Hormones, dopamine receptors and schizophrenia.
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Biomedical subjects
Publications and source records attributed to V S Fang.
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The ability of antidepressant drugs, electroconvulsive treatment (ECT), or lithium chloride (LiCl), to modify prolactin secretion in the rat was studied. Chlorimipramine, citalopram, fluoxetine, imipramine and zimelidine potentiated the low dose 5-hydroxytryptophan (5-HTP)-induced increase in prolactin secretion, suggesting inhibition of serotonin (5-HT) uptake by these drugs. Amitriptyline, doxepin, iprindole, mianserin and trazadone inhibited the prolactin stimulating effects of high doses of 5-HTP and quipazine, suggesting that these drugs have 5-HT receptor blocking properties. Tandamine inhibited only 5-HTP-induced increase in prolactin secretion. Chronic administration of imipramine, potentiated the effect of low dose 5-HTP significantly more than an acute dose. Amitriptyline, produced similar inhibition of the 5-HTP-induced increase in prolactin secretion after both acute and chronic administration. The ability of bupropion and mazindol to inhibit alpha-methylparatyrosine-induced prolactin secretion, and of nomifensine to inhibit reserpine-induced prolactin secretion, is consistent with other evidence that these agents are indirect dopamine (DA) agonists. Desipramine, acutely, had no effect on any of the above paradigms but after chronic administration, potentiated the effect of low dose 5-HTP on prolactin secretion. Nortriptyline had no effect on prolactin secretion after acute or chronic treatment. ECT for 10 days did not affect the ability of a 5-HT agonist or d-amphetamine to modify prolactin secretion. However, chronic, but not acute, treatment with LiCl markedly enhanced the prolactin response to 5-HT agonists and reserpine while shifting the dose response curve for d-amphetamine and apomorphine to the right. These results are discussed in light of current theories of the role of 5-HT and DA in depression.
The renal uptake of immunoreactive rat growth hormone (rGH), molecular weight 21,500 daltons, was examined in the isolated perfused rat kidney to determine whether peritubular removal of a protein greater than 12,000 daltons occurs and to assess the functional characteristics of renal GH uptake. Organ clearance of rGH (OCGH) in control kidneys was 1,039 +/- 99 microliters/min and was unaffected by an excess of insulin but markedly depressed by col (10 degrees C( and KCN. Although glomerular filtration rate (GFR) did not differ significantly from OCGH in the control rats, we suspected that filtration could not account for all the rGH removed because of glomerular protein sieving. However, GFR was significantly less than OCGH with cold and KCN treatment, indicating the occurrence of peritubular removal. In nonfiltering kidneys, rGH removal exceeded that of [14C]inulin (P less than 0.05), demonstrating peritubular rGH removal. Tubular absorption of rGH was unaffected by insulin but markedly depressed by cold and KCN. We conclude that rGH is removed from the renal circulation mainly by the glomerular filtration-tubular absorptive pathway, but, in addition, as with smaller proteins, that peritubular removal occurs.
The contribution of impaired prolactin (PRL) degradation to the altered dynamics of this hormone in uremia was investigated in rats. Hyperprolactinemia developed after bilateral nephrectomy (BNx) or ligation of both ureters (BUL), whereas PRL levels remained normal in comparably azotemic animals undergoing urine autoinfusion in which glomerular filtration rate (GFR) was maintained. The renal organ clearance of PRL in control rats accounted for two-thirds of its metabolic clearance rate and was consistently less than GFR. Following BUL and BNx the metabolic clearance of PRL decreased predictably also by two-thirds. The importance of the renal parenchyma in the degradation of prolactin was confirmed during perfusion of isolated rat kidneys. Renal PRL handling involves mainly glomerular filtration and tubular reabsorption, although uptake from peritubular blood is also demonstrable under the high plasma flow conditions obtaining during in vitro kidney perfusion. We conclude that the hyperprolactinemia associated with acute uremia in the rat is not the consequence of the uremic state per se, but results from impaired renal degradation of the hormone.
