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ABSTRACT
The binding and pharmacological characteristics of melatonin-binding sites labelled by [125I]iodomelatonin in membrane preparations from the pigeon brain were determined. Specific binding of [125I]iodomelatonin in the membrane preparations of pigeon brain was rapid, stable, saturable and reversible. The [125I]iodomelatonin-binding sites had the following order of pharmacological affinities: melatonin > 6-chloromelatonin > N-acetylserotonin > > 5-hydroxytryptamine > tryptamine > 5 -methoxytryptophol, > 1 - acetylin dole-3-carboxytryptamine, 5-hydroxyindole-3-acetic acid, l-tryptophan and 3-acetylindole. Compounds known to act on serotonin receptors, adrenoceptors or cholinoceptors were inactive compared with melatonin. Of the various brain regions studied, melatonin binding was greatest in the hypothalamus, intermediate in the mid-brain, pons-medulla and telencephalon, and low in the cerebellum. Subcellular fraction studies indicated that 39% of the binding was located in the mitochondrial fraction, 34% in the nuclear fraction, 21% in the microsomal fraction and 5·6% in the cytosol fraction. Scatchard analysis of the membrane preparations revealed a dissociation constant (K d) of 206·3±57·9 pmol/l and a total number of binding sites (Bmax) of 26·7±1·9 fmol/mg protein in the middle of the light period (mid-light). In addition, saturation studies demonstrated that [125I]iodomelatonin-binding sites in pigeon brain membrane preparations were 36·2% higher at mid-light (26·7±1·9 fmol/mg protein) than in the middle of the dark period (19·6±1·25 fmol/mg protein), with no significant variation in their binding affinities.
Journal of Endocrinology (1991) 128, 475–482
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Neuroactive steroids may be synthesised in the brain either de novo from cholesterol or from blood-borne precursors. Concentrations of a GABAA receptor agonist, allopregnanolone, in the fetal brain exceed those in the circulation, and are markedly higher than adult brain concentrations. We used fetal hypophysectomy or adrenalectomy to elucidate the contribution of hypothalamic-pituitary factors and adrenal steroid secretion to the overall neuroactive steroid level in both the fetal brain and the fetal circulation. Hypophysectomy or adrenalectomy was performed between 108 and 112 days of gestation (term approximately 147 days) and fetal tissues were collected at 140 days of gestation. Immunoreactive (ir) ACTH and cortisol in the plasma were significantly reduced after hypophysectomy, whereas adrenalectomy led to increased irACTH but significantly decreased cortisol concentrations, as expected. Brain concentrations of allopregnanolone, progesterone and pregnenolone did not change significantly in fetuses that underwent either hypophysectomy or adrenalectomy; however, concentrations in the plasma and content in the adrenal gland were decreased. Expression of cytochrome P450 scc and 5alpha-reductase type II (5alphaRII) in the brain, measured by western immunoblotting, did not change after either hypophysectomy or adrenalectomy but, after hypophysectomy, expression of P450 scc in the adrenal gland was significantly decreased and that of 5alphaRII remained unchanged. These findings suggest that the regulation of the neuroactive steroid content in the fetal brain is independent of adrenal steroidogenesis and hypothalamic-pituitary factors. Furthermore, the absence of a change in enzyme expression in the brain suggests that the control of the expression of these enzymes is independent of hypothalamic-pituitary factors. Thus local control mechanisms within the brain may be responsible for maintaining the high neurosteroid content present during fetal life, as these mechanisms are independent of adrenal steroid production.
Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, British Columbia, Canada
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Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, British Columbia, Canada
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Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, British Columbia, Canada
Department of Zoology, The University of British Columbia, Vancouver, British Columbia, Canada
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effects on the brain and reward-seeking behaviours. There is mounting evidence that early life exposure to sucrose influences brain function and behaviour in adulthood ( Wiss et al. 2018 ). This effect could be a function of changes in the
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ABSTRACT
Oestrogen is formed in the female dove brain. The aim of this study was to determine whether (a) the catalytic properties of the brain aromatase are similar to the ovarian enzyme and (b) aromatase activity in the female brain changes during the reproductive cycle and is influenced by steroids and environmental stimuli.
