Immunoneutralization of prolactin prevents stimulatory feedback of prolactin on hypothalamic neuroendocrine dopaminergic neurons

We have found that exogenous prolactin (PRL) stimulates all three populations of hypothalamic neuroendocrine dopaminergic neurons. In this study, we investigated the effects of immunoneutralization of endogenous PRL on the activity of these neurons. Injection of 17β-estradiol (E₂) (20 μg subcutaneously) 10 d after ovariectomy induced a proestrus-like increase in PRL in peripheral plasma the following afternoon. At 1000 h the day after E₂ injection, rats received either rabbit antirat PRL antiserum (PRL-AS) (200 μL) or normal rabbit serum (NRS, 200 μL, controls) intraperitoneally. Groups of rats were then decapitated every 2 h from 1100 h to 2100 h. Trunk blood was collected and serum extracted with protein A to remove the PRL-AS/PRL complex, and the remaining free PRL was measured by radio immunoassay. Sites of neuroendocrine dopaminergic nerve terminals, the median eminence (ME), and intermediate and neural lobes of the pituitary gland were excised and stored for determination of dopamine (DA) and 3,4-dihydroxyphenyl acetic acid (DOPAC) concentrations by high-performance liquid chromatography electrochemical detection (EC). In addition, the anterior lobe of the pituitary gland, the locus of DA action, was collected. The concentration of PRL in NRS-treated animals increased by 1500 h, peaked by 1700 h, and returned to low levels by 2100 h. PRL-AS prevented the increase in PRL secretion in response to E₂. The turnover of DA (DOPAC:DA ratio; an index of dopaminergic neuronal activity) in the ME of NRS-treated animals increased at 1500 h and rapidly returned to basal levels. Treatment with PRL-AS prevented the increase in DA turnover in the ME. DA turnover in the intermediate lobe increased coincident with the peak of PRL in serum of NRS-treated rats. PRL-AS administration prevented increased DA turnover in the intermediate lobe. The turnover of DA in the neural lobe increased by 1300 h and decreased steadily through 2100 h. However, administration of PRL-AS minimally suppressed the turnover of DA in the neural lobe. Moreover, administration of PRL-AS attenuated the rise of DA in the anterior lobe associated with the waning phase of the E₂-induced PRL surge. These results clearly indicate that endogenous PRL regulates its own secretion by activating hypothalamic neuroendocrine dopaminergic neurons.     

Histaminergic regulation of prolactin secretion: involvement of tuberoinfundibular dopaminergic neurons

It has been shown that histamine (HA) stimulates prolactin (PRL) secretion via H2 receptors following intra-cerebroventricular infusion and via H1 receptors following systemic (intra-arterial) infusion. Since the effect of HA appears to be exerted at a suprapituitary level, we investigated the involvement of the tuberoinfundibular dopaminergic (TIDA) system in HA-induced PRL secretion in urethane-anesthetized male rats. HA infused intracerebroventricularly (30 micrograms) or intra-arterially (420 micrograms) decreased the dopamine (DA) concentration in pituitary portal blood by 30 and 23%, respectively. Blockade of DA receptors by pimozide did not prevent the stimulation of PRL secretion induced by intracerebroventricular infusion of HA or the H2 receptor agonist dimaprit. Furthermore, during DA receptor blockade intracerebroventricular infusion of the H1 receptor agonist 2-thiazolylethylamine inhibited PRL secretion. In contrast, pimozide prevented the stimulation of PRL secretion induced by intra-arterial infusion of HA and the H1 receptor agonist 2-thiazolylethylamine. In fact, under these conditions intra-arterial infusion of HA or the H2-receptor agonist dimaprit inhibited PRL secretion. During treatment with alpha-methyl-p-tyrosine, which reduced the hypothalamic DA content by 50%, HA infused intracerebroventricularly stimulated PRL secretion, while HA infused intra-arterially inhibited the secretion, which is in accordance with the results obtained during pimozide treatment. Cholinergic blockade by atropine did not prevent the HA-induced PRL release, excluding the possibility that the observed effect of pimozide is due to its anticholinergic property. We suggest that intracerebroventricular infusion of HA by activation of H2 receptors may stimulate PRL secretion partly via inhibition of the TIDA system and partly via other mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sexual differences in kappa opioid receptor-mediated regulation of tuberoinfundibular dopaminergic neurons.

