Activation of Vasopressin Neurons in Aging and Alzheimer's Disease

The supraoptic (SON) and paraventricular nuclei (PVN) of the human hypothalamus are production sites of vasopressin (AVP) and oxytocin (OXT). Although the hypothalamus is affected in Alzheimer's disease (AD), previous work has not only shown that in these two nuclei no neurons are lost, neither during aging nor in AD, but that the number of AVP-expressing neurons and their nucleolar size had even increased with age. These observations indicated that the peptide synthesis of the AVP neurons was activated in the oldest age-groups. Recently published, qualitative observations, using the area of the Golgi Apparatus (GA) as a sensitive parameter for neurosecretory activity, confirmed the activation of SON and PVN neurons with age in human; however, in this report the neurons were not identified according to their neuropeptide content. In the present quantitative study we determined whether the AVP neurons were indeed activated as a result of the aging process in controls and AD patients. We applied a polyclonal antiserum directed against the medial cisternae of the GA on formalin-fixed, paraffin-embedded tissue sections taken from the dorsolateral SON (dl-SON) of 10 controls and 10 AD patients, and performed our measurements in this area that is known to be predominantly occupied (90–95%) by AVP neurons. In addition, the sparse OXT cells present in the area of study, were excluded from the measurements on the basis of alternative sections stained for OXT. In the dl-SON, the area occupied by the GA and the cellular profile area per patient were quantified by means of image analysis. The results show a significant increase in GA area with age in controls and in AD, demonstrating an activation of the AVP neurons in the dl-SON of the human hypothalamus in these two conditions. No changes were observed in the cellular profile areas with age, neither in the controls nor in AD, suggesting that the GA area is a much more sensitive parameter for monitoring activity changes in post-mortem material than neuronal size. It is proposed that this activation of AVP cells with age, which has been suggested to be a compensatory response to the age-related loss of AVP receptors in the kidney, might be the basis of the stability of these neurons in aging and AD.     

Chronic hypoosmolality induces a selective decrease in magnocellular neurone soma and nuclear size in the rat hypothalamic supraoptic nucleus

The magnocellular neurones of the hypothalamo-neurohypophysial system (HNS) play a vital role in the maintenance of body homeostasis by regulating oxytocin (OT) and vasopressin (VP) secretion from the posterior pituitary. During hyperosmolality, OT and VP mRNA levels are known to increase by approximately two-fold, whereas during chronic hypoosmolality, OT and VP mRNA levels decrease to approximately 10-20% of basal levels. In these studies, we evaluated changes in cell size associated with these physiological conditions. Cell and nuclear sizes of neurones in the supraoptic nucleus (SON), the nucleus of the lateral olfactory tract (LOT) and the medial habenular nucleus (MHB) were measured from neurones identified by in situ hybridization histochemistry for beta(III)-tubulin mRNA, and measurements were made from OT and AVP magnocellular neurones in the SON after phenotypic identification by immunohistochemistry. Under hypoosmolar conditions, the cell and nuclear sizes of OT and VP magnocellular neurones decreased to approximately 60% of basal values, whereas cell and nuclear sizes of OT and VP neurones in hyperosmolar rats increased to approximately 170% of basal values. In contrast, neither hyperosmolality, nor hypoosmolality significantly affected cell and nuclear sizes in the LOT and MHB. These results confirm previous studies that showed that magnocellular neurones increase cell size in response to hyperosmolar conditions and, for the first time, demonstrate a marked decrease in cell size in the SON in response to chronic hypoosmolar conditions. These dramatic changes in cell and nuclear size directly parallel changes in OT and VP gene expression in the magnocellular neurones of the SON and, consequently, are consistent with the pronounced bidirectional changes in gene expression and cellular activity found during these osmotic perturbations. Our results therefore support the concept of global alterations in the synthetic activity of magnocellular OT and AVP neurones in response to extracellular osmolality.     

