Homozygous Diabetes Insipidus Rats Research Articles

Influence of oxytocin on renal hemodynamics and sodium excretion.

Acute administration of physiological doses of synthetic OT to conscious Long-Evans and Brattleboro homozygous diabetes insipidus rats produced a modest increase in GFR and effective filtration fraction. Chronic administration of OT to DI rats for 9 days in dosages that were antidiuretic (plasma OT ca. 100 pg/ml) increased both GFR and ERPF by 40%. Table 1 summarizes these renal hemodynamic changes and compares them to the renal effects of VP. Further investigation is needed to define the mechanisms responsible for the changes in GFR and/or ERPF produced by acute and chronic administration of OT to conscious rats. Acute administration of physiological doses of synthetic OT to conscious LE and DI rats also produced a brisk natriuresis with a marked increase in the fractional excretion of sodium. A natriuresis was also observed in conscious Sprague-Dawley rats administered physiological amounts of OT by subcutaneous osmotic minipump. The natriuretic effect of the hormone was short lived, however, being observed only during the first 24-hr period of treatment. The nephron site where OT exerts its natriuretic action, either directly or indirectly, is unknown. Renal prostaglandins may contribute to OT-induced natriuresis, but other mechanisms such as increased renal production of nitric oxide and cGMP have not been tested. Although the natriuretic response to OT has also been described for conscious dogs, it probably does not occur in humans and nonhuman primates. Precise localization of specific renal OT receptors has recently been reported for the rat. OT receptors were identified in the macula densa cells of the adult, rat kidney. This location suggests a possible role for OT in the regulation of tubuloglomerular feedback and solute transport. The signal transduction of the renal OT receptor has been recently evaluated in various kidney epithelial cells in culture. OT stimulates phosphoinositide hydrolysis and increases cytosolic calcium concentrations. In fact, VP produces similar cellular responses in renal epithelia, possibly through the OT receptor. Also, OT stimulates soluble guanylate cyclase and increases intracellular cGMP. Whether OT activates soluble guanylate cyclase secondarily through the production of nitric oxide has not been tested. An important role for OT in renal sodium homeostasis under basal conditions is likely, at least for the rat. Moreover, OT possibly mediates dehydration natriuresis in lower animal species. The contribution of OT to renal physiology in humans and in nonhuman primates, if any, remains uncertain.

Regulation of hypothalamic magnocellular neuropeptides and their mRNAs in the Brattleboro rat: coordinate responses to further osmotic challenge

A paradigm was developed for the chronic osmotic stimulation of homozygous diabetes insipidus rats of the Brattleboro strain, a strain that fails to synthesize vasopressin. This study examines the adaptation of 2 sets of coexisting peptide hormone magnocellular neurons in the hypothalamoneurohypophyseal system (HNS) of Long Evans (LE), Brattleboro heterozygote (HZ), and Brattleboro homozygote (DI) rats: (1) the arginine8-vasopressin (AVP)/dynorphin (DYN) neurons, and (2) the oxytocin (OT)/cholecystokinin (CCK8) neurons of the paraventricular and supraoptic nuclei, which project to the posterior pituitary. The regimen of chronic intermittent salt-loading (CISL) involved the replacement of 2% saline for normal drinking water for 18 hr/d. This protocol effectively increased plasma levels of AVP and OT in LE and HZ rats, oxytocin in DI rats, and maintained the posterior pituitary in a state depleted of AVP, OT, CCK, and peptides derived from pro-dynorphin: DYN A 1-17, DYN A 1-8, and DYN B 1-13. The ratio of pituitary DYN A 1-17 to DYN A 1-8 content in DI rats or in LE, HZ, and DI rats following 6 d of CISL suggests a preferential release of DYN A 1-17 during periods of chronic secretory activity. In response to chronic secretory activity, mRNAs for AVP, OT, DYN, and CCK increased 1.5-2-fold in all 3 AVP rat strains, with mRNAs for coexisting peptide hormones displaying parallel increases. Mutant AVP mRNA in the DI rat was expressed at very low levels and DYN mRNA in very high levels, with each of these mRNAs continuing to be regulated by CISL in a normal manner. These results suggest a regulatory relationship between AVP and OT neurons, in which vasopressin neurons are feedback-regulated by AVP, most likely via plasma osmolarity, and that oxytocin neurons are modulated by peptides derived from pro-dynorphin.