The purpose of the present study was to examine the acute effects of kappa opioid receptor blockade or activation on the activity of tuberoinfundibular dopaminergic (TIDA) neurons in gonadally-intact or castrated male and female rats. In the absence of drug treatment, the basal activity of TIDA neurons (accumulation of 3,4-dihydroxyphenylalanine, DOPA, in the median eminence after administration of a decarboxylase inhibitor) in male rats was approximately one third of that in diestrous females. In male rats, blockade of kappa opioid receptors following administration of the kappa antagonist norbinaltorphimine (NOR-BNI) increased the activity of TIDA neurons suggesting that these neurons are tonically inhibited by endogenous kappa opioids. By contrast, NOR-BNI had no effect on TIDA neuronal activity in gonadally-intact diestrous female rats, but increased the activity of these neurons in ovariectomized female rats. These results suggest that ovarian hormones block the inhibitory effects of endogenous kappa opioids on the activity of TIDA neurons. Activation of kappa opioid receptors following administration of the kappa agonist U-50,488 caused a dose-related decrease in TIDA neuronal activity in diestrous female rats. U-50,488 had no effect on TIDA neuronal activity in gonadally-intact male rats, but decreased the activity of these neurons in orchidectomized male rats. Taken together, these results reveal a sexual difference in the responsiveness of TIDA neurons to kappa opioid receptor agonists and antagonists, and suggest that gonadal steroid-induced gender differences in the basal activity of TIDA neurons may be due, in part, to differences in tonic inhibitory regulation of these neurons by endogenous kappa opioids.     

Evidence that opioid peptides and dopamine participate in the suckling-induced release of prolactin in the ewe

A pharmacological approach was used to study the involvement of opioid peptides and dopamine in mediating the suckling-induced release of prolactin in the lactating ewe (10-20 days post partum). To promote reliable and predictable suckling activity lambs were fitted with elasticated masks to prevent sucking for 4.5 h. After a 1-hour control period of frequent blood sampling, ewes were treated (i.v. injections every 5 min) for a further 75 min with either saline vehicle, an opioid antagonist (naloxone; 4.17 mg/5 min), a dopamine antagonist (metoclopramide; 1.25 mg/5 min), a mixture of naloxone + metoclopramide or a dopamine agonist (apomorphine; 6.6 mg/5 min). Blood was withdrawn at 5-min intervals for determination of plasma prolactin and luteinizing hormone (LH) by radioimmunoassay. Plasma LH concentrations (less than or equal to 1 microgram/l) were not significantly affected by any of the drug treatments and there was no evidence for an acute fall in LH associated with suckling- or TRH-induced increases in prolactin secretion. Naloxone significantly (p less than 0.05) reduced the mean incremental change in prolactin concentration (delta PRL) in response to suckling (+7 +/- 18 micrograms/ml) compared with saline-infused controls (+79 +/- 26 micrograms/ml), an effect which was completely reversed by combined treatment with naloxone and metoclopramide (+146 +/- 56 micrograms/ml). Metoclopramide alone raised basal prolactin levels by 46% (p less than 0.01) but did not affect delta PRL in response to suckling (+115 +/- 52 micrograms/ml). Neither naloxone, metoclopramide nor a combination of the two drugs affected the subsequent prolactin to TRH (10 micrograms). Apomorphine, however, completely abolished both the suckling- and TRH-induced release of prolactin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Age-related loss of the responsiveness of the tuberoinfundibular dopaminergic neurons to prolactin in the female rat

