Tuberoinfundibular Dopaminergic Neurons Research Articles

Suppressive Effects of Neuromedin U Receptor 2-Selective Peptide Agonists on Appetite and Prolactin Secretion in Mice.

Neuromedin U receptor 2 (NMUR2), which is expressed in the central nervous system (CNS) including the hypothalamus, has been noted as a therapeutic target against obesity. We previously reported that intranasal administration of CPN-219, a NMUR2-selective hexapeptide agonist, suppresses body weight gain in mice; however, there is no detailed information regarding its CNS effects. Recently, in addition to appetite suppression, stress responses and regulation of prolactin (PRL) secretion have also attracted attention. NMUR2 expressed in the hypothalamic tuberoinfundibular dopaminergic neurons has emerged as an alternative target for treating hyperprolactinemia. Here, CPN-219 decreased food intake up to 24 h after administration at a dose of 200 nmol, resulting in body weight gain suppression, although grooming and anxiety-like behaviors were transiently induced. Interestingly, the restraint stress-induced increase in plasma PRL levels was significantly suppressed at a lower dose of 20 nmol, indicating the potential for drug development as an anti-PRL agent of NMUR2-selective agonists.

RFamide-related Peptide 3 Signaling via Neuropeptide FF Receptor Stimulates Prolactin Secretion in Female Rats.

The RF-amide peptides comprise a family of neuropeptides that includes the kisspeptin (Kp), the natural ligand of kisspeptin receptor (Kiss1r), and the RFamide-related peptide 3 (RFRP-3) that binds preferentially to the neuropeptide FF receptor 1 (Npffr1). Kp stimulates prolactin (PRL) secretion through the inhibition of tuberoinfundibular dopaminergic (TIDA) neurons. Because Kp also has affinity to Npffr1, we investigated the role of Npffr1 in the control of PRL secretion by Kp and RFRP-3. Intracerebroventricular (ICV) injection of Kp increased PRL and LH secretion in ovariectomized, estradiol-treated rats. The unselective Npffr1 antagonist RF9 prevented these responses, whereas the selective antagonist GJ14 altered PRL but not LH levels. The ICV injection of RFRP-3 in ovariectomized, estradiol-treated rats increased PRL secretion, which was associated with a rise in the dopaminergic activity in the median eminence, but had no effect on LH levels. The RFRP-3-induced increase in PRL secretion was prevented by GJ14. Moreover, the estradiol-induced PRL surge in female rats was blunted by GJ14, along with an amplification of the LH surge. Nevertheless, whole-cell patch clamp recordings showed no effect of RFRP-3 on the electrical activity of TIDA neurons in dopamine transporter-Cre recombinase transgenic female mice. We provide evidence that RFRP-3 binds to Npffr1 to stimulate PRL release, which plays a role in the estradiol-induced PRL surge. This effect of RFRP-3 is apparently not mediated by a reduction in the inhibitory tone of TIDA neurons but possibly involves the activation of a hypothalamic PRL-releasing factor.

Hypothalamic GnRH expression and pulsatility depends on a balance of prolactin receptors in the plains vizcacha, Lagostomus maximus.

In mammals, gestation is considered a physiological hyperprolactinemia status. Prolactin (PRL) is one of the modulators of gonadotropin-releasing hormone (GnRH) neurons function. The South American plains vizcacha (Lagostomus maximus) is a unique model to study the regulation of hypothalamic GnRH neurons by direct and indirect steroid-dependent pathways. The aim was to characterize the hypothalamic expression of endocrine markers in vizcacha during gestation as well as their response to experimental induced hyperprolactinemia. The possible involvement of PRL regulatory pathways on GnRH in the context of hypothalamic and pituitary reactivation in mid-gestating vizcachas was discussed. Using two in vivo approaches, we determined changes in the hypothalamic expression and distribution of prolactin receptor (PRLR), tyrosine hydroxylase (TH), and dopamine type 2 receptor. A significant increment in the number of tuberoinfundibular dopaminergic (TIDA) neurons was determined in the arcuate nucleus from early to term pregnancy. On the other hand, at preoptic area, the number of both TH+PRLR+ and GnRH+PRLR+ double-labeled neurons significantly decreased at mid-pregnancy probably allowing the recovery of GnRH expression indicating that both types of neurons may represent the key points of PRL indirect and direct pathways modulating GnRH. Moreover, in a model of induced hyperprolactinemic vizcachas, the inhibitory effect of PRL on GnRH at both expression and delivery levels were confirmed. These results suggest the concomitant participation of both PRL regulatory pathways on GnRH modulation and pinpoint the key role of PRL on GnRH expression enabling the recovery of the hypothalamic activity during the gestation in this species.