Hyperprolactinaemia alleviates behavioral alterations of rats with hereditary hypothalamic diabetes insipidus (Brattleboro strain)

Male rats homozygous for hereditary hypothalamic diabetes insipidus (HO) and their heterozygous (HE) and normal (NO) variants (Brattleboro rats) were made hyperprolactinaemic by homografting two adenopituitaries under the kidney capsule. The high water intake and urine output of homozygous diabetic sham-operated rats (sham-HO) were similar to those of homografted HO animals. Also, hyperprolactinaemia failed to change the water intake and urine output of HE and NO rats, as compared to those of heterozygous (sham-HE) and normal (sham-NO) sham-operated animals. Compared to sham-HE and sham-NO animals, sham-HO rats showed a slow acquisition of active avoidance responses, a facilitated extinction of a pole jumping avoidance behavior and a reduced retention of a passive avoidance response. However, an improved performance of acquisition and retention behaviors up to the level of sham-HEs and sham-NOs was observed in homografted HO rats. Hyperprolactinaemia resulted in a reduced responsiveness to electrical footshock in HO, HE and NO animals, and in facilitated acquisition of active avoidance responses in HE and NO rats, but it failed to affect avoidance extinction and retention in the latter variants. These results suggest that the behavioral alterations shown by homozygous diabetes insipidus rats are alleviated by hyperprolactinaemia although high levels of plasma prolactin do not interfere with the mechanisms regulating water intake and urine output. In addition, hyperprolactinaemia affects the behavior of heterozygous and normal variants of Brattleboro strain but in a selective way.

Vasopressin and oxytocin. Their presence in the central nervous system and their functional significance in brain processes related to behaviour and memory.

Vasopressin and oxytocin exert pronounced effects on behaviour by a direct action on the brain. A single injection of vasopressin results in a long-term inhibition of extinction of a conditioned avoidance response suggesting that vasopressin triggers a long-term effect on the maintenance of a learned response, probably by facilitation of memory processes. In addition vasopressin improves passive avoidance behaviour, delays extinction of appetitive discrimination tasks, affects approach behaviour to an imprinting stimulus in ducklings, improves copulation rewarded behaviour of male rats in a T-maze, prevents or reverses amnesia induced by electroconvulsive shock, CO2 inhalation, pentylenetetrazol or puromycin. The majority of these effects of vasopressin in the various and sometimes relatively complex tasks may be explained by stimulatory influences of this neuropeptide on memory processes. Generally oxytocin exerts effects which are opposite to those of vasopressin and it has been suggested that oxytocin may be an amnesic neuropeptide. Various limbic system structures seem to act as the anatomical substrate for the behavioural effects of vasopressin. In particular the amygdala, the dentate gyrus of the hippocampal complex, the ventral hippocampus and the dorsal septum seem to be involved. Evidence has been obtained from experiments with homozygous diabetes insipidus rats and from experiments in which antisera were applied that endogenous vasopressin and oxytocin play a physiological role in brain processes related to memory. It appears that highly active fragments can be generated from vasopressin and experiments in which a fragment of vasopressin ([pGlu4, Cyt6]AVP-(4-8)) as well as an AVP-antagonist were used, reveal that the vasopressin receptors mediating the behavioural effects are situated in the brain and differ in specificity from the peripheral (blood pressure) vasopressin receptors. Generally the clinical data obtained so far with vasopressin treatment are in agreement with the results from animal experiments and they support the notion on the involvement of vasopressin in memory function. The sometimes reported conflicting results on vasopressin effects in certain patients (Korsakoff or Alzheimer) may have to do with the wide-spread pathology in these diseases.

Relative importance of sympathetic nerves and of circulating adrenaline and vasopressin in mediating hypertension after lesions of the caudal ventrolateral medulla in the rat.