The results show that female preoptic aromatase has a higher substrate affinity than the enzyme in ovarian follicles (apparent K m: preoptic area, 7 nmol/l; ovarian follicles, 29 nmol/l), but a lower activity in the preoptic area (Vmax: preoptic area, 290 fmol/mg tissue per h; ovarian follicles, 843 fmol/mg tissue per h). In intact females with developing follicles, oestradiol-17β formation was higher in the posterior hypothalamus than the preoptic area. Females in a later stage of reproductive development (yolked follicles) had a different distribution of oestrogen formation with increased aromatase activity in the preoptic area. Preoptic and posterior hypothalamic aromatase activity of females paired with males for 10 days was positively correlated (r = 0·84, P = 0·0001; r = 0·75, P = 0·001 respectively) with ovarian development. Females with undeveloped ovaries which interacted with males had higher preoptic aromatase activity than visually isolated females with similar ovarian development, suggesting that behavioural stimuli have direct effects on brain aromatase activity which are independent of the ovary. Oestradiol benzoate treatment increased preoptic and posterior hypothalamic aromatase activity in intact and ovariectomized females, and testosterone propionate treatment increased anterior hypothalamic aromatase activity, but did not affect other areas, indicating that the distribution of induced aromatase activity is steroid-specific. Oestrogen treatment in ovariectomized or intact females did not replicate the maximal hypothalamic aromatase activity seen when the ovary contained yolked follicles.
We conclude that brain aromatase activity is related directly to ovarian condition during the reproductive cycle of the female dove. As in the male, steroids have a role in the regulation of oestrogen formation in the female hypothalamus; behavioural stimuli are also likely to be involved in the control of the brain enzyme.
Journal of Endocrinology (1992) 134, 385–396
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SUMMARY
The ribonucleic acid (RNA) base percentages were estimated in the hypothalamus, amygdala, hippocampus, frontal cortex, cerebellum and spinal cord of adult intact female rabbits, and after ovariectomy followed by replacement therapy with oestradiol-17β, progesterone and oestradiol plus progesterone. The results indicate a lack of effect on the spinal cord, but a variable effect on all other brain regions examined. In response to the various treatments, all regions examined produced RNA very rich in guanosine monophosphate indicating synthesis of specific RNA. The hypothalamus showed the most significant overall changes. Progesterone injections resulted in the most persistent effects of the hormonal treatments employed. Hypotheses are proposed to explain the variable hormonal effects on brain RNA base composition. It is suggested that ovarian hormones produce specific molecular changes in nervous tissue related either to 'receptors' for the hormones or to neural functions related to behavioural phenomena which are mediated by these hormones.
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ABSTRACT
In an effort to understand the physiological functions of cytochrome P-450 in the central nervous system and pituitary gland, we evaluated changes in the level of the enzyme as a function of the endocrine status of rats and the ability of these tissues to synthesize or degrade steroids. The P-450 content of microsomes prepared from the hypothalamic preoptic area (HPOA), the olfactory lobes and the cerebrum was 0·040 ± 0·009 and in the pituitary gland 2·2 ± 0·6 (s.d.) nmol/g tissue. The P-450 content of the HPOA and olfactory lobes, but not of the rest of the cerebrum, was influenced by the endocrine status of rats. In microsomes it increased five- to tenfold over control levels during late pregnancy in the olfactory lobes and during lactation in the HPOA, and in both brain regions treatment of rats with 5α-dihydrotestosterone (DHT) caused an eight- to tenfold increase in the P-450 content. Androstenedione was not a good substrate for brain P-450. The level of androstenedione 19-hydroxylase in the olfactory lobe microsomal fraction was 0·50± 0·06 nmol 19-hydroxyandrostenedione formed/g tissue per h. This activity was tenfold lower in other brain areas and was not detectable in the pituitary gland. The rate of aromatization of androstenedione to oestradiol in the HPOA and olfactory lobe of lactating rats was 0·46 ± 0·14 and 0·38 ± 0·05 pmol/oestradiol formed/g tissue per h respectively. 5α-Androstane-3β,17β-diol (A-5α-3β,17β-diol) was a much better substrate for P-450 throughout the brain and pituitary gland. Catalytic activity was 125 ± 46 and 307 ±108 nmol triols formed/g tissue per h in the brain and pituitary gland respectively. The P-450 responsible for this catalytic activity was isolated and its substrate specificity examined. In addition to A-5α-3β,17β-diol, 5-androstene-3β,17β-diol, dehydroepiandrosterone and DHT were also substrates, with turnover numbers of 27, 8, 12 and 1 mol product/mol P-450 per min respectively. None of these catalytic activities was induced in the rat brain during pregnancy, lactation or DHT treatment. The enzyme was also present in the brains of mice but not guinea-pigs.
