Ameliorating schizophrenia-like symptoms in vasopressin deficient male Brattleboro rat by chronic antipsychotic treatment.

Due to its various function vasopressin has been associated with many psychiatric disorders, including schizophrenia. Our previous study confirmed that vasopressin-deficient (di/di) Brattleboro rat can be a good genetic model for schizophrenia. Our present aim was to confirm whether the treatment effects of marketed antipsychotics are similar in di/di rats to those seen in human schizophrenic patients. Chronic subcutaneous administration of aripiprazole (5 mg/kg), clozapine (1 mg/kg), haloperidol (0.1 mg/kg), olanzapine (0.3 mg/kg) or risperidone (0.25 mg/kg) was used for 15 days in control (+/+ Brattleboro) and di/di rats. Social discrimination, social avoidance and prepulse inhibition tests were conducted on day 1, 8 and 15 of the treatment. Vasopressin-deficient rats showed social memory- and sensorimotor gating deficit. All used antipsychotics successfully normalized the reduced prepulse inhibition of di/di animals. However, most were effective only after prolonged treatment. Aripiprazole, clozapine, and olanzapine normalized the social memory deficit, while the effects of haloperidol and risperidone were not unequivocal. All drugs reduced social interest to some extent both in control and in di/di animals, aripiprazole being the less implicated in this regard during the social avoidance test. The restoration of schizophrenia-like behavior by antipsychotic treatment further support the utility of the vasopressin-deficient Brattleboro rat as a good preclinical model. Reduced social interest might be a general side-effect of antipsychotics, and aripiprazole has the most favorable profile in this regard.

[Hypothalamic intravascular B-cell lymphoma in an immunocompetent patient]. / Linfoma B intravascular hipotalamico en una paciente inmunocompetente.

TITLE: Linfoma B intravascular hipotalamico en una paciente inmunocompetente.

The genetic basis of parental care evolution in monogamous mice.

Parental care is essential for the survival of mammals, yet the mechanisms underlying its evolution remain largely unknown. Here we show that two sister species of mice, Peromyscus polionotus and Peromyscus maniculatus, have large and heritable differences in parental behaviour. Using quantitative genetics, we identify 12 genomic regions that affect parental care, 8 of which have sex-specific effects, suggesting that parental care can evolve independently in males and females. Furthermore, some regions affect parental care broadly, whereas others affect specific behaviours, such as nest building. Of the genes linked to differences in nest-building behaviour, vasopressin is differentially expressed in the hypothalamus of the two species, with increased levels associated with less nest building. Using pharmacology in Peromyscus and chemogenetics in Mus, we show that vasopressin inhibits nest building but not other parental behaviours. Together, our results indicate that variation in an ancient neuropeptide contributes to interspecific differences in parental care.

Frequent development of combined pituitary hormone deficiency in patients initially diagnosed as isolated growth hormone deficiency: a long term follow-up of patients from a single center.

BACKGROUND: Children initially diagnosed with isolated GH deficiency (IGHD) have a variable rate to progress to combined pituitary hormone deficiency (CPHD) during follow-up. OBJECTIVE: To evaluate the development of CPHD in a group of childhood-onset IGHD followed at a single tertiary center over a long period of time. PATIENTS AND METHODS: We retrospectively analyzed data from 83 patients initially diagnosed as IGHD with a mean follow-up of 15.2 years. The Kaplan-Meier method and Cox regression analysis was used to estimate the temporal progression and to identify risk factors to development of CPHD over time. RESULTS: From 83 patients initially with IGHD, 37 (45%) developed CPHD after a median time of follow up of 5.4 years (range from 1.2 to 21 years). LH and FSH deficiencies were the most common pituitary hormone (38%) deficiencies developed followed by TSH (31%), ACTH (12%) and ADH deficiency (5%). ADH deficiency (3.1 ± 1 years from GHD diagnosis) presented earlier and ACTH deficiency (9.3 ± 3.5 years) presented later during follow up compared to LH/FSH (8.3 ± 4 years) and TSH (7.5 ± 5.6 years) deficiencies. In a Cox regression model, pituitary stalk abnormalities was the strongest risk factor for the development of CPHD (hazard ratio of 3.28; p = 0.002). CONCLUSION: Our study indicated a high frequency of development of CPHD in patients initially diagnosed as IGHD at childhood. Half of our patients with IGHD developed the second hormone deficiency after 5 years of diagnosis, reinforcing the need for lifelong monitoring of pituitary function in these patients.