Electrolytic lesions of the A1 noradrenaline cells in the caudal ventrolateral medulla cause transient hypertension and bradycardia in the conscious rat, as previously described in the rabbit. The lesions produced 100-fold increases in plasma arginine vasopressin, 40-fold increases in plasma adrenaline and fourfold increases in plasma noradrenaline levels. Absence of circulating vasopressin [homozygous diabetes insipidus rats (DI)] or circulating adrenaline (adrenalectomized rats) did not affect A1 hypertension, but sympathectomy with systemic 6-hydroxydopamine (6-OHDA) significantly attenuated A1 hypertension. A factorial experiment was performed to assess the relative contributions of these three peripheral effector mechanisms in a quantitative manner, with combined deficiencies of any two or of all three of these effector systems. Results suggest A1 hypertension in the rat to be primarily mediated through increased sympatho-adrenal activity. The largest component of hypertension (66%) results from increased sympathetic vasoconstrictor nerve activity, and a smaller part (34%) reflects the action of circulating adrenaline. Increases in vasopressin levels do not contribute to A1 hypertension, although vasopressin makes a major contribution to A1 lesion bradycardia.

Brattleboro rats display increased sensitivity to arginine vasopressin-induced motor disturbances

Motor disturbances observed in Brattleboro rats (homozygous for the diabetes insipidus (DI) trait) following a first intracerebro-ventricular injection of 1.0 μg of arginine vasopressin (AVP) were not significantly different from those of the parent Long-Evans (LE) strain. These disturbances consisted of periods of staring and immobility, locomotor difficulties and discrete myoclonic jerks, often followed by scratching behavior. Following a second central injection of 10.0 ng AVP, however, the DI strain exhibited more pronounced motor disturbances than the LE strain. This increased sensitivity of the DI strain to the behavioral actions of AVP does not appear to be due to a generalized decrease of seizure threshold, since no significant differences were observed between the two strains in their susceptibility to convulse following pentylenetetrazol. As the behavioral and motor effects of AVP appear to be receptor-mediated, these findings suggest that homozygous DI rats possess central AVP receptors, which, in the absence of endogenous vasopressin, may have increased sensitivity to a second central injection of AVP.

Radioimmunoassays for individual rat neurophysins.

Radioimmunoassays are described for vasopressin-associated rat neurophysin (VP-RNP), oxytocin-associated rat neurophysin (OT-RNP) and a major metabolic derivative of oxytocin-associated rat neurophysin (OT-RNP′). The cross-reactions in the radioimmunoassay for VP-RNP with preparations of OT-RNP and OT-RNP′ were 4 and 2%. However, the very small values found for VP-RNP using this radioimmunoassay in concentrated extracts of neural lobes from rats homozygous for the condition of hypothalamic diabetes insipidus (DI) indicate that the sum of the cross-reactions of OT-RNP and OT-RNP′ in the assay is <0·02%. The radioimmunoassay for OT-RNP showed a 100% cross-reaction with OT-RNP′ and a 4% cross-reaction with VP-RNP, while cross-reactions in the radioimmunoassay for OT-RNP′ with OT-RNP and VP-RNP were 17 and 3%. All three radioimmunoassays had a range of measurement from 20 to 1280 pg protein (2–132 fmol). The radioimmunoassays for VP-RNP and OT-RNP were used to measure neurophysin levels in the neural lobes and serum of Long–Evans rats and rats homozygous and heterozygous for DI. Neurophysin values in neural lobes were compared with values for oxytocin and vasopressin obtained by radioimmunoassay. On a molar basis the storage levels of vasopressin in Long–Evans rats were similar to those of VP-RNP; oxytocin levels were similar to the levels of total OT-RNP (OT-RNP + OT-RNP′). The storage levels in oxytocinergic and vasopressinergic neurones were similar. Total OT-RNP and oxytocin levels were similar in homozygous DI rats, while vasopressin and VP-RNP in these animals were <0·013 and <0·1% of the oxytocin and OT-RNP levels respectively. Long–Evans rats given 2% NaC1 for 96 h had drastically reduced storage of all four neurohypophysial peptides, but there was no significant change in their subcellular distribution when compared with control animals. This is taken as evidence that the readily releasable pool is not extragranular. Oxytocin and total OT-RNP were reduced to about 50% by depriving homozygous DI rats of water for 24 h. The storage levels of oxytocin and OT-RNP in female homozygous DI rats were twice those of their male counterparts. Normal serum values of VP-RNP and OT-RNP were 221±41 and 312±43 ng/l for males, and 280 ± 40 and 462±116 ng/l for females. Heterozygous DI rats (all female) had serum values of 165 ± 5 ng VP-RNP/1 and 1130±136 ng OT-RNP/1. In the serum of homozygous DI rats VP-RNP levels were below detectable limits; OT-RNP levels of rats with free access to water were 442± 37 ng/l for males and 959 ± 121 ng/l for females. These values are approximately twice those in Long–Evans rats. In water-deprived homozygous DI rats values of OT-RNP were increased threefold to 1202± 87 ng/l in males and twofold to 1822± 259 ng/l in females. Data indicate that female DI rats have twice the production/release rate of OT-RNP as males.