In the old female rat the previous findings of a sustained reduction of the secretory activity of the hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons associated with a persistent hyperprolactinemia as well as the observation of a failure of the prolactin (PRL) short-loop feedback mechanism have been suggestive of an age-related loss of the responsiveness of the TIDA neurons to the stimulatory action of PRL. Yet the existence of significant impairments in the capacity of the neurons to respond to PRL could not be demonstrated in an earlier study using multiparous old rats in constant estrus compared to young nulliparous estrous rats. In the present study we have readdressed the issue using nulliparous old rats (24-26 months) compared to virgin young rats (4-5 months); two sets of old rats were studied which displayed distinct senile reproductive states, namely persistent diestrus or repetitive pseudopregnancy, and they were compared to young rats in diestrus or in repetitive pseudopregnancy, respectively. The secretory activity of the TIDA neurons was evaluated by measurement of dopamine biosynthesis in the neurons (DOPA accumulation in the median eminence after decarboxylase inhibition) and dopamine release into hypophysial portal blood, and PRL influence on the activity of the TIDA neurons was studied after repeated s.c. administrations of ovine PRL (oPRL) or the solvent vehicle. A reduced activity of the TIDA neurons was observed in both groups of nulliparous aged rats compared to their respective young control group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stimulatory and entraining effect of melatonin on tuberoinfundibular dopaminergic neuron activity and inhibition on prolactin secretion

The aims of the present study were to determine if melatonin exerts an effect on prolactin (PRL) secretion via the tuberoinfundibular dopaminergic (TIDA) neurons and if endogenous or exogenous melatonin has an entraining effect on the rhythmic changes of TIDA neuronal activity and PRL secretion. Melatonin given in the morning (10:00 h), dose- (0.01-1 mg/kg, ip) and time- (at 15 and 60 min, but not at 30 min) dependently stimulated TIDA neuronal activity in ovariectomized (OVX), estrogen-treated rats as determined by 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the median eminence (ME). Serum PRL was concurrently inhibited by the injection. Melatonin administered in the afternoon (15:00 h) was even more effective in stimulating the lowered TIDA neuronal activity and inhibiting the increased PRL level than that given in the morning (10:00 h). S-20098, a melatonin agonist was also effective in stimulating the TIDA neurons. In contrast, S-20928, a putative melatonin antagonist, while it had no effect by itself, blocked the effect of S-20098. Although S-20928 failed to prevent melatonin's effect on ME DOPAC levels, six interspaced injections of S-20928, from 18:00 to 01:30 h, significantly blocked the increase of ME DOPAC levels at 03:00 h, indicating that the endogenous melatonin may play a role. We further used rats that received daily injection of melatonin (1 mg/kg, ip) at 18:00 h for 10 days and found that the injection augmented basal TIDA neuronal activity at 11:00 h and blunted the afternoon PRL surge. In all, melatonin can have an inhibitory effect on PRL secretion by stimulating the TIDA neurons, and it may help to entrain the circadian rhythms of both TIDA neuronal activity and PRL secretion.     

Responsiveness of tuberoinfundibular dopaminergic neurons to 5-hydroxytryptophan

Serotonin is known to stimulate prolactin secretion by decreasing tyrosine hydroxylase (TH) activity in the tuberoinfundibular dopaminergic (TIDA) neurons. However, the effects of aging on the responsiveness of TIDA neurons to serotonin are not known. An effective way to increase serotonergic activity is to administer 5-hydroxytryptophan (5-HTP), a serotonin precursor. The present study was done to investigate the effects of 5-HTP on TIDA neuronal activity in aging animals. Middle-aged (10–12 mo), old (18–20 mo), and very old (22–24 mo) female Sprague-Dawley rats were bilaterally ovariectomized. Ten days later, they were injected iv with 50 mg/kg body wt of 5-HTP or the vehicle for 5-HTP (PBS-HCl). Twenty minutes later, m-hydroxybenzylhydrazine (NSD), a DOPA decarboxylase inhibitor, was administered. Ten minutes later, the animals were killed, and tyrosine hydroxylase (TH) activity was determined by measuring l-DOPA accumulation in the stalk median eminence by HPLC-EC. In all three groups, administration of 5-HTP increased serum prolactin levels significantly. In control middle-aged rats, TH activity (l-DOPA pg/μg protein) was 33.0 ± 5.6. Treatment with 5-HTP decreased TH activity by 60%. Similarly, 5-HTP treatment decreased TH activity by 52 and 56% in 18- to 20- and 22- to 24-mo-old rats, respectively, compared to the control rats. The magnitudes of the 5-HTP-induced decreases in TH activities in middle-aged, old, and very old rats were not different from each other. These results indicate that TIDA neuronal responsiveness to serotonin does not change with age and that 5-HTP is capable of stimulating PRL release even in very old rats.     