Oestradiol potentiates hormone secretion and neuronal activation in response to hypertonic extracellular volume expansion in ovariectomised rats

Secretion of vasopressin (VP), oxytocin (OT) and atrial natriuretic peptide (ANP) is an essential mechanism for the maintenance of hydromineral homeostasis. Secretion of these hormones is modulated by several circulating factors, including oestradiol. However, it remains unclear how oestradiol exerts this modulation. In the present study we investigated the participation of oestradiol in the secretion of VP, OT and ANP and in activation of vasopressinergic and oxytocinergic neurones of the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus in response to extracellular volume expansion (EVE). For this purpose, ovariectomised (OVX) rats treated for 7 days with vehicle (corn oil, 0.1 ml/rat, OVX+O group) or oestradiol (oestradiol cypionate, 10 μg/kg, OVX+E group) were subjected to either isotonic (0.15 m NaCl, 2 ml/100 g b.w., i.v.) or hypertonic (0.30 m NaCl, 2 ml/100 g b.w., i.v.) EVE. Blood samples were collected for plasma VP, OT and ANP determination. Another group of rats was subjected to cerebral perfusion, and brain sections were processed for c‐Fos‐VP and c‐Fos‐OT double‐labelling immunohistochemistry. In OVX+O rats, we observed that both isotonic and hypertonic EVE increased plasma OT and ANP concentrations, although no changes were observed in VP secretion. Oestradiol replacement did not alter hormonal secretion in response to isotonic EVE, but it increased VP secretion and potentiated plasma OT and ANP concentrations in response to hypertonic EVE. Immunohistochemical data showed that, in the OVX+O group, hypertonic EVE increased the number of c‐Fos‐OT and c‐Fos‐VP double‐labelled neurones in the PVN and SON. Oestradiol replacement did not alter neuronal activation in response to isotonic EVE, but it potentiated vasopressinergic and oxytocinergic neuronal activation in the medial magnocellular PVN (PaMM) and SON. Taken together, these results suggest that oestradiol increases the responsiveness of vasopressinergic and oxytocinergic magnocellular neurones in the PVN and SON in response to osmotic stimulation.     

Electrophysiological Identification of the Functional Presynaptic Nerve Terminals on an Isolated Single Vasopressin Neurone of the Rat Supraoptic Nucleus

Release of arginine vasopressin (AVP) and oxytocin from magnocellular neurosecretory cells (MNCs) of the supraoptic nucleus (SON) is under the control of glutamate‐dependent excitation and GABA‐dependent inhibition. The possible role of the synaptic terminals attached to SON neurones has been investigated using whole‐cell patch‐clamp recording in in vitro rat brain slice preparations. Recent evidence has provided new insights into the repercussions of glial environment modifications on the physiology of MNCs at the synaptic level in the SON. In the present study, excitatory glutamatergic and inhibitory GABAergic synaptic inputs were recorded from an isolated single SON neurone cultured for 12 h, using the whole‐cell patch clamp technique. Neurones expressed an AVP‐enhanced green fluorescent protein (eGFP) fusion gene in MNCs. In addition, native synaptic terminals attached to a dissociated AVP‐eGFP neurone were visualised with synaptic vesicle markers. These results suggest that the function of presynaptic nerve terminals may be evaluated directly in a single AVP‐eGFP neurone. These preparations would be helpful in future studies aiming to electrophysiologically distinguish between the functions of synaptic terminals and glial modifications in the SON neurones.     

Glucocorticoid modulation of neuronal activity and hormone secretion induced by blood volume expansion

The present study evaluated the involvement of glucocorticoid in the activation of vasopressinergic and oxytocinergic neurons of hypothalamic nuclei and plasma levels of vasopressin (AVP), oxytocin (OT), atrial natriuretic peptide (ANP) and corticosterone (CORT) in response to both isotonic and hypertonic blood volume expansion (BVE). Rats were subjected to isotonic (0.15 M NaCl, 2 ml/100 g b.w., i.v.) or hypertonic (0.30 M NaCl, 2 ml/100 g b.w., i.v.) BVE with or without pre-treatment with dexamethasone (1 mg/kg, i.p.). Results showed that isotonic BVE increased OT, ANP and CORT, and decreased AVP plasma levels. On the other hand, hypertonic BVE enhanced AVP, ANP, OT, and CORT plasma concentrations. Both hypertonic and isotonic BVE induced an increase in the number of Fos-OT double-labeled magnocellular neurons in the PVN and SON. Pre-treatment with dexamethasone reduced OT secretion, as well as Fos-OT immunoreactive neurons in response to both isotonic and hypertonic BVE. We also observed that dexamethasone pre-treatment had no effect on AVP secretion in response to hypertonic BVE, although this effect was associated with a blockade of Fos expression in the vasopressinergic magnocellular neurons in the PVN and SON. In conclusion, these data suggest that, not only the rapid OT release from storages, but also the oxytocinergic cellular activation induced by BVE are modulated by glucocorticoids. However, this pattern of response was not observed for AVP cells, suggesting that dexamethasone is not likely to influence rapid release of AVP but seems to modulate the activation of these neurons in response to hypertonic BVE.     