The yield of P-450 from the mitochondrial fraction of the HPOA and olfactory lobes in control rats was 0·01–0·02 nmol/g tissue. This increased tenfold during pregnancy. Immunological evidence for the presence of the cholesterol side-chain cleavage enzyme P-450 SCC was found in the HPOA and olfactory lobes of pregnant but not of control rats. However, no SCC catalytic activity was detectable in these brain mitochondrial P-450 fractions. From these studies we conclude that there is a major influence of the endocrine system on the content and quality of P-450 in the brain. However, the function and substrate specificities of these P-450s as well as of those in the pituitary gland remain to be characterized.
Journal of Endocrinology (1989) 122, 341–349
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Department of Physiology and Pharmacology, Medical School, Queen's Medical Centre, Clifton Boulevard, Nottingham, NG7 2UH
(Received 23 February 1978)
In addition to its well-known peripheral actions, angiotensin II has been implicated in central nervous mechanisms concerned with the modulation of blood pressure, drinking, the release of antidiuretic hormone (ADH) and the secretion of adrenocorticotrophin (ACTH; see Severs & Daniels-Severs, 1973). The receptors responsible for mediating these central effects are both central and peripheral in relation to the blood–brain barrier. Because angiotensin II does not cross this barrier rapidly (Volicier & Loew, 1971), the physiological significance of the receptive sites for angiotensin II which lie on the central side of the barrier (e.g. in the mid-brain peri-aqueductal grey matter and the supraoptic nucleus of the hypothalamus) is unclear.
Recently, an independent iso-renin-angiotensin system has been demonstrated in the central nervous system (for review see Ganten, Hutchinson, Schelling, Ganten & Fisher, 1976)
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ABSTRACT
TRH increases the pressor response to acetylcholine through an increment in muscarinic receptors. As chronic atropinization produces a similar effect, we hypothesized that both phenomena may be related. The effect of chronic atropine treatment on the TRH content of several brain areas in Wistar rats was studied. Atropine produced significant increases in TRH content in the preoptic and septal areas, while decreases were observed in the hypothalamus and hypophysis. The concentration of TRH in cerebrospinal fluid rose significantly in atropine-treated rats compared with controls. A similar effect was observed with eserine, an acetylcholinesterase inhibitor. Finally, perfusion of brain preoptic area slices from normal rats with Krebs–Ringer solution in the presence of pilocarpine increased basal TRH release significantly and this effect was blocked by atropine. These results are compatible with a muscarinic control on the activity of the central TRH system.
Journal of Endocrinology (1992) 134, 215–219
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ABSTRACT
Corticotrophin-releasing factor (CRF) bioactivity has been described in the extra-hypothalamic brain, but its relationship to hypothalamic CRF has remained questionable. Of the seven regions of the mouse brain examined, highest concentrations of CRF-like immunoreactivity (CRF-LI) and bioassayable CRF activity were present in the median eminence and hypothalamus. However, substantial CRF-LI and bioassayable CRF activity were also seen in brain extracts from the amygdala, thalamus, frontal cortex, pons medulla and cerebellum. Bioactivity was largely neutralized by prior incubation with heat-inactivated antiserum to ovine CRF. These findings, in conjunction with previous immunocytochemical evidence, strongly suggest that a substance closely resembling hypothalamic CRF is present in the extrahypothalamic brain of the mouse.
J. Endocr. (1986) 111, 143–149
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SUMMARY
The in-vitro conversion of testosterone to 17β-hydroxy-5α-androstan-3-one (5α-dihydrotestosterone, DHT) and 3α, 17β-dihydroxy-5α-androstane (3α-androstanediol, DIOL) in pituitary and slices of brain regions was compared between male and female rats. Intact pituitaries from male rats formed 2·5 times more DHT and 1·5 times more DIOL than those of females. A small sex difference was also detected in the hypothalamus, males again being higher than females. No sex differences could be detected in other brain regions. However, DHT formation in the brain was regionally differentiated with higher conversion rates in hypothalamus than in cortex, hippocampus, amygdala, pineal gland or cerebellum. The highest transformation, however, was found in the mid-brain. Metabolism in the pre-optic area was as low as that in the cortex.
5α-Dihydrotestosterone and DIOL formation in the pituitary increased several-fold after gonadectomy in both sexes and the sex difference disappeared. Little or no increase occurred after thyroidectomy or adrenalectomy. The increase in pituitary DHT formation after gonadectomy could be attenuated or prevented both by treatment with testosterone propionate and with oestradiol benzoate. Replacement therapy, particularly with oestradiol benzoate, gave rise to a sex difference reminiscent of that of normal animals. No significant change in pituitary DHT formation occurred in adult females which had been treated with testosterone propionate on the 4th day of life.
The results suggested a close relationship between DHT formation and activity of gonadotrophin secretion, particularly at the level of the pituitary.
