Hypothalamic Serotonin Content Research Articles

The influence of dehydroepiandrosterone and 8-OH-DPAT on the caloric intake and hypothalamic neurotransmitters of lean and obese Zucker rats

The 5 HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetraline (8-OH-DPAT) increases the food intake of satiated Zucker rats, both lean and obese. Associated with this increased intake are changes in the hypothalamic content of serotonin and its metabolite, 5-HIAA (5-hydroxyindole-3-acetic acid); serotonin is increased while the level of 5-HIAA is decreased. Analysis of individual 5-HIAA/5-hydroxytryptamine (5-HT) ratios, a measure of serotonin turnover indicate that 8-OH DPAT affected serotonin turnover equally and dramatically in both phenotypes. This would be an expected physiological action of an autofeedback mechanism by a 5-HT(1A) receptor agonist. Dehydroepiandrosterone (DHEA) at doses as low as 10 mg/kg blocks the 8-OH-DPAT-induced increase in food intake but does not alter food intake of control satiated Zucker rats. The mechanism of DHEA's action was investigated by monitoring the steroid's effect on hypothalamic neurotransmitters in this satiated model. DHEA by itself induced some change in 5-HIAA in the obese satiated model but not the lean. 8-OH-DPAT, by itself, dramatically decreased serotonin turnover in either lean or obese rats, and DHEA combined with 8-OH-DPAT did not further change serotonin turnover, suggesting DHEA may work through mechanisms other than monoamines to cause its inhibition of 8-OH-DPAT-induced behavioral effects at such low doses.

Effects of 14-methoxymetopon, a potent opioid agonist, on the responses to the tail electric stimulation test and plus-maze activity in male rats: neuroendocrine correlates

We have studied the effects of 14-methoxymetopon (HS 198), a potent opioid agonist, on the responses to the tail electric stimulation test and plus-maze activity of adult male rats. The prototype μ agonist morphine was used as the drug of reference. Besides we addressed the effects of HS 198 on the serum corticosterone levels and on serotonergic systems of discrete brain regions. Both drugs were administered subcutaneously. Morphine (5 mg/kg) and HS 198 (30 μg/kg) induced a similar effect on the nociceptive test, with both drugs significantly increasing the threshold for the vocalization afterdischarge, which is related to the emotional component of pain. In the plus-maze, morphine (5 mg/kg) and HS 198 (20 and 30 μg/kg) induced similar increases in the percentages of entries and time in the open arms, two parameters related to the anxiety state of the animals. The results indicate that HS 198 is far more potent than morphine in reducing the emotive/affective component of pain and in inducing an anxiolytic effect. HS 198 (30 μg/kg) also induced parallel increases in the serum corticosterone levels and the hypothalamic serotonin content. A possible correlation between the anxiolytic action of the drug and its effect on the hypothalamic serotonergic system is suggested.

Methylenedioxymethamphetamine-induced suppression of interleukin-1β and tumour necrosis factor-α is not mediated by serotonin

The purpose of the present study was to examine the role of serotonin release in methylenedioxymethamphetamine (MDMA)-induced immunosuppression in rats. We examined the effect of pretreatment with the selective serotonin reuptake inhibitor paroxetine, and the tryptophan hydroxylase inhibitor para-chlorophenylalanine on MDMA-induced suppression of interleukin-1β and tumour necrosis factor (TNF)-α secretion following an in vivo lipopolysaccharide challenge. Although paroxetine blocked MDMA-induced serotonin depletion in the cortex and hypothalamus, it failed to alter the suppressive effect of MDMA on lipopolysaccharide-induced TNF-α secretion. Similarly, although para-chlorophenylalanine caused a 90% depletion in cortical and hypothalamic serotonin content, it failed to alter the suppressive effect of MDMA on lipopolysaccharide-induced interleukin-1β or TNF-α secretion. In conclusion, although MDMA is a potent releaser of serotonin, the suppressive effects of MDMA on lipopolysaccharide-induced proinflammatory cytokine secretion cannot be attributed to its serotonin-releasing properties.