Partial loss of arcuate kisspeptin neurons in female rats stimulates luteinizing hormone and decreases prolactin secretion induced by estradiol.

Kisspeptin, neurokinin, and dynorphin (KNDy) neurons in the arcuate nucleus (ARC) control luteinizing hormone (LH) and prolactin (PRL) release, although their role in conveying the effects of estradiol (E2 ) to these hormones is not well understood. We performed a longitudinal evaluation of female rats in which KNDy neurons were ablated using a neurokinin-3 receptor agonist conjugated with saporin (NK3-SAP) to investigate the impact of the reduction of KNDy neurons on the E2 regulation of gonadal and PRL axes. NK3-SAP rats, bearing a moderate loss of ARC kisspeptin-immunoreactive (-IR) neurons (50%-90%), displayed irregular estrous cycles but essentially unaltered follicular development and a normal number of corpora lutea. Rats were then ovariectomized (OVX) and treated with a positive-feedback dose of E2 (OVX + E2 ). LH and PRL were measured in the tail blood by an enzyme-linked immunosorbent assay. The E2 -induced LH surge was amplified, whereas the PRL rise was decreased in NK3-SAP rats compared to Blank-SAP control. After 10 days of no hormonal treatment, basal LH levels were equally elevated in NK3-SAP and controls. Tyrosine hydroxylase (TH) phosphorylation in the median eminence, in turn, was increased in NK3-SAP rats, with no change in the number of ARC TH-IR neurons. Thus, KNDy neurons exert concurrent and opposite roles in the E2 -induced surges of LH and PRL. The partial loss of KNDy neurons disrupts ovarian cyclicity but does not preclude ovulation, consistent with the disinhibition of the LH preovulatory surge. Conversely, KNDy neurons tonically inhibit the enzymatic activity of tuberoinfundibular dopaminergic neurons, which appears to facilitate PRL release in response to E2 .

Impact of Chronic Prenatal Stress on Maternal Neuroendocrine Function and Embryo and Placenta Development During Early-to-Mid-Pregnancy in Mice.

Psychological stress, both leading up to and during pregnancy, is associated with increased risk for negative pregnancy outcomes. Although the neuroendocrine circuits that link the stress response to reduced sexual motivation and mating are well-described, the specific pathways by which stress negatively impacts gestational outcomes remain unclear. Using a mouse model of chronic psychological stress during pregnancy, we investigated 1) how chronic exposure to stress during gestation impacts maternal reproductive neuroendocrine circuitry, and 2) whether stress alters developmental outcomes for the fetus or placenta by mid-pregnancy. Focusing on the stress-responsive neuropeptide RFRP-3, we identified novel contacts between RFRP-3-immunoreactive (RFRP-3-ir) cells and tuberoinfundibular dopaminergic neurons in the arcuate nucleus, thus providing a potential pathway linking the neuroendocrine stress response directly to pituitary prolactin production and release. However, neither of these cell populations nor circulating levels of pituitary hormones were affected by chronic stress. Conversely, circulating levels of steroid hormones relevant to gestational outcomes (progesterone and corticosterone) were altered in chronically-stressed dams across gestation, and those dams were qualitatively more likely to experience delays in fetal development. Together, these findings suggest that, up until at least mid-pregnancy, mothers appear to be relatively resilient to the effects of elevated glucocorticoids on reproductive neuroendocrine system function. We conclude that understanding how chronic psychological stress impacts reproductive outcomes will require understanding individual susceptibility and identifying reliable neuroendocrine changes resulting from gestational stress.

Dysregulation of serum prolactin links the hypothalamus with female nociceptors to promote migraine.