The α2-adrenoceptors do not modify the activity of tyrosine hydroxylase, corticoliberine, and neuropeptide Y producing hypothalamic magnocellular neurons ion the Long Evans and Brattleboro rats.

The hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei are activated by body salt-fluid variations. Stimulation of alpha(2)-adrenoceptors by an agonist-xylazine (XYL) activates oxytocinergic but not vasopressinergic magnocellular neurons. In this study, tyrosine hydroxylase (TH), corticoliberine (CRH), and neuropeptide Y(NPY) magnocellular phenotypes, were analysed in response to alpha(2)-adrenoceptor manipulations and sustained hyperosmolality in vasopressin deficient homozygous Brattleboro (di/di) rats. Saline (0.9% NaCl, 0.1 ml/100g/bw), XYL (10 mg/kg/bw), atipamezole (ATIP, alpha(2)-adrenoceptors antagonist, 1 mg/kg/bw), and ATIP 5 min later followed by XYL, were applied intraperitoneally. Presence of immunolabeled Fos peptide signalized the neuronal activity. Ninety minutes after injections, the rats were anesthesized and sacrificed by transcardial perfusion with fixative. Coronal sections of 30 mum thickness double immunolabeled with Fos/neuropeptide were evaluated under light microscope. Under basal conditions, di/di in comparison with control Long Evans rats, displayed significantly higher number of TH, CRH, and NPY immunoreactive neurons in the SON and PVN (except NPY cells in PVN) and more than 90%, 75%, and 86% of TH, NPY, and CRH neurons, respectively, displayed also Fos signal in the SON. XYL did not further increase the number of Fos in the PVN and SON and ATIP failed to reduce the stimulatory effect of hypertonic saline in all neuronal phenotypes studied. Our data indicate that hyperosmotic conditions significantly influence the activity of TH, CRH, and NPY magnocellular neuronal phenotypes, but alpha(2)-adrenoceptors do not play substantial role in their regulation during osmotic challenge induced by AVP deficiency.

Central diabetes insipidus due to cytomegalovirus infection of the hypothalamus in a patient with acquired immunodeficiency syndrome: a clinical, pathological, and immunohistochemical case study.

We report a case of central diabetes insipidus (CDI) in a patient with AIDS due to cytomegalovirus (CMV) infection of the vasopressin-producing areas of the hypothalamus. The clinical diagnosis is established by definitive clinical and laboratory evidence of CDI. Detailed histopathological and immunohistochemical studies establish CMV as the causative agent and demonstrate the deficit of vasopressin in the synthesizing neurons. Physicians caring for patients with AIDS should be aware of CDI and adipsic hypernatremia as potential complications of CMV infection. The case also demonstrates that patients with diabetes insipidus do not have polyuria when glucocorticoid deficiency coexists.

Attenuation of the polypeptide 7B2, prohormone convertase PC2, and vasopressin in the hypothalamus of some Prader-Willi patients: indications for a processing defect.

7B2 is a neuroendocrine chaperone interacting with the prohormone convertase PC2 in the regulated secretory pathway. Its gene is located near the Prader-Willi syndrome (PWS) region on chromosome 15. In a previous study we were able to show 7B2 immunoreactivity in the supraoptic nucleus (SON) or the paraventricular nucleus (PVN) in only three of five PWS patients. Here we report that in contrast with five other PWS patients, the neurons in the hypothalamic SON and PVN of the two 7B2-immunonegative PWS patients also failed to show any reaction using two antibodies directed against processed vasopressin (VP). On the other hand, even these two cases reacted normally with five antibodies that recognize different parts of the VP precursor. This finding pointed to a processing defect. Indeed, the same patients had no PC2 immunoreactivity in the SON or PVN, whereas PC1 immunoreactivity was only slightly diminished. In conclusion, in the VP neurons of two PWS patients, greatly reduced amounts of 7B2 and PC2 are present, resulting in diminished VP precursor processing.

Idiopathic hypothalamic diabetes insipidus, pituitary stalk thickening, and the occult intracranial germinoma in children and adolescents.