Methallibure-induced inhibition of hypothalamo-hypophyseal-ovarian activity in the catfish Heteropneustes fossilis involves changes in hypothalamic monoamine activity

Administration of Methallibure, a non-steroidal gonadotropin (GTH) inhibitor 20 μg g−1 body weight; i.p., daily for 10 days, to prespawning phase female Heteropneustes fossilis inhibited the brain-pituitary-ovarian axis as indicated by significant reductions in plasma and pituitary levels of GTH-II, and plasma levels of 17β-estradiol (E2) and testosterone. Concurrently, the treatment resulted in significant reductions in the hypothalamic content of serotonin, noradrenaline (and adrenaline) that stimulate, and a significant elevation of dopamine that inhibits GTH-II release in this species. Activities of the monoamine degrading enzymes, monoamine oxidase and catechol-O-methyltransferase were significantly increased, while that of the synthesizing enzymes, dopamine-β-hydroxylase and phenylethanolamine-N-methyltransferase were significantly decreased. These results suggest that the mechanism of inhibition of GTH-II secretion includes, among others, differential actions of the drug on hypothalamic monoamine metabolism.

Effects of cyclosporine at the hypothalamic-pituitary axis in pituitary-grafted young female rats

This work was designed to investigate the effects of cyclosporine on prolactin secretion by an ectopically grafted heterologous pituitary gland, and on the hypothalamic content of norepinephrine, dopamine and serotonin. The administration of cyclosporine prevented the augmentation in plasma prolactin levels which occurred following an ectopic graft of a litter-mate pituitary gland. In contrast, in sham-operated rats, cyclosporine increased prolactin levels on day 8 of treatment. Both pituitary grafting and cyclosporine treatment in sham-operated rats decreased hypothalamic norepinephrine content. In grafted rats, cyclosporine returned hypothalamic norepinephrine to normal. Hypothalamic serotonin content decreased 8 days after pituitary grafting but increased to the values of control animals after cyclosporine administration. Cyclosporine treatment for 2 and 8 days increased serotonin content in sham-operated animals. As expected, the hypothalamic dihydroxphenylacetic acid/dopamine index increased after pituitary grafting and administration of cyclosporine for 8 days resulted in a further increase. Cyclosporine administration for 2 days, however, decreased this index to the values observed in control animals while drug treatment of control rats for 8 days decreased the dihydroxyphenylacetic acid/dopamine index. In vitro release of prolactin from the ectopic gland was markedly decreased in animals treated with cyclosporine for 2 days and this effect was less evident in 8-day treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of photoperiod alterations on day-night variations in hypothalamic serotonin content and turnover, and monoamine oxidase activity in the female catfish, Heteropneustes fossilis (Bloch)

The effects of different photoperiod regimes, and total darkness on day-night variations in hypothalamic serotonin (5-HT) content and turnover index (TI), and monoamine oxidase (MAO) activity that occur exclusively during the gonadal preparatory phase (February-March) were investigated in female Heteropneustes fossilis. Exposure of the fish to long photoperiods (16L:8D; light between 06.00-22.00h, for 40 days elevated both the midphotophase and midscotophase values of 5-HT content and MAO, and abolished their day-night differences. The daily variations of 5-HT-TI was further intensified by the treatment. Under short photoperiods (4L:20D; light between 18.00-22.00h for 40 days), there was a significant decrease in both 5-HT content and TI, a reversal of the day-night variations of 5-HT content and MAO activity, and loss of the 5-HT-TI pattern. In fish maintained in total darkness the day-night variations were not found and there was a significant inhibition of 5-HT. Exposure of the fish to continuous light abolished the day-night variations of these correlates and elevated their values at both intervals. When the LD cycle was reversed, there was a corresponding shift in the day-night patterns. The gonadosomatic index (GSI) was significantly elevated in the long photoperiod and continuous illumination groups, significantly decreased in the short photoperiod and total darkness groups, and unchanged in the reversed LD cycle regime. The results indicate that the day-night variations of 5-HT and MAO are photoperiod-dependent and are controlled by the prevailing LD cycle during the gonadal preparatory phase of the annual reproductive cycle. The photoperiod effects on the gonadal activity may be mediated through the hypothalamic serotonergic system.