Migraine headache results from activation of meningeal nociceptors, however, the hypothalamus is activated many hours before the emergence of pain. How hypothalamic neural mechanisms may influence trigeminal nociceptor function remains unknown. Stress is a common migraine trigger that engages hypothalamic dynorphin/kappa opioid receptor (KOR) signalling and increases circulating prolactin. Prolactin acts at both long and short prolactin receptor isoforms that are expressed in trigeminal afferents. Following downregulation of the prolactin receptor long isoform, prolactin signalling at the prolactin receptor short isoform sensitizes nociceptors selectively in females. We hypothesized that stress may activate the kappa opioid receptor on tuberoinfundibular dopaminergic neurons to increase circulating prolactin leading to female-selective sensitization of trigeminal nociceptors through dysregulation of prolactin receptor isoforms. A mouse two-hit hyperalgesic priming model of migraine was used. Repeated restraint stress promoted vulnerability (i.e. first-hit priming) to a subsequent subthreshold (i.e. second-hit) stimulus from inhalational umbellulone, a TRPA1 agonist. Periorbital cutaneous allodynia served as a surrogate of migraine-like pain. Female and male KORCre; R26lsl-Sun1-GFP mice showed a high percentage of KORCre labelled neurons co-localized in tyrosine hydroxylase-positive cells in the hypothalamic arcuate nucleus. Restraint stress increased circulating prolactin to a greater degree in females. Stress-primed, but not control, mice of both sexes developed periorbital allodynia following inhalational umbellulone. Gi-DREADD activation (i.e. inhibition through Gi-coupled signalling) in KORCre neurons in the arcuate nucleus also increased circulating prolactin and repeated chemogenetic manipulation of these neurons primed mice of both sexes to umbellulone. Clustered regularly interspaced short palindromic repeats-Cas9 deletion of the arcuate nucleus KOR prevented restraint stress-induced prolactin release in female mice and priming from repeated stress episodes in both sexes. Inhibition of circulating prolactin occurred with systemic cabergoline, a dopamine D2 receptor agonist, blocked priming selectively in females. Repeated restraint stress downregulated the prolactin receptor long isoform in the trigeminal ganglia of female mice. Deletion of prolactin receptor in trigeminal ganglia by nasal clustered regularly interspaced short palindromic repeats-Cas9 targeting both prolactin receptor isoforms prevented stress-induced priming in female mice. Stress-induced activation of hypothalamic KOR increases circulating prolactin resulting in trigeminal downregulation of prolactin receptor long and pain responses to a normally innocuous TRPA1 stimulus. These are the first data that provide a mechanistic link between stress-induced hypothalamic activation and the trigeminal nociceptor effectors that produce trigeminal sensitization and migraine-like pain. This sexually dimorphic mechanism may help to explain female prevalence of migraine. KOR antagonists, currently in phase II clinical trials, may be useful as migraine preventives in both sexes, while dopamine agonists and prolactin/ prolactin receptor antibodies may improve therapy for migraine, and other stress-related neurological disorders, in females.

Melatonin Modulates Lactation by Regulating Prolactin Secretion Via Tuberoinfundibular Dopaminergic Neurons in the Hypothalamus- Pituitary System.

In-depth studies have identified many hormones important for controlling mammary growth and maintaining lactation. One of these is melatonin, which is synthesized and secreted by the pineal gland to regulate circadian rhythms, improve antioxidant capacity, and enhance immunity. Prolactin is secreted by the pituitary gland and is associated with the growth and development of mammary glands as well as initiation and maintenance of lactation. The hypothalamus-pituitary system, the most important endocrine system in the body, regulates prolactin secretion mainly through dopamine released from tuberoinfundibular dopaminergic neurons. This review provides a reference for further study and describes the regulation of lactation and prolactin secretion by melatonin, primarily via the protection and stimulation of tuberoinfundibular dopaminergic neurons.

Dopaminergic, Noradrenergic, Adrenal, and Thyroid Abnormalities in Psychotic and Affective Disorders.