We report nine consecutive children and adolescents [five females and four males; aged 2 yr 8 months (m) to 18 yr 1 m] studied over the last 5 yr with idiopathic central diabetes insipidus. In addition to vasopressin deficiency, anterior pituitary hormone deficiencies were detected, either on evaluation at presentation or during follow-up studies over the following 3 yr. Four patients had an increased concentration of plasma PRL. One patient had multiple pituitary hormone deficiencies at diagnosis, and two others developed the same by 21 m of follow-up. Brain magnestic resonance imaging scans, performed at presentation, were originally interpreted as normal in four of nine patients, except for absence of the bright posterior pituitary signal; after retrospective review, two of nine were considered normal. All of the brain magnetic resonance imaging (MRI) scans showed positive findings by 14 m of follow-up. The first abnormal finding in all patients was isolated pituitary stalk thickening. Evaluation of cerebrospinal fluid (CSF) for hCG was positive in three of eight evaluated patients; the three positive CSF values were found at presentation and 3 and 9 m after presentation. All eight patients assessed were negative for CSF alpha-fetoprotein and cytology, and no patient had serum tumor markers. Transsphenoidal biopsy of the lesion in seven of nine patients showed a germinoma in six patients and inflammatory cells in one. The six patients with documented germinoma comprise 31% of the intracranial germinomas diagnosed in this age group at the University of California-San Francisco during the last 5 yr. The patient with mononuclear inflammatory cells on biopsy along with one other patient have had spontaneous resolution of their stalk thickening. So-called "idiopathic" central diabetes insipidus warrants close follow-up to determine the etiology, especially if anterior pituitary hormone deficiencies are detected. Normal brain MRI scans or scans that show isolated pituitary stalk thickening merit follow-up with serial contrast enhanced brain MRI for the early detection of an evolving occult hypothalamic-stalk lesion. CSF evaluation is recommended at presentation because elevated CSF hCG may precede MRI abnormalities.

Cathepsin L immunoreactivity in the hypothalamus of normal, streptozotocin-diabetic and vasopressin-deficient Brattleboro rats.

The immunolocalization of cathepsin L in the hypothalamus of normal rats was compared with the distribution of the enzyme in streptozotocin-treated animals and in vasopressin-deficient rats (Brattleboro strain). In rats with a normal metabolic status the neurons of magnocellular nucl. supraopticus and paraventricularis stood out by intense immunostaining for cathepsin L. In rats suffering from an experimentally induced diabetes mellitus and in homozygous Brattleboro rats we observed a strong reduction in enzyme immunoreactivity in these nuclei. Since cathepsin L is capable of splitting certain hypothalamic neuropeptides that are changed in diabetic animals, a role of the enzyme in the metabolism of these peptides is imaginable. Decrease in immunoreactive cathepsin L in vasopressin-deficient rats points to a possible involvement of the enzyme in the control of fluid homeostasis.

Ultrastructure of hypothalamic paraventricular neurons.

The hypothalamic paraventricular nucleus (PVN) plays a pivotal role in the regulation of endocrine processes and the modulation of autonomic functions. The multi-channel outputs of the nucleus are directed toward the anterior and posterior lobes of the pituitary, autonomic centers, and limbic structures. Counterbalancing the wide spectrum of efferent projections, the nucleus receives humoral signals from endocrine glands and neuronal afferents from several loci of the brain. The multiple functions of the nucleus are executed by neurons that are organized in distinct subnuclei and display complex chemotypes. The review demonstrates and discusses the organization, architecture, chemical composition, plasticity, and pathology of paraventricular neurons of the rat hypothalamus from the perspective of ultrastructural analysis. Electron microscopy--by its high resolution--offers a powerful tool that is suitable for revealing the structural background of physiological processes that modulate and govern the operation of paraventricular neurons.

Complete dissociation of DOCA-salt hypertension and red cell ion transport alterations.

Our previous study revealed major ion transport alterations that resulted in a pronounced elevation of red cell Na+ content in DOCA-salt treated homozygous vasopressin-deficient (DI) Brattleboro rats in which only a moderate increase of systolic blood pressure occurred. In contrast, no changes of red cell Na+ content were observed in heterozygous vasopressin-secreting (non-DI) Brattleboro rats with a severe DOCA-salt hypertension. Using a chronic supplementation of DI rats with an antidiuretic agonist dDAVP (1-desamino-8-D-arginine vasopressin) we did not demonstrate any significant changes of red cell ion transport in dDAVP-treated DI rats with a fully developed DOCA-salt hypertension. The absence of ion transport alterations seems to be mainly due to dDAVP-induced correction of altered K+ metabolism seen in DOCA-salt treated DI animals. It can be concluded that DOCA-salt hypertension can develop even without red cell ion transport alterations which are usually caused by cell K+ depletion.

Effect of surgical deafferentation of the hypothalamic supraoptic nucleus on urinary vasopressin levels in twenty-month-old rats.