Antidiuretic activity and immunoreactive arginin-vasopressin levels in eye plexus blood during passive avoidance behavior in rats

Experiments were designed to investigate the release of endogenous vasopressin (AVP) as related to passive avoidance behavior and the significance of circulating AVP levels for memory processes using a radioimmunoassay (RIA) and bioassay (AD activity). The levels in plasma obtained from eye plexus blood were very high. A good correlation was found between AD activity and immunoreactive AVP (y = 21.10 + 3.00x, r = 0.895, n = 59). Vasopressin levels in eye plexus blood of male rats were significantly higher than in female rats. The rate of AVP release in Wistar and Brattleboro homozygous normal rats at the 24 h retention test was related to the intensity of the electric footshock during the learning trial and the avoidance latency at the 24 h retention test. The release of AVP immediately after the learning trial was much higher than after the 24 h retention test. Blood levels were not different whether rats received electric footshock or not and were not related to the intensity of the aversive stimulus or to passive avoidance latencies at the 24 h retention test. Brattleboro homozygous diabetes insipidus rats, which had no detectable vasopressin levels in eye plexus blood failed to show passive avoidance behavior even after exposure to high shock intensity. Rats heterozygous for diabetes insipidus exhibited maximal avoidance when a high shock intensity was used. Plasma AVP levels of these rats were however not different from those measured in non-shocked rats either after the learning trial or the 24 h retention test. Passive avoidance behavior was markedly attenuated in male Wistar rats treated with AVP antiserum icv either before the learning trial or the 24 h retention test. This treatment prevented AVP release at the retention trial but not after the learning trial. These results suggest that the long term memory effect originates from AVP of central origin.

Oxytocin action: lipid metabolism in adipocytes from homozygous diabetes insipidus rats (Brattleboro strain).

Oxytocin, like insulin, stimulates glucose oxidation in normal rat adipocytes. Fat cells from homozygous Brattleboro rats that exhibit diabetes insipidus (HoDI animals) and that have a normal number of oxytocin receptors, however, are unable to respond to oxytocin in terms of glucose oxidation. We now report that in adipocytes from HoDI animals that are responsive to insulin, oxytocin was also unable to stimulate lipogenesis. In contrast, oxytocin like insulin was able to inhibit epinephrine-stimulated lipolysis in adipocytes from HoDI animals. Thus, in HoDI adipocytes, the results indicate that the receptor-effector system is only partially defective.

Vasopressin-related peptides increase the hippocampal corticosterone receptor capacity of diabetes insipidus (Brattleboro) rats.