Differential recovery of adrenocortical responses to neural stimuli following administration of 5,7-dihydroxytryptamine into the hypothalamus.

In view of the role of serotonin in adrenocortical regulation, the effects of depletion of hypothalamic serotonin, using localized injections of the neurotoxin 5,7-dihydroxytryptamine into the hypothalamic paraventricular nucleus, on the rise in plasma corticosterone following afferent neural stimulation, were studied. The neurotoxin caused a significant reduction (p less than 0.001) in hypothalamic serotonin content of about 50% during the first month and about 30% up to two months later. Basal and ether stress-induced rises in plasma corticosterone levels were unaffected at all times after this treatment, but responses to stimulation of the sciatic nerve were reduced for up to four weeks (p less than 0.01), recovering at later times. Responses to photic and acoustic stimuli were almost entirely prevented up to four weeks following the treatment (p less than 0.001) but showed a gradual recovery to full, or almost full, adrenocortical responses at eight weeks, following acoustic and photic stimulation respectively. These results demonstrate a differential recovery of the adrenocortical responses, following the neurotoxin injection and indicate that different neural modalities require different 5-HT concentrations in the PVN for the expression of a full adrenocortical response.

Paraventricular nucleus neuronal responses following electrical stimulation of the midbrain dorsal raphe: evidence for cotransmission

In order to determine the responses of paraventricular nucleus neurones following activation of central serotonergic pathways, single unit activity was recorded and responses following electrical stimulation of the midbrain dorsal raphe nucleus were examined. Excitation was recorded from approximately 50% of the cells, independent of whether they were antidromically identified as projecting to the median eminence or unidentified. Approximately 20% of cells were inhibited by the stimulation, the majority of these being unidentified. Parachlorophenylalanine-induced inhibition of serotonin synthesis reduced hypothalamic serotonin levels by 77% and caused a significant reduction in the proportion of cells excited by the stimulation, whereas the inhibitory responses were not affected. Intracerebroventricular administration of the serotonergic neurotoxin, 5,7-dihydroxytryptamine, which caused similar reductions in hypothalamic serotonin content (77%), reduced still further the proportion of excitatory responses and also reduced the proportion of cells inhibited by the stimulation. The data obtained suggest that serotonin acts as an excitatory neurotransmitter in the paraventricular nucleus; this is discussed particularly with respect to the regulation of the hypothalamo-hypophysial-adrenocortical axis. The loss of inhibitory responses in 5,7-dihydroxytryptamine treated, as opposed to the parachlorophenylalanine treated, animals suggests that the serotonergic fibers innervating the recorded cells may contain a cosecreted substance that may have important physiological actions in the control of neuronal activity in the region recorded.

Neuroendocrinology of pyridoxine deficiency

Dihydroxyphenylalanine decarboxylase and 5-hydroxytryptophan decarboxylase respectively have high and low affinities for pyridoxal phosphate. In the pyridoxine-deficient animal, hypothalamic serotonin content is significantly reduced without any change in catecholamine levels. Hypothalamic neurotransmitters affect the hypothalamo-pituitary-end organ axes. Specifically, the decrease in hypothalamic serotonin in the pyridoxine-deficient rat results in tertiary hypothyroidism. In addition, pineal function is affected in deficient animals due to decreased synthesis of melatonin.

Effect of intravenous 5-hydroxytryptophan on hypothalamic concentration of norepinephrine, dopamine, serotonin and hydroxyindole acetic acid in the fetal lamb

To investigate the neurochemical mechanism of the response of growth hormone to 5-hydroxytryptophan (5-HTP), we administered 5-HTP (20 mg/kg) to 10 ovine fetuses (110 or 130 days old; term gestation 147 days). Ninety minutes after 5-HTP administration, and following increases in plasma growth hormone concentrations, the fetus was delivered by hysterotomy. After local anesthesia of the fetus and sacrifice by cervical spinal cord transection the hypothalamus rapidly dissected, and stored at −80°C for later analysis of norepinephrine, dopamine, serotonin and hydroxyindole acetic acid. Compared to the administration of saline, 5-HTP caused a significant increase in the hypothalamic content of serotonin, and norepinephrine, at both gestational ages. 5-hydroxyindole acetic acid increased significantly only in the older fetuses. These results indicate that serotonin may not be the only neurotransmitter active in the growth hormone response to 5-HTP.