Activation of the human supraptic and paraventricular nucleus neurons with aging and in Alzheimer's disease as judged from increasing size of the Golgi apparatus

The supraoptic (SON) and paraventricular nucleus (PVN) of the human hypothalamus produce vasopressin (AVP) and oxytocin (OXT). Since in these nuclei no cells are lost during aging or Alzheimer's Disease (AD), factors are searched for which may be responsible for this remarkable stability. Earlier work in both rat and human indicated that the peptide synthesis of these neurons was activated in the oldest age groups as judged from increased and nuclear size and AVP plasma levels. The size of the Golgi Apparatus (GA) has proved to be a very sensitive parameter for the synthetic activity of these neurosecretory cells in animal experiments. In order to determine changes in the GA during aging and in Alzheimer's Disease, we applied a polyclonal antiserum against immunoaffinity purified MG-160, a sialoglycoprotein of the medial cisternae of the GA, on formalin-fixed and paraffin-embedded sections of the SON and PVN of patients ranging in age from 29 to 97 years. However, our standard fixation procedure masked antigenic sites resulting in a minimal immunocytochemical staining in most of the tissue examined. It appeared to be possible, however, to retrieve the antigen and to obtain an excellent staining of the GA by heating sections in a microwave oven before immunostaining. Following this procedure, an increase in size and intensity of the GA became apparent in individuals from about 70 years and older. In AD patients a similar increase in size and intensity of the immunostained GA was observed. Taken together, these results indicate that SON and PVN neurons are activated during the course of aging and also in AD and that this activation takes place at an earlier age then observed previously by other cellular parameters.     

CB1 modulation of hormone secretion, neuronal activation and mRNA expression following extracellular volume expansion

The endocannabinoid system includes important signaling molecules that are involved in several homeostatic and neuroendocrine functions. In the present study, we evaluated the effects of the type 1 cannabinoid (CB₁) receptor antagonist, rimonabant (10 mg/kg, p.o.), on hormone secretion, neuronal activation and mRNA expression in the hypothalamus following isotonic (I-) or hypertonic (H-) extracellular volume expansion (EVE). The total nitrate content in the PVN and SON was also assessed under the same experimental conditions. Our results showed that OT and AVP plasma concentrations were increased in response to H-EVE, while decreased AVP levels were found following I-EVE. Accordingly, both I- and H-EVE stimulated oxytocinergic neuronal activation, as evidenced by the increased number of c-Fos/OT double labeled neurons in the hypothalamus. The vasopressinergic cells of the PVN and SON, however, were only activated in response to H-EVE. Furthermore, increased amounts of both AVP and OT mRNAs were found in the hypothalamus following EVE. Pretreatment with rimonabant significantly potentiated hormone secretion and also vasopressinergic and oxytocinergic neuronal activation induced by EVE, although decreased AVP and OT mRNA expression was found in the hypothalami of rimonabant pretreated groups. In addition, the nitrate content in the PVN and SON was not altered in response to EVE or rimonabant pretreatment. Taken together, these results suggest that the CB₁ receptor may modulate several events that contribute to the development of appropriate responses to increased fluid volume and osmolality.     

Metabolic activity of the human ventromedial nucleus neurons in relation to sex and ageing

The ventromedial nucleus (VMN) in animals is involved in a number of sexually dimorphic behaviors, including reproduction, and is a well-documented target for sex steroids. In rats and in lizards, it is also characterized by the presence of structural sexual dimorphisms. In the present study, we determined whether the metabolic activity of human ventromedial nucleus neurons was sex- or age-related. The size of the immunocytochemically defined Golgi apparatus (GA) and cell profiles were determined as measures for neuronal metabolic activity in 12 male and 16 female control brains sub-divided into four groups with the dividing line being the age of 50. It appeared that the size of the GA relative to cell size was 34% larger in young women (<50 years old) than in young men and was 25% larger in elderly men (> or = 50 years old) than in young men. In addition, the GA/cell size ratio correlated significantly with age in men and not in women. Our data suggest that androgens play an inhibitory role with respect to the metabolic activity of the human VMN neurons.     