BackgroundThis study aimed to assess hypothalamic-pituitary dopaminergic (DA), noradrenergic (NA), thyroid (HPT), and adrenal (HPA) activity in schizophrenia, in schizoaffective disorder, and in bipolar disorder.MethodWe investigated a combined approach of hormone responses to (1) apomorphine (APO), a short-acting DA receptor agonist which decreases prolactin secretion (PRL), and stimulates secretion of growth hormone (GH), adrenocorticotropin (ACTH), and cortisol; (2) clonidine (CLO), an alpha 2-adrenoceptor agonist which stimulates GH secretion; (3) 8 AM and 11 PM protirelin (TRH) which stimulates thyrotropin (TSH) secretion; and (4) dexamethasone which suppresses cortisol secretion, in 13 hospitalized healthy male controls and 39 untreated male inpatients: 13 with DSM-IV paranoid schizophrenia, 13 with DSM-IV schizoaffective disorder (bipolar subtype, depressed at the time of the study), and 13 with DSM-IV bipolar disorder (depressed).ResultsCompared to controls, paranoid schizophrenic patients showed (1) lower APO-induced ACTH and cortisol stimulation, and (2) higher post-dexamethasone cortisol values. Compared to controls, schizoaffective and bipolar patients showed (1) lower ΔΔTSH values (i.e., difference between 11 PM and 8 AM TRH-TSH responses), (2) lower APO-induced PRL suppression, (3) lower CLO-induced GH stimulation, and (4) higher post-dexamethasone cortisol values.ConclusionsAlthough results must be interpreted with caution because of the small sample, this preliminary study suggests that depressed bipolar and schizoaffective patients share common biological dysregulations, distinct from that of paranoid schizophrenic patients. From a pathophysiological viewpoint, paranoid schizophrenic patients can be characterized by hyposensitivity of the hypothalamic DA receptors (possibly resulting from an increase in presynaptic DA release) associated with increased HPA axis activity, while depressed bipolar and schizoaffective patients can be characterized by hyposensitivity of the pituitary TRH and DA-D2 receptors (possibly linked to the activation of the hypothalamic TRH and tuberoinfundibular DA neurons, respectively), together with subsensitive postsynaptic α2-adrenoreceptors at the hypothalamic level (possibly secondary to an erratic release of NA) and increased HPA axis activity.

Impaired prolactin transport into the brain and functional responses to prolactin in aged male mice.

Ageing is related to changes in a number of endocrine systems that impact on the central actions of hormones. The anterior pituitary hormone prolactin is present in the circulation in both males and females, with widespread expression of the prolactin receptor throughout the forebrain. We aimed to investigate prolactin transport into the brain, as well as circulating levels of prolactin and functional responses to prolactin, in aged male mice (23months). Transport of 125 I-labelled prolactin (125 I-prolactin) from the peripheral circulation into the brain was suppressed in aged compared to young adult (4months) male mice, with no significant transport into the brain occurring in aged males. We subsequently investigated changes in the negative-feedback regulation of prolactin secretion and prolactin-induced suppression of luteinising hormone (LH) pulsatile secretion in aged male mice. Feedback regulation of prolactin secretion appeared to be unaffected in aged males, with no change in levels of circulating prolactin, and normal prolactin-induced phosphorylated signal transducer and activator of transcription 5(pSTAT5) immunoreactivity in tuberoinfundibular dopaminergic (TIDA) neurones in the arcuate nucleus. There were, however, significant impairments in the ability of prolactin to suppress LH pulsatile secretion in aged males. In young adult males, acute prolactin administration significantly decreased LH pulses from 1.5±0.19 pulses of LH in 4hours to 0.5±0.27 pulses. In contrast, prolactin did not suppress LH pulse frequency in aged males, with prolactin leading to an increase in mean LH concentration. These data demonstrate the emergence of impairments in prolactin transport into the brain and deficits in specific functional responses to prolactin with ageing.

Morphological plasticity of the tuberoinfundibular dopaminergic neurones in the rat during the oestrous cycle and lactation

The hypothalamic tuberoinfundibular dopaminergic (TIDA) neurones are critical with respect to regulating prolactin secretion from the anterior pituitary. Under most physiological conditions, they are stimulated by prolactin to release dopamine into the median eminence which subsequently suppresses further prolactin secretion from the lactotrophs. During lactation, the TIDA neurones are known to undergo both electrophysiological and neurochemical changes that alleviate this negative-feedback, thus allowing circulating prolactin levels to rise. The present study aimed to determine whether TIDA neurone morphology, most notably spine density, is also modified during lactation. This was achieved by stereotaxically injecting the arcuate nucleus of female, tyrosine hydroxylase-promoter driven Cre-recombinase transgenic rats with Cre-dependent adeno-associated virus-expressing Brainbow. This resulted in the highly specifici transfection of between 10% and 30% of the TIDA neurones, thus allowing the morphologies on multiple individual neurones to be examined in a single hypothalamic slice. The transfected neurones exhibited a range of complex forms, including a diversity of soma and location of axonal origin. Neuronal spine counting showed that the density of somatic, but not dendritic, spines was significantly higher during lactation than at any other reproductive stage. There was also a significant fall in somatic spine density across the oestrous cycle from dioestrus to oestrus. Although the functional characteristics of the additional somatic spines have not been determined, if, as might be expected, they represent an increased excitatory input to the TIDA neurones, this could have important physiological implications by perhaps supporting altered neurotransmitter release at their neuroendocrine terminals. Enhanced excitatory input may, for example, favour the release of the opioid peptide enkephalin rather than dopamine, which is potentially significant because the expression of the peptide is known to increase in the TIDA neurones during lactation and, in contrast to dopamine, it stimulates rather than inhibits prolactin secretion from the pituitary.