The binding of [3H]corticosterone to receptors in cytosol of several brain regions and of [3H]dexamethasone to receptors in pituitary cytosol was measured after chronic treatment of homozygous diabetes insipidus rats (Ho-Di) with various neuropeptides. All rats were adrenalectomized 24 h before sacrifice for depletion of endogenous adrenal hormones and at that time administration of the peptides was discontinued. At sacrifice the rats were perfused with saline to remove plasma transcortin from the tissues. The apparent maximal binding capacity for corticosterone and dexamethasone was significantly lower in hippocampus and anterior pituitary (36.8% and 39.2%, respectively) of Ho-Di rats than of homozygous nondiabetic rats (Ho-No) of the same strain. In contrast, the neurointermediate pituitary lobe of Ho-Di rats had more than twice as many (211%) binding sites, whereas neither receptor capacity in hypothalamus and septum nor plasma transcortin in these rats were significantly different from those in Ho-No rats. Treatment of Ho-Di rats with arginine-vasopressin, des-glycinamide arginine vasopressin, or 1-desamino-8-D-arginine-vasopressin daily for 1 week resulted in an elevation of receptor capacity in hippocampus and anterior pituitary near the level observed in nondiabetic controls. No effects on the other brain regions, the neurointermediate pituitary lobe, and on plasma transcortin were observed with these peptide treatments. Administration of oxytocin and ACTH-(4-10) did not affect receptor binding. It is concluded that in the Ho-Di Brattleboro rat the glucocorticoid receptor system in the hippocampus and in the anterior pituitary is selectively affected by neuropeptides related to vasopressin.

Deoxycorticosterone acetate-induced renin suppression in the absence of antidiuretic hormone.

AbstractSprague-Dawley rats and Brattleboro rats homozygous and heterozygous for hereditary diabetes insipidus were treated with deoxycorticosterone acetate (DOCA; 100 mg/kg) for periods of up to 2 weeks and the activities of renin in plasma (PRA) and kidney tissue (RRA) were measured. PRA decreased dramatically in all groups within 4 days of DOCA treatment, suggesting that the presence of antidiuretic hormone (ADH) is not necessary for DOCA-induced renin suppression. After 11 and 14 days of treatment, PRA was suppressed less in the homozygous diabetes insipidus rats than in the other two groups, suggesting that the lack of ADH alters the response of PRA to DOCA treatment in the chronic state. RRA was not changed by DOCA treatment in any group, thus demonstrating that the initial response of the renin-angiotensin system to DOCA treatment is a suppression of secretion. These results suggest that the initial response of the renin-angiotensin system to DOCA is not dependent on the presence of ADH.

The renin and isorenin-angiotensin system in rats with hereditary hypothalamic diabetes insipidus

It is known that the active end product of the renin-angiotensin system, angiotensin II, will stimulate ADH release in the brain and corticosteroid release from the adrenal gland and it is possible that isorenin-angiotensin systems present in those tissues are important control mechanisms for that release. In these experiments plasma renin and adrenal gland and brain isorenin concentration (ISO-RC) measurements were made in rats of the Brattleboro strain with hereditary hypothalamic diabetes insipidus (DI) both with and without ADH substitution. Heterozygous DI rats have low storage levels of ADH but can maintain normal water balance. These animals had normal plasma renin concentrations and increased ISO-RC in the hypothalamus and neurohypophysis compared to Long-Evans control rats. Substitution with 100 mU ADH/day, given subcutaneously, decreased ISO-RC in both hypothalamic and neurohypophyseal tissues of heterozygous DI to control levels. In comparison with Long-Evans control rats, higher plasma renin concentrations and increased ISO-RC were found in adrenal gland and brain hypothalamus tissue of homozygous DI rats while no differences were observed in frontal cortex, medulla oblongata or choroid plexus. Substitution of homozygous DI rats with 100 mU ADH/day decreased plasma renin concentration but resulted in no correction of adrenal gland or brain ISO-RC. These results suggest the plasma renin-angiotensin system is altered by changes in fluid balance in the DI rat which can be corrected by ADH substitution. Changes in tissue ISO-RC in DI compared to controls are not related to fluid balance but may be correlated with brain ADH content.

Neuroanatomical studies on corticotropin releasing factor (CRF)