Long-term treatment with estradiol induces reversible alterations in tuberoinfundibular dopaminergic neurons: a decreased responsiveness to prolactin

Previous studies have demonstrated that short-term (3-5 days) treatment with estradiol increases the rate of turnover and synthesis of dopamine (DA) in terminals of tuberoinfundibular (TI) neurons in the median eminence by virtue of the ability of this hormone to increase circulating concentrations of prolactin. The present studies were undertaken to examine the long-term effects of estradiol on serum prolactin concentrations and TIDA neuronal activity (estimated by the rate of DOPA accumulation in the median eminence after the administration of a decarboxylase inhibitor). Female rats, ovariectomized for 2 weeks, were implanted subcutaneously with silastic capsules containing estradiol benzoate and sacrificed 6, 12 and 18 days after capsule implantation. Serum prolactin concentrations were markedly increased at 6, 12 and 18 days whereas the rate of DOPA accumulation was increased at 6 days but not at 12 days, and was decreased at 18 days. The concentration of DA in the median eminence was reduced at 6 days and further reduced at 12 and 18 days. The low rate of DOPA accumulation in the median eminence despite the high circulating concentrations of prolactin suggests that long-term estradiol treatment reduces the ability of TIDA neurons to respond to prolactin. This was confirmed by the finding that direct intracerebroventricular (icv) injections of prolactin increased the rate of DOPA accumulation in the median eminence of sham-implanted rats but not in 18 day estradiol-treated rats. To determine if the effects of estradiol were reversible, ovariectomized rats were implanted with estradiol-containing capsules for 18 days.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mass and activity of tyrosine hydroxylase in tuberoinfundibular dopaminergic neurons of the aged brain. Control by prolactin and ovarian hormones

The roles of prolactin (PRL) and the ovarian hormones, estradiol and progesterone, in the control of tuberoinfundibular dopaminergic neurons of aged female rats were investigated. The in situ molar activity of tyrosine hydroxylase (TH) in neurites of these neurons was assayed by measuring the rate of accumulation of L-dihydroxyphenylalanine in the median eminence following the administration of a L-dihydroxiphenylalanine decarboxylase inhibitor. The TH mass was measured by an immunoblot assay using rat TH as the standard. Pituitary implants in aged ovariectomized animals resulted in a significant increase in the median eminence of both the mass and in situ molar activity of TH. When circulating PRL of aged rats was neutralized by administration of antiserum against rat PRL, the activity of TH was reduced significantly compared to that of animals treated with preimmune serum. In aged ovariectomized rats treated with both estradiol and progesterone, the in situ molar activity of TH increased significantly compared to animals treated only with the solvent vehicle, estradiol, or progesterone. The stimulatory effect of estradiol and progesterone appeared to be mediated through a mechanism that did not involve PRL, since neutralization of circulating PRL failed to prevent an increase in TH activity in estradiol-progesterone-treated animals. None of these treatments affected the in situ activity of TH in the superior cervical ganglion. We conclude that PRL as well as combined estradiol-progesterone treatment have important roles in the maintenance of TH activity in aged tuberoinfundibular dopaminergic neurons.     

Hypoprolactinemia induced by hypophysectomy and long-term bromocriptine treatment decreases tuberoinfundibular dopaminergic neuronal activity and the responsiveness of these neurons to prolactin

The effect of long-term decreases in circulating concentrations of prolactin was determined on the responsiveness of tuberoinfundibular dopamine (DA) neurons to this hormone. The activity of these neurons in ovariectomized rats was estimated by measuring the rate of DA synthesis (DOPA accumulation after the administration of a decarboxylase inhibitor) in the median eminence at various times after serum concentrations of prolactin had been reduced by hypophysectomy or the chronic administration of a DA agonist (bromocriptine, 3 mg/kg/day). The concentration of DA in the median eminence, but not in striatum, declined progressively up to 12 days after hypophysectomy, but did not change at any time during bromocriptine treatment. On the other hand, norepinephrine concentrations in the median eminence were increased 12 days after both treatments. Within 24 h after hypophysectomy or the first injection of bromocriptine the rate of DA synthesis in the median eminence was decreased; this decrease was maintained for at least 12 days suggesting that tuberoinfundibular DA neuronal activity is normally maintained by endogenous prolactin. Intracerebroventricular (ICV) injections of prolactin (10 micrograms, 12 h prior to sacrifice) increased the rate of DA synthesis in the median eminence of control, 24-hour hypophysectomized and 24-hour bromocriptine-treated rats. After longer periods (6-12 days) of bromocriptine treatment or after hypophysectomy the responsiveness of tuberoinfundibular DA neurons to prolactin was reduced. Dose-response studies revealed that the sensitivity and magnitude of response to ICV prolactin was markedly reduced in 12-day hypophysectomized rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calmodulin and a cyclic nucleotide-dependent protein kinase facilitate the prolactin-induced increase in tyrosine hydroxylase activity in tuberoinfundibular dopaminergic neurons