Interaction of Putative Endogenous Tryptolines with the Hypothalamic Serotonergic System and Prolactin Secretion in Adult Male Rats

The effect of 5-methoxytryptoline (5-MeOT), 5-hydroxytryptoline (5-OHT) and tryptoline (Tp), putative endogenous derivatives of the tryptamines, on plasma prolactin (PRL) concentrations has been investigated in the adult male rat. The possible involvement of the hypothalamic serotonergic system has been considered in the mediation of the hormonal effect of the tryptolines. Therefore, plasma PRL levels have been evaluated in rats receiving tryptolines after different pharmacological manipulations of central serotonergic function. Although the three compounds increased the plasma titers of PRL in a dose-dependent manner and enhanced the hypothalamic content of serotonin (5HT), they appear to affect the serotonergic system through different mechanisms. In particular, 5-OHT might act at a presynaptic level, since its hyperprolactinemic effect was antagonized both by the depletion of central 5HT content after p-chlorophenylalanine and by the degeneration of serotonergic terminals after 5,7-dihydroxytryptamine. In contrast, 5-MeOT behaved as if it had a postsynaptic site of action, being counteracted by the serotonergic postsynaptic antagonists metergoline and cyproheptadine. The unsubstituted tetrahydro-beta-carboline, Tp, is probably active at both pre- and postsynaptic sites. The enhancing effect of Tp on PRL secretion was antagonized by chronic treatment with p-chlorophenylalanine, while it was also maintained in 5,7-dihydroxytryptamine-lesioned rats. These findings suggest that tryptolines may play a functional role in PRL secretion by interacting with central serotonergic systems through different biochemical mechanisms.

Reinstatement of LH surges by serotonin neuroleptics in aging, constant estrous rats

Aged rats in constant estrous (CE) were treated with drugs which effect monoamine metabolism in an attempt to restore the positive-feedback response to estrogen. Prior to treatment, the rats were ovariectomized so as to eliminate indirect effects of drug: ovary interaction which might alter the steroid environment. They then received silastic capsules containing estradiol 17β, SC, immediately (IME, immediate implant group) or 4 weeks after surgery (DEL, delayed implant group), to provide a constant, stable source of estrogen, mimicking the CE condition. Blood samples were taken 3 days after estrogen capsules were implanted to determine if the exogenous steroid induced LH surges in IME or DEL rats. LH surges occurred in 80% of DEL rats, but no IME rats suggesting that a 30-day hiatus from ovarian steroids restored the positive-feedback response in previously acyclic rats. Progesterone (0.5 mg) administered at 1100 hr increased the size of the surge in DEL rats but did not change serum LH levels in IME rats. After 3 days of estrogen exposure, hypothalamic content of serotonin was significantly lower ( p <0.05) in DEL rats vs. IME rats, while norepinephrine was not different in either group. Differential effects of estrogen on norepinephrine were not apparent in IME or DEL rats. The changes in serotonin metabolism following estrogen treatment in DEL rats occurred with the onset of LH surges, suggesting a functional correlation. On the other hand, serotonin levels did not change in response to estrogen in IME rats, and LH surges were absent as well. Monoamine neuroleptics were administered to IME rats in an attempt to reestablish positive feedback. I-Dihydroxyphenylalanine (l-DOPA; 200 mg/kg at 1100 hr) stimulated LH surges in 31% of the rats; however, its effectiveness was diminished (8% responding with LH surges) by pretreatment with p-chlorophenylalanine (pCPA; 250 mg/kg at 1600 hr, 19 hours before l-DOPA). LH surges were reinstated in the majority (77%) of IME rats following combined treatment with pCPA + 5-hydroxytryptophan (5-HTP; 50 mg/kg at 1100 hr, 43 hours after pCPA). Since this combination of pCPA + 5-HTP enhances sensitivity to serotonin signals, the drugs may have restored the facilitatory effect of serotonin on LH secretion which is lost in aging constant estrous rats. In conclusion, loss of the positive-feedback response in aging female rats may follow changes in monoamine metabolism resulting from life-long exposure to estrogen. Although metabolic changes occur in all hypothalamic monoamines, this study suggests that a major deficit with regard to this feedback loss residues with serotonin.