The outer layer of the median eminence of various vertebrates contains lightmicroscopically visible granules which in histological sections can be stained by the so-called Gomori-method or its modifications (Bock et al., 1976). In rats it has been shown that there is a relationship between the amount of these "Gomori-positive" granules and the activity of the hypothalamo-adrenocortical axis. Whereas in the normal rat the number of the granules is very small, it increases strongly after adrenalectomy (Arko et ai.,1963), hypophysectomy (Bock and Forstner, 1969) or during chronic pantothenic acid deficiency (Pietrzik et al., 1974). However, no significant changes in the amount of the granules have been observed after thyroidectomy or castration (Arko et al., 1963). The augmentation of the granules following adrenalectomy can be blocked dose-dependently (Bock, 1972) by various corticoids according to their ACTH-suppressing potency (Brinkmann and Bock, 1973), if the administration of the substances is begun on the day of operation. Treatment with corticoids from the 15th to the 21st day after adrenalectomy does not inhibit but enhances the granule augmentation. Under appropriate conditions a decrease in the amount of granules is induced by stress. This effect can be prevented by application of the glucocorticoid dexamethasone (Schwabedal et al, 1975). The quantitative changes of the granules after adrenalectomy, corticoid treatment and stress correspond to those which have been described for the CRF activity under the same experimental conditions (Schwabedal et al., 1975; Bock et al., 1976). According the electronmicroscopical studies of Wittkowski (1973) the granules consist of smaller subunits, so-called "elementary granules", which are localized in nerve fibres terminating on primary capillaries of the hypophyseal portal vascular system. Histochemically it has been demonstrated that the granules contain proteins digestible by pepsin or trypsin and rich in disulfide groups (Bocket al., 1976). As shown by immunohistochemical studies the granules react with antibodies against neurophysin II or vasopressin (Bocket al., 1976; Dierickx et al., 1976). These results correspond to the detection of vasopressin and neurophysin in hypophyseal portal blood (Zimmermann et al., 1973] and to the observation that after adrenalectomy in homozygous diabetes insipidusrats (Brattleboro strain] no augmentation of the granules occurs (Schwabedal et al., 1976). The findings suggest that a neurosecretory substance which biochemically is identical with or closely related to vasopressin-neurophysin II is involved in the regulation of adrenocortical function. The substance might represent a corticotrophinreleasing factor.

Electron microscope immunohistochemical localization of neurophysin in the rat with hereditary diabetes insipidus.

In order to study the subcellular distribution of neurophysin in the rat with hypothalamic hereditary diabetes insipidus (DI), an immunoelectron microscopic localization of neurophysin was performed in the hypothalamo-neurohypophysial system of both homozygous and heterozygous DI rats. Whereas in control rats neurophysin was localized in the granules present in the secretory neurons, in the homozygous DI rats neurophysin was found in the granules and outside the granules in the perikarya and axons of neurons of both supraoptic and paraventricular nuclei. In the heterozygous DI rats findings similar to those observed in homozygous DI rats were observed, although in the posterior pituitary, the exgranular material appeared to be less abundant than in homozygous DI rats. These results clearly demonstrated that in hyperstimulated neurons neurophysin was distributed in both granular and extragranular compartments.

Monamines in brain and urine of rats with hereditary hypothalamic diabetes insipidus.

Monoamine levels in brain and urine of homozygous and heterozygous diabetes insipidus (DI) rats (Brattleboro strain) were assessed. Homozygous DI rats had a higher whole brain content of serotonin than their heterozygous littermates. However, when corrected for differences in brain weight, homozygous DI also appeared to have higher brain concentrations of noradrenaline, tyrosine and GABA. The total 24 h excretion of all amines and their precursors was greater in the homozygous than in the heterozygous rats.

Impaired development of tolerance to morphine analgesia in rats with hereditary diabetes insipidus.

Recently it was reported that vasopressin facilitates the development of resistance to the analgestic action of morphine. Therefore, the development of tolerance to daily administration of morphine-HCl (10 mg/kg i.p.) was studied in a series of trials on a hot plate using rats with hereditary diabetes insipidus (DI), which lack the ability to synthesize vasopressin. In contrast to heterozygous DI rats, who developed full tolerance after the fifth injection, homozygous DI rats showed a delayed development of tolerance. Substitution of HO-DI rats with either arginine-8-vasopressin (3 mug/rat, s.c. daily) or the endocrinologically inert fragment of vasopressin desglycinamide lysine-8-vasopressin (5 mug/100 g, s.c. daily) restored the impaired development of tolerance towards normal. The data support the notion that vasopressin is important to the development of tolerance to narcotic analgesics and that its mechanism of action is dissociated from its endocrine effect but rather resembles that of its known influence on memory consolidation.