Many aspects of tuberoinfundibular dopaminergic neuronal function are increased by elevated prolactin (PRL) levels, including the activity of tyrosine hydroxylase, the rate-limiting enzyme in the biosynthesis of dopamine. This study evaluated the roles of calmodulin, cyclic nucleotide-dependent protein kinase, and calcium/calmodulin-dependent protein kinase II in the PRL-induced increase in tyrosine hydroxylase activity. Ovariectomizerd rats were treated with haloperidol or ovine PRL (oPRL) for 20–30 h before the experiment, respectively. Treatment with haloperidol increased circulating PRL levels 8-fold and tyrosine hydroxylase activity in the stalk-median eminence 1.8-fold. Treatment with oPRL increased tyrosine hydroxylase activity 1.9-fold. W-7, a calmodulin antagonist, reversed both the haloperidol- and oPRL-induced increase in tyrosine hydroxylase activity to control levels. H-8, a cyclic nucleotide-dependent protein kinase inhibitor, also reversed the haloperidol induced increase in tyrosine hydroxylase activity. KN62, a selective calcium/calmodulin-dependent protein kinase II inhibitor, attenuated the haloperidol-induced increase in tyrosine hydroxylase activity, but KNO4, a structurally related control compound, had no effect. By contrast, the oPRL- and haloperidol-induced increases in tyrosine hydroxylase activity were not altered by KN93, a selective calcium/calmodulin-dependent protein kinase II inhibitor. These data indicate that calmodulin and a cyclic nucleotide-dependent protein kinase contribute to the PRL-induced increase in tyrosine hydroxylase activity, but the role of calcium/calmodulin-dependent protein kinase II is still unclear.     

Effects of endogenous opioid peptides and opiates on luteinizing hormone and prolactin secretion in ovariectomized rats

Adult female rats were implanted with permanent cannulae in the third ventricle of the brain and ovariectomized. 3 weeks later, blood samples were withdrawn every 5 min from intraatrial cannulae placed the previous day. After a control sampling period of 30 min, the rats received an intraventricular bolus injection of saline (2 microliter) or beta-endorphin (beta E; 10 micrograms); sampling was continued for an additional 2 h. Saline injection caused no effect on luteinizing hormone (LH) and prolactin (PRL) secretion. beta E stimulated PRL secretion within 5-10 min, the values peaked in the next 10 min. Thereafter, as PRL levels fell, a suppression of LH secretion became apparent. Inhibition of LH release started 20-35 min after beta E injection and lasted for 35-65 min. The antecendent PRL secretion was apparently not responsible for the observed delayed LH response, since blockade of PRL response with bromocriptine failed to affect the beta E-induced LH suppression. Further, continuous intraventricular infusion of beta E (5 or 10 micrograms/h) for 3 h markedly suppressed the amplitude and frequency of LH episodes in long-term ovariectomized rats. Bolus intraventricular injection of other endogenous opioid peptides and opiate receptor agonists produced different PRL and LH responses. Dynorphin (10 micrograms) similarly suppressed LH release but was only moderately effective in stimulating PRL. Leucine enkephalin (50 micrograms) stimulated LH and inhibited PRL release, while methionine-enkephalin (50 micrograms) selectively stimulated PRL release. The methionine-enkephalin analogs, FK-33824 (50 ng) and DALAMID (50 micrograms), evoked sequential PRL and LH responses similar to those seen after beta E injection. Interestingly, morphiceptin (a specific mu receptor agonist; 10 micrograms) markedly suppressed LH release, but only sparingly stimulated PRL release. Delta receptor peptide (a specific delta receptor agonist; 10 micrograms) selectively suppressed LH release. Bremazocine (a specific kappa receptor agonist; 0.5 mg/kg) administered intravenously suppressed LH release selectively. These studies show that of the four endogenous opioid peptides tested beta E was most effective in evoking sequential PRL and LH responses, and these effects may be mediated by either epsilon receptors or multiple opiate receptor subtypes; stimulation of kappa receptors by bynorphin or bremazocine suppressed LH release, and further studies would be needed to understand the mode of action of the two enkephalins and the delta opiate receptors in eliciting disparate PRL and LH responses.     