Suckling and genital stroking induces Fos expression in hypothalamic oxytocinergic neurons of rabbit pups

Maternal behaviour in the rabbit is unusual among mammals because the doe visits her litter to nurse once every 24 h. In the present study we examined the consequences of milk intake on oxytocinergic (OT) and vasopressinergic (AVP) neurons of the supraoptic (SON) and paraventricular (PVN) nuclei of 7-day-old pups before suckling, after suckling and following anogenital stroking in un-nursed pups. To determine neuronal activation we assessed the expression of the Fos protein combined with antibodies against OT and AVP at two levels in the SON (supraoptic rostral, SOr, and supraoptic retrochiasmatic, SOrch), and three levels in the PVN (anterior, PVab; medial PVm and caudal, PVc). Daily nursing bouts lasted only 228+/-6 s throughout the observed 7 days, and pups ingested up to 34.95+/-9.0% of their body weight in milk on day 7, the day of perfusion. Suckling induced a significant increase in the number of double-labeled Fos/OT cells in both subdivisions of the SON (P<0.01) and in PVab and PVm (P<0.01). The effect in the SON was related to suckling, as it was not seen in stroked, un-nursed pups, which showed Fos increases only in PVab and PVm. All regions in the SON and PVN showed significant increases in the number of Fos/AVP neurons after suckling or stroking but, contrary to OT, the number of double-labeled Fos/AVP cells was very low. In conclusion, our results show that the oxytocinergic system of the SON and PVN is differentially activated by suckling of milk and anogenital stroking, and that the vagal-hypothalamic axis is mature in 7-day-old rabbits.     

Oestradiol acts through its beta receptor to increase vasopressin neuronal activation and secretion induced by dehydration

Vasopressinergic neurones of the supraoptic (SON) and paraventricular (PVN) nuclei express oestrogen receptor (ER)β and receive afferent projections from osmosensitive neurones that express ERα. However, which subtype of these receptors mediates the effects of oestradiol on vasopressin (AVP) secretion induced by hydromineral challenge has not yet been demonstrated in vivo. Moreover, AVP secretion induced by hyperosmolality is known to involve activation of TRPV1 (transient receptor potential vanilloid, member 1) in magnocellular neurones, although whether oestradiol modulates expression of this receptor is unknown. Thus, the present study aimed to clarify the mechanisms involved in the modulation exerted by oestradiol on AVP secretion, specifically investigating the involvement of ERβ, ERα and TRPV1 receptors in response to water deprivation (WD). We observed that treatment with an ERβ agonist potentiated AVP secretion and vasopressinergic neuronal activation induced by WD. This increase in AVP secretion induced by WD was reversed by an ERβ antagonist. By contrast to ERβ, the ERα agonist did not alter plasma AVP concentrations or activation of AVP neurones in the SON and PVN. Additionally, Fos expression in the subfornical organ was not altered by the ERα agonist. TRPV1 mRNA expression was increased by WD in the SON, although this response was not altered by any treatment. The results of the present study suggest that ERβ mediates the effects of oestradiol on AVP secretion in response to WD, indicating that the effects of oestradiol occur directly in AVP neurones without affecting TRPV1.     

The effects of sympathectomy on capsaicin-evoked fos expression of spinal dorsal horn GABAergic neurons

In various hypothalamic and adjacent brain regions we have previously found a remarkable increase in nuclear estrogen receptor staining in Alzheimer's disease (AD). In order to see whether this was a general phenomenon or rather specific for those areas that are affected by the AD process we investigated ERalpha and ERbeta expression in the arginine-vasopressin (AVP) neurons of the human dorsolateral suparoptic nucleus (dl-SON), that is the major source of plasma AVP. These neurons remain exceptionally intact in AD. Changes in ER expression were studied in relation to early Alzheimer changes (i.e. hyperphosphorylated tau) and neuronal metabolism in AD as determined by the size of the Golgi apparatus (GA) or cell size. No difference in neuronal metabolism (i.e. GA size or cell size) of AVP neurons was observed between AD and control patients and no early cytoskeletal AD alterations were found confirming the resistance of the dl-SON to AD. While no differences between AD and control patients were present for ERalpha and ERbeta staining except for a lower proportion of nuclear ERbeta AVP-positive neurons in AD subjects, complex sex differences not directly related to AD were observed within each group. The main finding of the present study is that in the dl-SON, that remains active and spared of AD changes, the increase in nuclear ERs seen in adjacent affected areas in AD patients does not occur. This indicates that a rise of nuclear ERs is not a generally occurring phenomenon but rather related to the pathogenetic alterations of the AD process.     

Developmental regulation of a local positive autocontrol of supraoptic neurons.

