and pulse rate neither in DI nor in the control patients. Thus, the memory effects of DG-AVP are probably mediated by a direct action on the central nervous system.

In order to investigate the synthesis of squalene and lanosterol in the human foeto-placental unit at midgestation, two complete foeto-placental units, two isolated midgestation foetuses and two isolated midgestation placentas were perfused with [14C] sodium acetate immediately following their removal at laparotomy. The perfusions were carried out at 36°C for 90 minutes, administering 5.0 mCi (foeto-placental units), or 2.5 mCi (separate perfusions of foetuses or placentas) amounts of [14C] sodium acetate.Chromatographic evidence indicated the presence of [14C] squalene-like material in the extracts of all adrenals and livers. Radiochemically homogeneous squalene was isolated in the form of squalene dodecabromide from one adrenal and two liver extracts, which were studied more in detail. In the extracts of all placentas, testicles, carcasses and perfusates, the presence of any [14C] squalene was excluded by crystallization.Sufficient material for the identification of [14C] lanosterol was present in the extracts of three adrenals, three livers, four testicles and two carcasses. From all these extracts radiochemically homogeneous [14C]-lanosterol was isolated. The [14C] lanosterol-like material present in all perfusates was so limited that it precluded further identification.In the extracts of three placentas, the presence of any [14C] lanosterol was excluded by crystallization. From the extract of a separately perfused placenta a minute amount of radiochemically homogeneous [14C] lanosterol was isolated.It is concluded that the midgestation human foetus is capable of synthesizing major quantities of squalene and lanosterol. Little, if any, squalene and lanosterol are formed by the midgestation human placenta.

Three midgestation and three term placentas were perfused in vitroeach with 5 mCi of [7α-3H] cholesterol. Perfusions were carried out at 37°C for 120 minutes, using diluted blood oxygenated with an air + CO2mixture (23.1% O2+ 3.6% CO2).Radiochemically homogenous pregnenolone, progesterone, dehydroepiandrosterone and 17β-oestradiol were isolated from each placenta and each perfusate. Carbon-14 labelled internal standards were used in order to assess procedural losses.On an average 0.01 per cent of the perfused cholesterol was converted to the four steroids studied by midgestation placentas and 0.015 per cent by term placentas.Approximately equal amounts of the individual steroids were recovered from the placentas and from the perfusates. The amounts of pregnenolone + progesterone isolated exceeded those of dehydroepiandrosterone + 17β-oestradiol by a factor of 7 to 8.It is suggested that the human placenta is capable of converting circulating cholesterol not only to pregnenolone and progesterone, but also to dehydroepiandrosterone and 17β-oestradiol.

Two complete foeto-placental units were perfused at midgestation with 5.0 mCi of uniformly labelled 14C-sodium acetate plus 5.0 mCi of cholesterol-7α-3H and two isolated foetuses were perfused with 2.5 mCi of 14C-labelled sodium acetate plus 2.5 mCi of cholesterol-7α-3H. The perfusions were carried out at 35–36°C for 90 min. The foetal adrenals, livers, testes and perfusates were analyzed and various labelled steroids were isolated in a radiochemically homogeneous form.Major quantities of 14C- and 3H-labelled pregnenolone (3β-hydroxy-pregn-5-en-20-one) and dehydroepiandrosterone (3β-hydroxy-androst-5-en-17-one) were isolated from the foetal perfusates, livers and adrenals. Minor amounts of 14C- and 3H-labelled progesterone (pregn-4-ene-3,20-dione) were isolated from the perfusates and adrenals, and 17α-hydroxy-progesterone (17α-hydroxy-pregn-4-ene-3,20-dione) and androstenedione (androst-4-ene-3,17-dione) from the perfusates. Smaller amounts of exclusively 14C-labelled androstenedione were isolated also from the adrenals. No labelled progesterone, androstenedione or testosterone (17β-hydroxy-androst-4-en-3-one) was detected in the testes. Attempts to isolate 20α-dihydroprogesterone (20α-hydroxy-pregn-4-en-3-one) or 20β-dihydroprogesterone (20β-hydroxy-pregn-4-en-3-one) from the perfusates, adrenals and livers failed. No labelled cortisol (11β,17,21-trihydroxy-pregn-4-ene-3,20-dione) or corticosterone (11β,21-dihydroxy-pregn-4-ene-3,20-dione) was detected in the adrenals, and no testosterone, oestrone (3-hydroxy-oestra-1,3,5(10)-trien-17-one) or 16α-hydroxy-dehydroepiandrosterone (3β,16α-dihydroxy-androst-5-en-17-one) in the perfusates.Pregnenolone and dehydroepiandrosterone (which were present in approximately equal amounts) accounted for as much as 95% of all steroids isolated from all sources. The bulk of these two steroids was isolated from the perfusates. The 14C/3H ratio of the pregnenolone and dehydroepiandrosterone isolated from the conjugated fraction of the perfusates was much higher than that of the unconjugated compounds.It is concluded that the midgestation human foetus is capable per seof carrying out the de novosynthesis of major quantities of pregnenolone and dehydroepiandrosterone. It is suggested that in foetal steroidogenesis acetate is utilized predominantly viaa conjugated pathway and circulating cholesterol mainly viaan unconjugated pathway.

The concentration of progesterone in the ovarian venous blood of female dogs varied between 0.13 and 2.70 μg/h per ovary and per kg body weight, in the different phases of the oestrous cycle. There was no evidence of progesterone secretion in the absence of the corpus luteum. The highest values of progesterone secretion were detected in the early stage of pregnancy (12.9-16.2 μg/h per ovary and per kg body weight). In the course of pregnancy, a gradual decrease in progesterone secretion was found which fell below detectable amounts 48 hours after parturition. The ovarian venous blood did not contain any progesterone in the presence of a corpus luteum of lactation. There was some progesterone in the extracts of placental tissue, however, though in much smaller quantities than in the human placenta.