A trophoblast-specific factor(s) suppresses circulating prolactin levels and increases tyrosine hydroxylase activity in tuberoinfundibular dopaminergic neurons.

Rat choriocarcinoma (Rcho) cells, which are morphologically similar to trophoblast giant cells of the normal placenta and produce placental lactogen-I in vivo, were used to investigate placental feedback on PRL secretion and tuberoinfundibular dopaminergic neuronal activity. Rcho cells were injected into female rats either intracerebroventricularly 60-65 h before use or under the kidney capsule 10-14 days before use. The following endocrine conditions were used: 1) ovariectomized rats with or without bromocriptine treatment, 2) immature (40-44 days old) rats, 3) adult cycling (diestrous) rats, and 4) pregnant rats. Serum PRL levels in ovariectomized, diestrous, and immature female rats were suppressed to less than 20% of control levels by secretions from the Rcho cells. Tyrosine hydroxylase (TH) activity in the stalk-median eminence (SME) was increased 2-fold above control activity in Rcho-treated ovariectomized and immature female rats. When TH activity was reduced to 40% of control levels by 50 h of bromocriptine treatment, secretions from Rcho cells increased TH activity 3.5-fold to levels similar to those for Rcho alone. Even though Rcho treatment suppressed PRL levels, TH activity in the SME of cycling (diestrous) rats was not altered after either central (65 h) or peripheral (12 days) administration of cells. TH mRNA levels in the arcuate nuclei were unaltered by Rcho cells in immature female and adult cycling rats. TH mRNA levels in ovariectomized rats were markedly reduced 75% by 50 h of bromocriptine treatment and modestly reduced 33% 65 h after injection of Rcho cells. However, Rcho cells partially reversed the bromocriptine-induced decline in TH mRNA to levels seen for Rcho cells alone. On day 7 of pregnancy, secretions from Rcho cells abolished the nocturnal and diurnal PRL surges characteristic of early pregnancy and suppressed circulating PRL levels throughout the day to less than 20% of intersurge PRL levels. Rcho cells eliminated the semicircadian rhythm in TH activity in the SME, which was out of phase with the twice daily PRL surges of early pregnancy. TH activity was increased by Rcho factor(s) at 0330 h (nocturnal surge) and 1800 h (diurnal surge), but not at 1000 h (intersurge). MMQ cells, pituitary-derived clonal PRL-secreting cells, similarly terminated the biphasic rhythm of PRL release and tuberoinfundibular dopaminergic neuronal activity during early pregnancy.(ABSTRACT TRUNCATED AT 400 WORDS)     

The secretory activity of the tuberoinfundibular dopaminergic neurons is modulated by the thyroid status in the adult rat: consequence on prolactin secretion

An influence of thyroid status on the secretory activity of hypothalamic dopaminergic neurons was observed in adult rats and its involvement in the regulation of prolactin (PRL) secretion was examined. The secretory activity of the tuberoinfundibular dopaminergic (TIDA) neurons was evaluated by measurement of dopamine (DA) biosynthesis in the neurons and DA release into hypophysial portal blood. The accumulation of DA and PRL in the adenohypophysis as well as PRL concentration in plasma were also estimated, and the various parameters were studied in thyroidectomized (TX), sham TX, TX rats treated for 7 days with thyroxine (T4; 20 micrograms/kg body weight daily) as well as in intact rats treated similarly with T4. An enhanced secretory activity of the TIDA neurons was observed in TX compared to sham TX rats, as attested by an increased synthesis of DA in the neurons, a greater concentration of DA in hypophysial portal plasma as well as an augmented accumulation of DA in the adenohypophysis. In the same animals, PRL was reduced in the adenohypophysis and in plasma, reflecting a blunted secretion of PRL in severe hypothyroidism. Treatment of TX rats with T4 for 7 days abolished all effects observed in TX rats, DA synthesis in TIDA neurons of TX rats treated with T4 being even less than in neurons of sham TX animals. A similar treatment with T4 administered to intact rats did not affect the secretory activity of the TIDA neurons nor the secretion of PRL.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of testosterone in the regulation of tuberoinfundibular dopaminergic neurons in the male rat