Mature oxytocin (OT) and vasopressin (AVP) magnocellular neurons of the hypothalamic supraoptic nuclei (SON) autocontrol their electrical activity via somatodendritic release of their respective peptides. Because OT and AVP are synthesized early in development and could play an important role in the maturation of these neurons, we checked whether the peptides are released within the SON and act on their secreting neurons during 3 weeks of postnatal development. We used patch-clamp recordings from SON neurons in rat hypothalamic horizontal slices to show that the spontaneous electrical activity of immature SON neurons is blocked by OT or AVP receptor antagonists, demonstrating a basal somatodendritic release of the peptides. Application of OT or AVP depolarizes SON neurons and stimulates activity typical of the corresponding mature neurons. This effect is directly on SON neurons because it is recorded in dissociated neurons. Radioimmunoassays from isolated SON were used to show that each peptide facilitates its own release at a somatodendritic level, exhibiting a self-sustaining positive feedback loop. This autocontrol is not uniform during development because the proportion of neurons depolarized by the peptides, the amplitude of the depolarization, and the propensity of the peptides to facilitate their own release are maximal during the second postnatal week and decrease thereafter. These data are consistent with a role of autocontrol in the maturation of SON neurons because it is maximal during the delimited period of postnatal development that corresponds to the period of major synapse formation.     

Sex differences in estrogen receptor α and β expression in vasopressin neurons of the supraoptic nucleus in elderly and Alzheimer’s disease patients: no relationship with cytoskeletal alterations

In various hypothalamic and adjacent brain regions we have previously found a remarkable increase in nuclear estrogen receptor staining in Alzheimer’s disease (AD). In order to see whether this was a general phenomenon or rather specific for those areas that are affected by the AD process we investigated ERα and ERβ expression in the arginine–vasopressin (AVP) neurons of the human dorsolateral suparoptic nucleus (dl-SON), that is the major source of plasma AVP. These neurons remain exceptionally intact in AD. Changes in ER expression were studied in relation to early Alzheimer changes (i.e. hyperphosphorylated tau) and neuronal metabolism in AD as determined by the size of the Golgi apparatus (GA) or cell size. No difference in neuronal metabolism (i.e. GA size or cell size) of AVP neurons was observed between AD and control patients and no early cytoskeletal AD alterations were found confirming the resistance of the dl-SON to AD. While no differences between AD and control patients were present for ERα and ERβ staining except for a lower proportion of nuclear ERβ AVP-positive neurons in AD subjects, complex sex differences not directly related to AD were observed within each group. The main finding of the present study is that in the dl-SON, that remains active and spared of AD changes, the increase in nuclear ERs seen in adjacent affected areas in AD patients does not occur. This indicates that a rise of nuclear ERs is not a generally occurring phenomenon but rather related to the pathogenetic alterations of the AD process.     

Oxytocin in the Central Amygdaloid Nucleus Modulates the Neuroendocrine Responses Induced by Hypertonic Volume Expansion in the Rat

The present study investigated the involvement of the oxytocinergic neurones that project into the central amygdala (CeA) in the control of electrolyte excretion and hormone secretion in unanaesthetised rats subjected to acute hypertonic blood volume expansion (BVE; 0.3 M NaCl, 2 ml/100 g of body weight over 1 min). Oxytocin and vasopressin mRNA expression in the paraventricular (Pa) and supraoptic nucleus (SON) of the hypothalamus were also determined using the real time‐polymerase chain reaction and in situ hybridisation. Male Wistar rats with unilaterally implanted stainless steel cannulas in the CeA were used. Oxytocin (1 μg/0.2 μl), vasotocin, an oxytocin antagonist (1 μg/0.2 μl) or vehicle was injected into the CeA 20 min before the BVE. In rats treated with vehicle in the CeA, hypertonic BVE increased urinary volume, sodium excretion, plasma oxytocin (OT), vasopressin (AVP) and atrial natriuretic peptide (ANP) levels and also increased the expression of OT and AVP mRNA in the Pa and SON. In rats pre‐treated with OT in the CeA, previously to the hypertonic BVE, there were further significant increases in plasma AVP, OT and ANP levels, urinary sodium and urine output, as well as in gene expression (AVP and OT mRNA) in the Pa and SON compared to BVE alone. Vasotocin reduced sodium, urine output and ANP levels, although no changes were observed in plasma AVP and OT levels or in the expression of the AVP and OT genes in both hypothalamic nuclei. The results of the present study suggest that oxytocin in the CeA exerts a facilitatory role in the maintenance of hydroelectrolyte balance in response to changes in extracellular volume and osmolality.     