Reduced dopaminergic tone during lactation is permissive to the hypothalamic stimulus for suckling-induced prolactin release.

Dopamine from tuberoinfundibular dopaminergic (TIDA) neurones tonically inhibits prolactin (PRL) secretion. Lactational hyperprolactinaemia is associated with a reduced activity of TIDA neurones. However, it remains controversial whether the suckling-induced PRL surge is driven by an additional decrease in dopamine release or by stimulation from a PRL-releasing factor. In the present study, we further investigated the role of dopamine in the PRL response to suckling. Non-lactating (N-Lac), lactating 4hour apart from pups (Lac), Lac with pups return and suckling (Lac+S), and post-lactating (P-Lac) rats were evaluated. PRL levels were elevated in Lac rats and increased linearly within 30 minutes of suckling in Lac+S rats. During the rise in PRL levels, dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the median eminence (ME) and neurointermediate lobe of the pituitary did not differ between Lac+S and Lac rats. However, dopamine and DOPAC were equally decreased in Lac and Lac+S compared to N-Lac and P-Lac rats. Suckling, in turn, reduced phosphorylation of tyrosine hydroxylase in the ME of Lac+S. Domperidone and bromocriptine were used to block and activate pituitary dopamine D2 receptors, respectively. Domperidone increased PRL secretion in both N-Lac and Lac rats, and suckling elicited a robust surge of PRL over the high basal levels in domperidone-treated Lac+S rats. Conversely, bromocriptine blocked the PRL response to suckling. The findings obtained in the present study provide evidence that dopamine synthesis and release are tonically reduced during lactation, whereas dopamine is still functional with respect to inhibiting PRL secretion. However, there appears to be no further reduction in dopamine release associated with the suckling-induced rise in PRL. Instead, the lower dopaminergic tone during lactation appears to be required to sensitise the pituitary to a suckling-induced PRL-releasing factor.

MON-016 Neural Circuits and Hormonal Mechanisms Underlying the Negative Impact of Stress on Pregnancy Outcomes

Despite numerous findings detailing the negative impact of stress on female reproductive health, the means by which stress acts on the CNS and periphery to compromise reproductive success remains poorly understood. As a result, the current study sought to clarify the neuroendocrine mechanisms by which stress acts on the brain to deleteriously influence pregnancy outcomes. Reproduction is regulated by the hypothalamo-pituitary-gonadal (HPG) axis, with hypothalamic gonadotropin-releasing hormone (GnRH) neurons representing the final, common pathway of this axis. Cells expressing the inhibitory neuropeptide, RFamide-related peptide-3 (RFRP-3), lie upstream of the GnRH system and are markedly regulated by environmental and psychosocial factors, including stress. In the present study, we asked whether RFRP-3 neurons mediate the effects of stress on pregnancy outcomes through the regulation of prolactin secretion, as prolactin is critical for pregnancy maintenance. More specifically, because specialized hypothalamic dopaminergic neurons, namely tubero-infundibular dopaminergic (TIDA) neurons, are major regulators of prolactin secretion, we hypothesized that RFRP-3 neurons directly target TIDA cells to negatively influence fetal development. To test this possibility, we subjected pregnant mice to chronic restraint stress for the first half of pregnancy and performed a broad screen of hypothalamic neuroendocrine function compared to non-stressed controls. Stressed mice exhibited elevated baseline concentrations of corticosterone that remained high at least 6 days after the final exposure to stress. Whereas progesterone concentrations were reduced by stress early in pregnancy, stressed mice recovered typical progesterone secretion during late gestation. These early, stressful experiences resulted in persistent developmental delays, reduced embryo weight, and abnormal placental histology. Significantly, a small percentage of TIDA cells receive close contacts from RFRP-3 axons, providing a mechanism for the control of prolactin secretion by stress. However, contrary to expectation, the percentage of TIDA neurons receiving input from RFRP-3 cells was not impacted by stress. Together, these findings identify a potential pathway of control for the impact of stress on neuroendocrine factors critical to pregnancy success, although further work using more sensitive approaches is needed to examine the putative role of RFRP-3 on stress-induced pregnancy outcomes.