The effects of testosterone on the tuberoinfundibular dopamine (DA) neuronal activity was examined by determining the rate of DA synthesis-accumulation of 3,4-dihydroxyphenylalanine (DOPA) after administration of a decarboxylase inhibitor and the concentration of a DA metabolite,--3,4-dihydroxyphenylacetic acid (DOPAC)--in the median eminence in the male rat. Within 1 week after orchidectomy, there was an increase in the accumulation of DOPA and the concentration of DOPAC in the median eminence, but there was no change in the concentration of DA. Conversely, 1 day after testosterone administration to orchidectomized rats, the elevated DOPAC concentrations in the median eminence returned to levels comparable to those in gonadally intact rats. Neither orchidectomy nor testosterone replacement had any effect on plasma prolactin concentrations, but inhibition of prolactin secretion following administration of the DA agonist bromocriptine blocked the increase in DOPA accumulation in the median eminence of orchidectomized rats; this latter effect was reversed by intracerebroventricular administration of prolactin. On the other hand, intracerebroventricular injection of prolactin caused a similar increase in the accumulation of DOPA in the median eminence of gonadally intact, orchidectomized, and testosterone-treated orchidectomized rats. Immobilization stress decreased the accumulation of DOPA and the concentration of DOPAC in the median eminence of orchidectomized rats, but had no effect in intact or testosterone-treated orchidectomized rats. These results indicate that testosterone inhibits the basal activity of tuberoinfundibular DA neurons and blocks the inhibitory effects of physical restraint on these neurons, but does not alter the ability of these neurons to respond to delayed activation by prolactin.     

Stress and the endogenous opioid system. II. Stress, stress models and endogenous opioid peptides

Biochemical and pharmacological findings indicate an activation of the opioid system under certain stress influences. In this paper findings are discussed, according to which the activation of the opioid system depends on the temporary distribution pattern and the kind of the stressor. In response to stress opioid peptides are involved in excitatory and inhibitory processes. The participation of different types of opioids in central and peripheral stress-induced effects is discussed. Some findings suggest that beta-endorphin acts mainly centrally rather than peripherally, whereas the enkephalins take part in peripheral regulatory processes (gastrointestinal system, adrenal glands). Now there is evidence that the endogenous opioids modulate stress-induced effects, but there has been much controversy on how this fact should be established. These controversies mainly resulted from the many factors that influence activation.     

Potentiation of suckling-induced release of prolactin by inhibition of brain catecholamine synthesis.

The effects of a catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine (alpha-MT), on the accumulation of newly synthesized brain catecholamines and plasma prolactin concentration were studied in lactating rats. [3H]tyrosine was administered to rats 10 minutes before decapitation, and the rate of its incorporation into [3H]dopamine and [3H]norepinephrine was measured in whole brain. Injection of alpha-MT (3.15--12.50 mg/kg) via a carotid cannula increased plasma prolactin levels and decreased the accumulation of newly synthesized brain catecholamines in nonsuckled, lactating rats compared to rats injected with .9% saline solution. Mother rats pretreated with saline solution were suckled for 20 minutes by pups which previously were separated from the mother rats for 5 hours. This treatment resulted in significantly increased plasma prolactin levels compared to nonsuckled controls. In rats pretreated with alpha-MT for 20 minutes, suckling resulted in a further increase in plasma prolactin levels which was significantly greater than the increase caused by suckling or alpha-MT alone. These results suggest that inhibition or catecholamine synthesis had a facilitatory effect on the brain mechanisms responsible for prolactin release in response to suckling.