Basel plasma levels and pituitary content of TSH and PRL were measured in young male rats after bilateral adrenalectomy with and without corticosterone replacement. Adrenal ablation for a period of 4 days resulted in the arrest of body weight gain, a remarkable hemoconcentration, the slight and insignificant increase in plasma TSH and PRL, but no significant changes in the pituitary content of TSH and PRL and the hypothalamic content of catecholamines, as compared with the control animals. Adequate glucocorticoid replacement in adrenalectomized rats, as determined by the plasma level of corticosterone, did not result in a comparable weight gain, as in the control group, but did reduce plasma protein to almost normal levels. The plasma levels of TSH and PRL in the adrenalectomized animals were significantly suppressed, although the pituitary contents of TSH and PRL were not different from the control values. Four days after adrenalectomy, pituitary stimulation tests with TRH, chlorpromazine, and metoclopramide produced much higher levels of plasma TSH and PRL in the adrenalectomized rats than in the control group. Replacement of corticosterone in the adrenalectomized rats diminished the excess of TSH and PRL responsiveness. These results suggest that adrenal glands may not be directly involved in the hypothalamic control of the pituitary content of TSH and PRL, as they are in the case of ACTH. However, physiological levels of glucocorticoids clearly exert an inhibitory effect on TSH and PRL release by the pituitary gland in response to provocative stimulation.
The PRL-stimulating effect of metoclopramide (2-methoxy-5-chloroprocainamide) was examined in normal and adrenalectomized male rats pretreated with DL-p-chlorophenylalanine methyl ester (PCPA), an inhibitor of serotonin biosynthesis. PCPA significantly reduced the hypothalamic content of serotonin, increased basal PRL in adrenalectomized rats but not in controls, and potentiated PRL elevation in response to metoclopramide. In the PCPA-pretreated groups, the maximal PRL response to metoclopramide was 60% and 85% higher than that in the saline controls of normal and adrenalectomized rats, respectively. PCPA did not enhance the PRL-stimulating effect of haloperidol, a well established dopamine antagonist, L-alpha-Methyl-p-tyrosine pretreatment in rats depleted hypothalamic dopamine without any change in serotonin and elevated basal PRL, but failed to show an additive effect with metoclopramide's action on serum PRL. Rats pretreated with mianserin, a specific brain serotonin receptor blocker, attenuated PRL elevation in response to low doses of metoclopramide but produced the same response to high doses of metoclopramide as the control rats. These data indicated that metoclopramide stimulated rats pituitary PRL secretion by a serotonergic mechanism in addition to its dopamine antagonist properties.
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Serum prolactin levels in psychiatric inpatients were measured at 8:00 AM prior to administration of oral chlorpromazine (CPZ) at 9:00 AM, and at hourly intervals throughout the day until 3:00 PM. Sixteen patients receiving CPZ 400 mg in equally divided doses of 200 mg twice daily at 9:00 AM and 9:00 PM and six patients who had received fluphenazine decanoate (FD) in doses of 25 to 75 mg 2 to 3 weeks prior to study were evaluated. In patients receiving oral CPZ, serum prolactin levels were elevated in the 8:00 AM samples; serum prolactin levels decreased between 8:00 AM and 10:00 AM and then increased sharply, reaching their peak from 11:00 AM to 2:00 PM. Serum prolactin levels were moderately elevated but relatively stable throughout the day in patients who had received im FD. The 8:00 AM serum prolactin levels were correlated with the peak serum prolactin levels during the day in female patients receiving oral CPZ, but not in male patients. The lack of correlation between base line and peak serum prolactin levels in male patients is most likely due to interference from the sleep-induced prolactin increase in 8:00 AM samples. Serum prolactin levels at 9:00 AM were significantly correlated with peak serum prolactin levels in both male and female patients. The importance of determining diurnal variation in serum prolactin levels in psychiatric patients is discussed.