Hypothalamic Kisspeptin Expression in Hyperandrogenic Female Rats and Aging Rats.

Hypothalamic kisspeptin neurons stimulate gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) release. Kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) of rats induce an LH surge for ovulation, and those in the arcuate nucleus (ARC) regulate pulsatile LH secretion for follicle development and spermatogenesis. Dysfunction of kisspeptin neurons thus reduces the reproductive function. This review focuses on the effect of androgen or aging on kisspeptin expression in rats. Although androgen directly suppresses ARC kisspeptin neurons in female rats, the AVPV kisspeptin neurons are hardly affected. In rats, plasma LH concentrations decrease in both sexes with aging, and ARC kisspeptin expression also decreases in old rats compared with young rats. In addition, kisspeptin neurons may be associated with hyperprolactinemia in old female rats because they are known to release prolactin through hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons. Hypothalamic kisspeptin neurons are thus the main regulator to secrete LH, and inhibition of kisspeptin expression leads to various kinds of reproductive dysfunction.

Elevated Prolactin during Pregnancy Drives a Phenotypic Switch in Mouse Hypothalamic Dopaminergic Neurons

Altered physiological states require neuronal adaptation. In late pregnancy and lactation, a sub-population of the mouse hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons alters their behavior to synthesize and release met-enkephalin rather than dopamine. These neurons normally release dopamine to inhibit prolactin secretion and are activated by prolactin in a short-loop feedback manner. In lactation, dopamine synthesis is suppressed in anopioid-dependent (naloxone-reversible) manner, meaning that prolactin secretion is disinhibited. Conditional deletion of the prolactin receptor in neurons reveals that this change in phenotype appears to be driven by prolactin itself, apparently through an alteration in intracellular signaling downstream of the prolactin receptor that favors enkephalin production instead of dopamine. Thus, prolactin effectively facilitates its own secretion, which is essential for lactation and maternal behavior. These studies provide evidence of a physiologically important, reversible alteration in the behavior of a specific population of hypothalamic neurons in the adult brain.

Kisspeptin Stimulation of Prolactin Secretion Requires Kiss1 Receptor but Not in Tuberoinfundibular Dopaminergic Neurons.

Kisspeptin has been shown to stimulate prolactin secretion. We investigated whether kisspeptin acts through the Kiss1 receptor (Kiss1r) to regulate dopamine and prolactin. Initially, we evaluated prolactin response in a Kiss1r-deficient mouse line, in which Kiss1r had been knocked into GnRH neurons (Kiss1r-/-R). Intracerebroventricular kisspeptin-10 (Kp-10) increased prolactin release in wild-type but not in Kiss1r-/-R female mice. In ovariectomized, estradiol-treated rats, the Kiss1r antagonist kisspeptin-234 abolished the Kp-10-induced increase in prolactin release but failed to prevent the concomitant reduction in the activity of tuberoinfundibular dopaminergic (TIDA) neurons, as determined by the 3,4-dihydroxyphenylacetic acid/dopamine ratio in the median eminence. Using whole-cell patch clamp recordings in juvenile male rats, we found no direct effect of Kp-10 on the electrical activity of TIDA neurons. In addition, dual-label in situ hybridization in the hypothalamus of female rats showed that Kiss1r is expressed in the periventricular nucleus of the hypothalamus (Pe) and arcuate nucleus of the hypothalamus (ARC) but not in tyrosine hydroxylase (Th)-expressing neurons. Kisspeptin also has affinity for the neuropeptide FF receptor 1 (Npffr1), which was expressed in the majority of Pe dopaminergic neurons but only in a low proportion of TIDA neurons in the ARC. Our findings demonstrate that Kiss1r is necessary to the effect of kisspeptin on prolactin secretion, although TIDA neurons lack Kiss1r and are electrically unresponsive to kisspeptin. Thus, kisspeptin is likely to stimulate prolactin secretion via Kiss1r in nondopaminergic neurons, whereas the colocalization of Npffr1 and Th suggests that Pe dopaminergic neurons may play a role in the kisspeptin-induced inhibition of dopamine release.