Regulation of hypothalamic corticotropin‐releasing hormone neurone excitability by oxytocin

Oxytocin (OT) is a neuropeptide that exerts multiple actions throughout the brain and periphery. Within the brain, OT regulates diverse neural populations, including neural networks controlling responses to stress. Local release of OT within the paraventricular nucleus (PVN) of the hypothalamus has been suggested to regulate stress responses by modulating the excitability of neighbouring corticotropin‐releasing hormone (CRH) neurones. However, the mechanisms by which OT regulates CRH neurone excitability are unclear. In the present study, we investigated the morphological relationship between OT and CRH neurones and determined the effects of OT on CRH neurone excitability. Morphological analysis revealed that the processes of OT and CRH neurones were highly intermingled within the PVN, possibly allowing for local cell‐to‐cell cross‐talk. Whole‐cell patch‐clamp recordings from CRH neurones were used to study the impact of OT on postsynaptic excitability and synaptic innervation. Bath‐applied OT did not alter CRH neurone holding current, spiking output or any action potential parameters. Recordings of evoked excitatory and inhibitory postsynaptic currents (EPSCs/IPSCs) revealed no net effect of OT on current amplitude; however, subgroups of CRH neurones appeared to respond differentially to OT. Analysis of spontaneous EPSC events uncovered a significant reduction in spontaneous EPSC frequency but no change in spontaneous EPSC amplitude in response to OT. Together, these data demonstrate that OT exerts a subtle modulation of synaptic transmission onto CRH neurones providing one potential mechanism by which OT could suppress CRH neurone excitability and stress axis activity.     

Distribution and morphometric characteristics of oxytocin- and vasopressin-immunoreactive neurons in the rabbit hypothalamus

The distribution, morphological features, and morphometric characteristics of cell bodies producing oxytocin (OT) and vasopressin (AVP) were studied in the rabbit hypothalamus by means of a conventional immunoperoxidase method. The aim of the present study was to determine the existence or not of a species-specific OT-cell group that might be involved in the dense OT innervation of the intermediate lobe in the leporidae. No OT-cell group clearly distinct from the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei was found, even in colchicine-treated animals. Most immunoreactive perikarya were found within these nuclei. In addition, small AVP neurons occurred in the suprachiasmatic nucleus. In the SON, the predominant, tightly packed AVP cells occupied the ventral part of the nucleus, whereas OT neurons were dorsolaterally located. The PVN presented a loose organization without any obvious subdivision. OT cells, which predominated, occupied the medial part of the nucleus. The PVN had a prominent rostral anterobasal extension composed mainly of OT cells. Laterally to the nucleus, numerous large AVP neurons, with few and smaller OT cells, dispersed along the neurosecretory tract without forming definite cell clusters. AVP cell bodies had a rough granular aspect contrasting with the smooth and fine one of OT cells. Spinelike processes were rarely observed on the perikarya, except on large scattered AVP neurons, but frequently covered the proximal dendrites of both types of neurons. Throughout the hypothalamus, OT neurons had definitely smaller mean somal areas and were more homogeneous in size than AVP cells.     

Sequential Exposure to Estrogen and Testosterone (T) and Subsequent Withdrawal of T Increases the Level of Arginine Vasopressin Messenger Ribonucleic Acid in the Hypothalamic Paraventricular Nucleus of the Female Rat

The hypothalamic peptides arginine vasopressin (AVP) and oxytocin (OT) have been implicated as mediators of socio-sexual behaviors in addition to their roles in osmolar homeostasis (AVP), milk ejection and uterine contractility (OT). Within 24  h of parturition, OT and AVP messenger ribonucleic acid (mRNA) levels increase in the hypothalamic paraventricular, and to a lesser degree, the supraoptic nucleus (PVN and SON) of the rat. We previously reported that the prepartum increase in OT mRNA is related to the spontaneous decline in progesterone levels prior to parturition. We also reported that increases in PVN and SON OT mRNA can be induced by exposing the ovariectomized rat to a steroid regimen that mimics the steroid milieu of pregnancy, namely sequential estrogen and progesterone and subsequent progesterone withdrawal. Levels of PVN and SON AVP mRNAs were not affected by progesterone withdrawal in late pregnant rats or the steroid regimen that increased OT mRNA in ovariectomized rats. These observations suggest that other factors, perhaps hormonal, may influence AVP mRNA levels. A decline in testosterone coincident with waning progesterone levels also occurs prepartum. Since peak levels of AVP mRNA prepartum coincide with the prepartum decline in testosterone, we questioned whether declining testosterone levels are important for the increase in AVP mRNA levels.