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We have measured bioactive LH in the plasma of 60 normal boys and 45 normal girls throughout puberty because the rise in immunoreactive LH has seemed too small to account for the profound changes in sexual maturation during adolescence. Bioactive LH was determined using an in vitro bioassay (rat interstitial cell testosterone production); I-LH was measured by radioimmunoassay using the same LH standard, LER 907. Bioactive LH was measurable in all 270 plasma samples; I-LH in 218. In both boys and girls, B-LH rose more than I-LH when compared to chronological age, bone age, and pubertal stage. In boys, B-LH increased 8.2-fold (P < 0.001) from prepuberty to late puberty, whereas I-LH rose 3.0-fold (P < 0.001). Similarly, in girls B-LH increased 23.1-fold (P < 0.001) while I-LH increased 4.9-fold (P < 0.001). Between pubertal stages there was less overlap of individual values of B-LH, in comparison to those of I-LH. We conclude that B-LH increases more than I-LH during normal puberty and is a more discriminating measure of maturation. One implication of these findings is that a qualitative change in gonadotropin secretion may occur during puberty.
Since luteinizing hormone levels by radioimmunoassay (I-LH) have rarely been useful in distinguishing true isosexual precocity from other less serious disorders of puberty, we have studied bioassayable B-LH in 17 prepubertal girls, seven girls with premature adrenarche, 12 girls with premature thelarche, and six girls with true isosexual precocity. The I-LH levels were three times higher in the girls with true precocious puberty than in the other groups but there was overlap between those with premature thelarche and true precocious puberty. The B-LH levels were 16 times higher in the girls with isosexual precocity than in the others, and there was no overlap. We conclude that B-LH better discriminates between true isosexual precocity and other disorders of puberty and may be a very useful laboratory test for the early diagnosis of true precocious puberty.
Twenty oligospermic young men have undergone a 6-month trial of intermittent low dose clomiphene therapy. Three-fourths of the patients enjoyed an increase in semen quality and 8 patients impregnated their wives. Plasma luteinizing hormone, follicle-stimulating hormone and testosterone levels increased in all patients on clomiphene. Development of stringent criteria for the use of clomiphene citrate should result in a conception rate of more than 50 per cent in selected patients. Hypotheses concerning the mechanism of therapeutic response to clomiphene included the induction of higher levels of testosterone locally around the germinal epithelium and the induction of increased follicle-stimulating hormone levels.
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Exogenous and endogenous opioids are known to stimulate PRL release by the anterior pituitary. Morphine and the opioid peptides [D-Ala2, D-Leu5]enkephalin and beta-endorphin have also been shown to decrease dopamine (DA) release by nerve terminals in the median eminence. The present study examined the ability of morphine sulfate (MS) to decrease DA turnover in the median eminence and increase plasma PRL concentrations in rats made tolerant to opioids by chronic treatment with MS. In naive rats, MS (10 mg/kg, sc) caused a mean increase in serum PRL of 79 ng/ml. After treatment with increasing doses of MS for 4 days, the same dose of MS caused an increase of only 18 ng/ml, indicating that tolerance to the PRL-releasing action of MS occurred. In the same animals, tolerance to the ability of MS to slow DA turnover in the median eminence also occurred, as demonstrated by an attenuation of the action of MS to decrease median eminence DA turnover. These results are consistent with the idea that MS and endogenous opioids increase the rate of release of PRL from the adenohypophysis by slowing the release of DA from the median eminence. This, in turn, results in a decrease in the inhibitory tone exerted on pituitary lactotropic cells and, consequently, a greater rate of PRL release.
Using feminizing adrenal neoplastic gland (FANG) cells we showed that hPRL stimulated cGMP biosynthesis. Also we could clearly demonstrate a stimulatory effect of db-cGMP plus theophylline on estrogen production without concomitant stimulation of cell growth. These findings indicate that a stimulatory effect of hPRL on estrogen biosynthesis by Fang-8 cells may act via increased cGMP concomitant with depressed cAMP.
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