Chronic estrogen affects TIDA neurons through IL-1β and NO: effects of aging.

Women are chronically exposed to estrogens through oral contraceptives, hormone replacement therapy or environmental estrogens. We hypothesized that chronic exposure to low levels of estradiol-17β (E2) can induce inflammatory and degenerative changes in the tuberoinfundibular dopaminergic (TIDA) system leading to reduced dopamine synthesis and hyperprolactinemia. Young (Y; 3–4 months) and middle-aged (MA; 10–12 months) Sprague-Dawley rats that were intact or ovariectomized (OVX) were either sham-implanted or implanted with a slow-release E2 pellet (20 ng E2/day for 90 days). To get mechanistic insight, adult 3- to 4-month-old WT, inducible nitric oxide synthase (iNOS) and IL-1 receptor (IL-1R) knockout (KO) mice were subjected to a similar treatment. Hypothalamic areas corresponding to the TIDA system were analyzed. E2 treatment increased IL-1β protein and nitrate levels in the arcuate nucleus of intact animals (Y and MA). Nitration of tyrosine hydroxylase in the median eminence increased with E2 treatment in both intact and OVX animals. There was no additional effect of age. This was accompanied by a reduction in dopamine levels and an increase in prolactin in intact animals. E2 treatment increased nitrate and reduced dopamine levels in the hypothalamus and increased serum prolactin in WT mice. In contrast, the effect of E2 on nitrate levels was blocked in IL-1R KO mice and the effect on dopamine and prolactin were blocked in iNOS KO animals. Taken together, these results show that chronic exposure to low levels of E2 decreases TIDA activity through a cytokine-nitric oxide-mediated pathway leading to hyperprolactinemia and that aging could promote these degenerative changes.

IGF-1 Gene Therapy as a Potentially Useful Therapy for Spontaneous Prolactinomas in Senile Rats.

Insulin-like Growth Factor1 (IGF1) is a powerful neuroprotective molecule. We have previously shown that short-term hypothalamic IGF1 gene therapy restores tuberoinfundibular dopaminergic neuron function in aging female rats. Our aim was to implement long-term IGF-I gene therapy in pituitary prolactinomas in senile female rats. Here, we assessed the long-term effect of IGF1 gene therapy in the hypothalamus of young (4 mo.) and aging (24 mo.) female rats carrying spontaneous pituitary prolactinomas. We constructed and injected a Helper-Dependent (HD) adenovector expressing the gene for rat IGF1 or the reporter red fluorescent protein DsRed. Ninety-one days post vector injection, all rats were sacrificed and their brains and pituitaries fixed. Serum prolactin (PRL), Estrogen (E2) and progesterone (P4), as well as hypothalamic IGF1 content, were measured by RIA. Anterior pituitaries were immunostained with an anti-rat PRL antibody and submitted to morphometric analysis. DsRed expression in the Mediobasal Hypothalamus (MBH) was strong after the treatment in the DsRed group while IGF1 content in the MBH was higher in the IGF1 group. The IGF1 treatment affected neither pituitary weight nor PRL, E2 or P4 serum levels in the young rats. In the old rats, IGF1 gene therapy reduced gland weight as compared with intact counterparts and tended to reduce PRL levels as compared with intact counterparts. The treatment significantly rescued the phenotype of the lactotropic cell population in the senile adenomas. We conclude that long-term hypothalamic IGF1 gene therapy is effective to rescue spontaneous prolactinomas in aging female rats.