Unimpaired maintenance of a conditioned avoidance response in the rat with diabetes insipidus

The ability to maintain a conditioned avoidance response (CAR) was studied in normal Long-Evans rats and rats of the Brattleboro strain which were either homozygous or heterozygous for hereditary hypothalamic diabetes insipidus (DI). Homozygous DI rats had a lower CAR acquisition rate than did normal or heterozygous DI rats. However, the homozygous DI rats exhibited significantly greater CAR retention than did the other animals over the total period of extinction testing. The greater CAR retention could not be accounted for by either increased sensitivity to the electric foot shock used as the unconditioned stimulus or by perching on the metal center barrier of the training shuttle box, a form of behavior unique to the homozygous DI rats. Since the homozygous DI rat is totally lacking in hypothalamic antidiuretic hormone (ADH), the greater CAR retention of these animals indicates that ADH is not a requirement for CAR retention.

The Role of Vasopressin in Memory Processes

This chapter discusses the role of Vasopressin in memory processes. During the last 10 years, evidence has accumulated that peptides from pituitary origin play an important role in acquisition and/or extinction of conditioned avoidance behavior. Administration of pitressin, a crude vasopressin preparation extracted from posterior pituitary tissue, induces resistance to extinction of a shuttlebox avoidance response. The principle present in pitressin responsible for this “long-term” effect seemed to be vasopressin and proof of this assumption was obtained in experiments in which a pole jump avoidance response was studied. The significance of vasopressin for the consolidation of learned behavior is also demonstrated by experiments in rats with hereditary hypothalamic diabetes insipidus (DI) that lack the ability to synthesize vasopressin. It appeared that homozygous DI rats in contrast to heterozygous littermates were unable to retain the passive avoidance response. Administration of vasopressin and vasopressin analogues induces resistance to the extinction of active and passive avoidance behavior.

Changes in organ weights and blood parameters in ageing Brattleboro rats with hereditary diabetes insipidus.

Organ weights and blood parameters were measured in male and female Brattleboro rats with hereditary diabetes insipidus (DI) and in normal rats of the same strain, between 37 and 138 weeks old. Although differences in body weight between the homozygous DI and heterozygous normal rats accounted for differences in the weights of the heart and gonads, the weights of the spleen, liver and kidney were not solely body-weight dependent; there were significant sex and genotype differences in the mean weights of these organs. The liver, heart and gonads were the only organs showing age-dependent changes. No genotype-dependent differences were observed in the haematocrit and haemoglobin concentration, although there was a sex difference; the mean values of these parameters were higher in males. Plasma glucose concentrations were significantly lower in homozygous than in heterozygous rats; in the latter, plasma glucose concentration decreased with age. No significant changes occurred in the mean plasma concentrations of sodium or potassium with age or genotype. Total plasma lipids of heterozygous female rats showed both age- and genotype-dependent changes; this parameter reached a plateau at 90-100 weeks old, and was significantly higher in heterozygous females than in all other groups. Plasma proteins showed no age-dependent changes, but were of higher mean value in heterozygous than in homozygous rats and were greater in females than in males. Differences in blood parameters of homozygous and heterozygous Brattleboro rats are discussed in terms of differences in hormone concentrations.

Neurophysin in rats with hereditary hypothalamic diabetes insipidus (Brattleboro strain).

Neurophysin is a carrier-protein for vasopressin and oxytocin in the posterior pituitary lobe. In rats (Brattleboro strain) with diabetes insipidus (DI), neurophysin was virtually absent in the hypothalamo-neurohypophysial system (HNS), but the serum concentration of neurophysin was even higher than that in normal rats, 7.1 ± 0.8 mμg/ml and 4.4 ± 0.6 mμg/ml respectively. The values of neurophysin in the HNS and in the serum of heterozygous rats fell between those of homozygous DI and normal rats. The serum neurophysin level was higher in the external jugular vein than in the inferior vena cava in both normal and DI rats. In DI rats, serum neurophysin was not increased by dehydration or hemorrhage, which in both heterozygous and normal rats elevated serum levels of neurophysin several- fold. Lesions in the median eminence of normal and DI rats lowered serum neurophysin significantly. The estimated molecular weight and the immunological cross-reactivity of neurophysin from DI and normal rats was similar; bu...