Indices of water balance (daily water consumption, urine volume, and urine osmolality), and vasopressin (VP) urinary excretion were measured in 3-month-old (m.o.) and 20 m.o. F344 rats after neurosurgical lesion of noradrenergic afferents to the supraoptic nucleus (SON) in the medial forebrain bundle (mfb), in order to assess whether morphological denervation (21) was functionally effective. Lesion of the mfb was accomplished using a mechanical knife cut placed stereotaxically medial and caudal to SON. The experiment was performed three times. Morphological evaluation consistently indicated a marked depletion of noradrenergic afferents in SON after lesion placement. The effect of the lesion on daily excreted VP was assessed by paired t-test, using means of equal numbers of urinary VP measurements representing 13-15 days each pre- and postsurgically for each animal. The postsurgical interval for assessing the functional effect of the lesion was chosen based upon morphological evidence for mfb regeneration at 14 days (21). Three m.o. rats showed comparable urinary VP levels before (mean = 328.4 +/- 97.3 pg/24 hr/100 g b.wt., for 10 rats for 2 weeks) and after (354.7 +/- 63.0 pg/24 hr/100 g b.wt.) lesion placement. In 20 m.o. rats, overall mean postsurgical VP excretion was 199.4 +/- 44.8 pg for 15 rats for 2 weeks, compared with a presurgical mean of 343.2 +/- 86.2 pg/24 hr/100 g b.wt. Mean urine VP was lower in 20 m.o. rats in each of three experiments; VP levels after lesion in 3 m.o. rats was lower in 2, but higher in one experiment; mean differences were not statistically significant for treatment (lesion) effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of vasopressin increases hypothalamic atrial natriuretic peptide binding sites.

Atrial natriuretic peptide (ANP) binding sites were measured by quantitative autoradiography in the supraoptic and paraventricular nuclei and in the subfornical organ of hypophysectomized, adrenalectomized, and genetically vasopressin-deficient (Brattleboro) rats. Hypophysectomized and Brattleboro rats had significantly higher numbers of ANP binding sites in the supraoptic nucleus and in the magnocellular subdivision of the paraventricular nucleus than their respective controls. ANP binding density was also increased in the parvocellular subdivision of the paraventricular nucleus in hypophysectomized rats and in the subfornical organ of homozygous Brattleboro rats. When homozygous Brattleboro rats were treated with vasopressin, the density of ANP binding sites was restored to control level in the subfornical organ but not in the supraoptic or paraventricular nuclei. Adrenalectomy did not influence ANP binding in the brain areas studied. Increased ANP binding density in Brattleboro rats and after hypophysectomy in the nuclei in which vasopressin neurons are located suggest that ANP binding sites may represent physiologically active receptors and may mediate the inhibitory action of ANP on vasopressin secretion.

Atrial natriuretic peptide in plasma, atria, ventricles, and hypothalamus of Long-Evans and vasopressin-deficient Brattleboro rats.

To evaluate the role of vasopressin in the regulation of atrial natriuretic peptide (ANP) secretion, the plasma, atrial, ventricular, and hypothalamic levels of ANP were measured in Long-Evans (LE) and vasopressin-deficient Brattleboro (DI) rats. Total atrial immunoreactive ANP (IR-ANP) as well as right auricular IR-ANP concentration were higher in the DI than in the LE rats, whereas no significant difference was noted in left auricular IR-ANP concentration. In the left ventricle of DI rats, the IR-ANP concentration was 82% greater than that in the LE rats, while no substantial difference was found in the right ventricular IR-ANP concentration between the strains. Normal LE rats had low levels of left ventricular ANP mRNA and barely detectable ANP mRNA in the right ventricle, DI rats showed a 3-fold greater ANP mRNA concentration in the left ventricle than age-matched LE controls, and ANP mRNA levels were also increased in the left auricle of DI rats. The hypothalamic IR-ANP content, but not the concentration, was significantly increased in the DI compared to the LE rats. Despite increased cardiac IR-ANP and ANP mRNA levels, plasma IR-ANP concentrations were similar in the conscious DI rats (97 +/- 9 pg/ml; n = 13) and the LE rats (95 +/- 8 pg/ml; n = 15). Volume expansion (1.1 ml/100 g BW of 0.9% saline, iv) increased right atrial pressure and caused a significant rise in plasma IR-ANP in both strains (P less than 0.01). Elevations of plasma IR-ANP concentrations caused by volume loading were comparable in LE and DI rats in either the absence or presence of exogenous vasopressin (5 ng/kg.min, iv), which, when infused alone, did not significantly influence the plasma IR-ANP concentration. However, the relation between the change in IR-ANP concentration and the change in right atrial pressure shifted to the left, and thus, for a given increase in right atrial pressure, a greater amount of IR-ANP was released in the vasopressin-treated rats than in the control animals. These results demonstrate that although acute volume expansion does not necessarily require endogenous vasopressin for the ANP secretory response, vasopressin increased the ability of volume expansion to induce ANP release, thus modulating the direct mechanical stimulus-induced ANP secretion. The increased left ventricular levels of immunoreactive ANP and augmentation of ANP mRNA levels in Brattleboro rats despite normal left ventricular weight to body weight ratio show that increased ANP gene expression may occur in the ventricles independently of hypertrophy.