Galactorrhea and hyperprolactinemia during vortioxetine use: case report

Abstract Background: Hyperprolactinemia is one of the most common endocrine disorders of the hypothalamic-pituitary axis. Hyperprolactinemia and galactorrhea are rarely seen as adverse effects of antidepressant drugs. Case presentation: Thirty-three years old women, between 2011 and 2017, three depressive episodes were observed. Initially, fluoxetine was used, no galactorrhea was detected. Secondly, she was given escitalopram and visited the clinic with amenorrhea and galactorrhea. Her serum prolactin levels were 50.88 ng/mL and MRI findings were normal. Escitalopram was discontinued and prescribed cabergoline and then prolactin levels were 16.56 ng/mL in the third month. During the vortioxetine treatment, she developed galactorrhea and prolactin level was 43.65 ng/mL. Vortioxetine was discontinued and it was measured at 20.14 ng/mL after 4 weeks of drug-free observation. Conclusion: Vortioxetine is a multimodal agent that modulates a select population of 5-HT receptors. To literature, there was no case presentation of galactorrhea observed during the use of vortioxetine. Galactorrhea associated with SSRIs are limited to case presentations. Antidepressants are thought to cause galactorrhea through tuberoinfundibular dopaminergic neurons or postsynaptic serotonergic neurons in the hypothalamus. When galactorrhea was observed during antidepressant drug use, prolactin levels and MRI should be investigated, and termination/replacement of antidepressant treatment is recommended if necessary.

Short-term fasting decreases excitatory synaptic inputs to ventromedial tuberoinfundibular dopaminergic neurons and attenuates their activity in male mice

Tuberoinfundibular dopaminergic (TIDA) neurons in the arcuate nucleus (ARC) of the hypothalamus play a role in inhibiting prolactin (PRL) secretion from the anterior pituitary. PRL is involved in a variety of behaviors, including feeding. Consequently, we hypothesized that fasting might reduce the activity of TIDA neurons, which might alter PRL secretion. However, direct examinations of TIDA neuron activity are difficult. Recently, transgenic mice were generated that expressed green fluorescent protein (GFP) under the control of the rat tyrosine hydroxylase gene. We first determined that GFP in the dorsomedial ARC was a reliable marker of TIDA neurons. Then, we performed electrophysiology and immunocytochemistry in GFP-labeled TIDA neurons to examine whether different feeding conditions could change their activity. Eight-week-old male mice were fed or fasted for 24 h. After sacrifice, we prepared acutely isolated brain slices for conducting whole-cell voltage-clamp recordings. TIDA neurons were identified with fluorescence microscopy. The mean amplitude of miniature excitatory postsynaptic currents (mEPSCs) was significantly reduced in fasting mice compared to fed mice, but different feeding conditions did not affect the mean mEPSC intervals. This result suggested that fasting reduced the number of excitatory synaptic inputs to TIDA neurons. To determine whether a reduction in excitatory synaptic inputs would cause a reduction in TIDA neuron activity, we examined the effect of 24-h fasting on c-Fos expression in the ARC. We found that fasting significantly reduced the number of Fos-positive TIDA neurons. In addition, serum PRL levels were significantly increased. Taken together, the present findings suggested that short-term fasting attenuated TIDA neuron activity.

Insulin-like growth factor I and its binding protein-3 are regulators of lactation and maternal responsiveness

Adaptation to motherhood includes maternal behaviour and lactation during the postpartum period. The major organizing centres of maternal behaviour and lactation are located in the hypothalamic medial preoptic area (MPOA) and the arcuate nucleus, respectively. Insulin-like growth factor I (IGF-I) is an effector of the growth hormone axis; however, its function in the brain is largely unexplored. We identified increased maternal IGF binding protein-3 (IGFBP-3) expression in preoptic rat microarray data and confirmed it by RT-PCR. In situ hybridization histochemistry showed markedly elevated IGFBP-3 expression in the MPOA and the arcuate nucleus in rat dams. Prolonged intracerebroventricular injection of IGF-I or antagonism of brain IGFBP-3 with an inhibitor (NBI-31772) using osmotic minipumps increased pup retrieval time, suggesting reduced maternal motivation. Suckling-induced prolactin release and pup weight gain were also suppressed by IGF-I, suggesting reduced lactation. In addition, IGF-I-induced tyrosine hydroxylase expression and its specific phosphorylation in tuberoinfundibular dopaminergic neurons suppress prolactin secretion. Thus, IGF-I may inhibit both behavioural and lactational alterations in mothers. Neurons in the MPOA and arcuate nuclei express IGFBP-3 during the postpartum period to neutralize IGF-I effects. IGFBP-3 can prevent the blockade of maternal behaviour and lactation exerted by IGF-I, suggesting a novel modulatory mechanism underlying the behavioural and hormonal effects during central maternal adaptations.