Diurnal variation in hypothalamic monoamines and plasma corticosterone in the turkey after inhibition of tyrosine hydroxylase or tryptophan hydroxylase.

Circadian rhythms occur in hypothalamic serotonin content in the turkey. Inhibition of serotonin (5-HT) synthesis by parachlorophenylalanine (PCPA) blocks circadian variation in hypothalamic serotonin levels suggesting that the major cause of diurnal fluctuations is differing rates of synthesis of the amine. PCPA treatment also abolishes the diurnal rhythm in plasma corticosterone and elevates the basal levels of this steroid suggesting that 5-HT terminals in the hypothalamus may inhibit the release of ACTH at certain times of the day and in this fashion generate diurnal fluctuations in plasma corticosterone. Hypothalamic levels of dopamine (DA) and norepinephrine (NE) also vary diurnally, and synthesis inhibition with alpha-methyl-para-tyrosine abolishes the diurnal rhythm in NE but not DA or in plasma corticosterone. Temporal changes in release and/or degradation of DA are significant factors contributing to the diurnal rhythms of this amine in the hypothalamus. Diurnal fluctuations in plasma corticosterone do not depend on recent synthesis of catecholamines.

A possible control of food intake during pregnancy in the rat.

1. Brain hypothalamic concentrations of serotonin and norepinephrine have been implicated in the control of food intake. During pregnancy and lactation a rat dam's food consumption is increased and so a study was performed to ascertain whether this was associated with changes in the hypothalamic content of serotonin and norepinephrine. 2. In the first experiment, forty-eight Sprague Dawley rat dams were given a diet containing 250 g casein/kg adlib. After 2 weeks, eight were killed and their hypothalmic analysed for the previously-mentioned neurotransmitters. The rest were mated and continued on the diet. On each of days 7, 14 and 20 of gestation, day 14 of lactation and 2 weeks after weaning of their pups a further eight dams were killed and their hypothalami assayed as described previously. Food intake was monitored throughout the experimental period. 3. The increase food intake of the dams during gestation and lactation increased to the same extent as elevation in hypothalamic norepinephrine content and depression in serotonin content. After lactation food intake returned to pre-pregnancy levels as did the hypothalamic levels of norepinephrine and serotonin. 4. By using the same experimental design but limiting the increase in food intake in pregnancy and lactation to half the expected amount the same changes were found in hypothalamic norepinephrine and serotonin contents. 5. The possibility of hypothalamic neurotransmitter contents controlling food intake is discussed.

A serotonergic mechanism of the prolactin-stimulating action of metoclopramide.

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.

Effects of para-chlorophenylalanine, a brain serotonin depletor, on pituitary cyclic AMP levels in the rainbow trout, Salmo gairdneri

The tryptophan hydroxylase inhibitor para-chlorophenylalanine (pCPA) was employed in an investigation of the role of brain serotonin in the regulation of pituitary cyclic AMP levels in Salmo gairdneri. Hypothalamic serotonin content was measured with a fluorometric assay, while pituitary cAMP was determined by means of a double-antibody radioimmunoassay. A time-course study revealed that 250 mg pCPA/kg significantly reduced hypothalamic serotonin content within 1 hr after injection. Lower doses were effective in reducing serotonin content after 48 hr. Pituitary cAMP levels declined significantly 1 hr after injection of 250 mg pCPA/kg. Administration of pCPA at 50 and 250 mg/kg doses reduced cAMP levels within 24 hr. These data indicate that a serotonergic mechanism is involved with the regulation of pituitary cyclic AMP levels in the rainbow trout.