Phospholipid and glycolipid synthesis in brain structures of Brattleboro rats.

The incorporation of labeled precursors in phospholipids and glycolipids was studied in discrete brain areas of rats with innate vasopressin deficiency (Brattleboro, DI) and intact Long Evans animals (LE). Tracer incorporation was found to be reduced in septal, hypothalamic and hippocampal phospholipids, but enhanced in the glycolipid fraction isolated from the hypothalamus and hippocampus of Brattleboro rats. The results indicate that inherited vasopressin deficit seems to be associated with altered lipid synthesis in some brain areas of the Brattleboro rat, suggesting a probability for impaired translation of chemical signals.

Radioautographic study of glycoprotein synthesis and fate in the hypothalamo-neurohypophyseal system of vasopressin-deficient Brattleboro rats.

L-3H-fucose was injected into the lateral cerebral ventricle of vasopressin-deficient Brattleboro and control Long-Evans rats which were subsequently killed at several time intervals after the injection. The hypothalamus and the neurohypophysis were processed for light- and electronmicroscopic radioautography. Other complementary experiments using immunocytochemical and enzyme-histochemical techniques were also undertaken. L-3H-fucose was incorporated into newly synthesized glycoproteins in the Golgi apparatus of supraoptic and paraventricular neurons, and later on labelled glycoproteins migrated to lysosomes and the plasma membrane surrounding the perikaryon. The Golgi apparatus of the vasopressin-deficient neurons remained heavily labelled as long as 3 days after injection, in sharp contrast with the normal neurons in which there was a remarkable decrease of label in the Golgi region between 4 and 24 h after the isotope administration. Labelled glycoproteins also migrated to the neurohypophysis and were mainly found in the axonal plasma membrane, vesicles and axoplasm. The renewal of glycoproteins in the neurohypophysis of Brattleboro rats was faster than in the normal rats and this was attributed to the lack of formation of products which are normally packaged in secretory granules in the perikaryon and released at the axon terminal in the neurohypophysis. Colchicine caused a disturbance in the topography of the organelles of the perikaryon and the most striking features were the displacement of Golgi stacks to the periphery of the perikaryon and an accumulation of mitochondria in this neuronal region. No secretory granules were observed in the vasopressin-deficient neurons of untreated or colchicine-treated Brattleboro rats. By contrast, secretory granules (most of them labelled with 3H-fucose) were concentrated in the perikaryon of colchicine-treated Long-Evans rats. In these rats, colchicine caused a severe block in the migration of 3H-fucose-labelled glycoproteins to the neurohypophysis, but this did not occur in the Brattleboro rats. The results of the experiments were interpreted in the light of the genetic defect known to occur in Brattleboro rats which causes the inability to produce vasopressin and also remarkable morphological and physiological changes in the affected neurons.

The content of vasopressin and oxytocin in the hypothalamus and neurohypophysis of pinealectomized male rats.

The content of vasopressin in the neurohypophysis as well as the content of oxytocin in both hypothalamus and neurohypophysis were found to decrease considerably 8 weeks following pinealectomy in male rats. It may be, therefore, concluded that the pineal body is in some way involved in the regulatory mechanisms for vasopressinergic and oxytocinergic neurons.

Supraoptic nucleus of the Brattleboro rat has an altered afferent noradrenergic input.

The distribution of fluorescent varicosities in the supraoptic nucleus of Brattleboro rats was compared to that in normal rats. The Brattleboro rat, which is characterized by a genetic absence of vasopressin, had fewer fluorescent varicosities in apposition to the vasopressin-deficient perikarya. The oxytocin-producing neurons in the same nucleus were hyperinnervated. These data suggest that the target neuron peptide (vasopressin) is necessary for the maintenance of normal noradrenergic innervation patterns.