Pinealectomy and melatonin effects on daily variations of the hypothalamic serotonergic system in the goldfish

1. 1. Day-night variations of hypothalamic serotonergic activity were noted in goldfish maintained on a 16L/8D, 20°C regime but were not found in fish kept on an 8L/16D, 20°C regime. 2. 2. Pinealectomy had a significant effect on hypothalamic serotonin content and serotonergic activity in fish exposed to the long, but not short, photoperiod. 3. 3. Melatonin administration to control animals (100 μg per day for 10 days) modified the day-night variations of hypothalamic serotonin content and serotonergic activity regardless of photoperiod. 4. 4. The effects of melatonin on hypothalamic serotonin content in pinealectomized animals were dependent upon the photoperiod regime, whereas effects on serotonergic activity were not. 5. 5. It is concluded that the goldfish pineal organ and melatonin may play a role in hypothalamic adjustments to changing photoperiods.

Naloxone stimulation of luteinizing hormones release in prepubertal female rats; role of serotonergic system

The purpose of this study was to determine whether naloxone stimulated LH release via a serotonergic mechanism. Injection of naloxone hydrochloride (2 mg/kg B.W.) into 25-day old female prepubertal rats resulted in a significant elevation in serum LH 30 min later. Injection of this dose of naloxone together with morphine sulfate (2 or 5 mg/kg B.E.) resulted in inhibition of naloxone-induced LH release. When rats were first injected with 5-hydroxytryptophan (5-HTP) to increase hypothalamic serotonin content, naloxone failed to increase serum LH levels. On the other hand, when parachlorophenylalanine (PCPA) was given first to reduce hypothalamic serotonin content, naloxone-induced LH release was potentiated. Morphine failed to inhibit the naloxone-induced rise in serum LH when PCPA was first administered. Neither 5-HTP nor PCPA, when injected alone, altered serum LH values. These results suggest that naloxone promotes LH release by reducing hypothalamic serotonergic activity, and morphine inhibits LH release by increasing hypothalamic serotonergic activity. This does not exclude possible involvement of other neurotransmitters.

Photoperiod effects on hypothalamic serotonergic activity in the goldfish, Carassius auratus

1. 1. The nature of hypothalamic serotonergic activity in goldfish exposed to various photo-period regimes was examined for day -night differences. 2. 2. Fish maintained throughout the course of these experiments on a short photoperiod (8L/16D, 20°C) showed no day-night differences in hypothalamic serotonin content or in serotonergic activity. 3. 3. Fish transferred from the short photoperiod to a long photoperiod (16L/8D, 20°C) developed day-night differences in hypothalamic serotonin content within 72 h, while day night differences in hypothalamic serotonergic activity were observed after 2 weeks. 4. 4. Data presented suggest that hypothalamic serotonergic mechanisms play a role in mediating the effects of photoperiod on physiological processes in goldfish.

Inhibition of hypoglycemia-induced growth hormone secretion by the serotonin antagonists cyproheptadine and methysergide.

Abstract Growth hormone secretion is provoked by hypoglycemia. Since hypothalamic serotonin content increases during insulin-induced hypoglycemia, the role of hypothalamic serotonin in growth hormone secretion in man was examined. Hypoglycemia-induced growth hormone release in normal volunteers was studied during a control period and after two days of administration of serotonin antagonists, cyproheptadine and methysergide. Plasma growth hormone was measured by radioimmunoassay, and total growth hormone secretion was expressed as the area under the growth hormone curve from 0 to 120 minutes. Cyproheptadine administration resulted in a 59 per cent reduction (p<0.01), and methysergide in a 35 per cent reduction (p<0.05) in growth hormone secretion. The decrease in plasma glucose during the control and treatment periods indicated a comparable stimulus for growth hormone release in both study groups. If these drugs act by antagonizing serotonin, as assumed, this study suggests that serotonin is involved in hy...