Vasopressin antagonizes retrograde amnesia in rats following electroconvulsive shock

Rats given an electroconvulsive shock immediately following training in a passive avoidance task showed amnesia when tested 24 hr after training. This amnesia was prevented if lysine vasopressin was injected either one hr before the training trial or one hr before the first test trial. The results indicate that it is unlikely that either electroconvulsive shock or lysine vasopressin affect memory storage.     

Modulation of memory retrieval by pre-testing vasopressin: involvement of a central cholinergic nicotinic mechanism.

Lysine vasopressin (LVP, 0.003-1.0 mcg/kg, s.c.) and the central acting nicotinic cholinergic agonist nicotine (N, 1.0-30.0 mcg/kg, s.c.) enhanced, whereas the vasopressin receptor antagonist 1-beta-mercapto-beta, beta-cyclopentamethylenepropionic acid-2-(O-methyl)tyrosine, arginine vasopressin (AAVP, 0.01-0.3 mcg/kg, s.c.) impaired retention test performance on a one-trial step-through inhibitory avoidance task when injected into male Swiss mice 20 min before the retention test. Tests were done 48 h following training. In all cases, the effects on retention test performance were dose-dependent. Neither LVP, N nor AAVP when given prior to testing modified latencies to step-through of mice that had not received a footshock during training. These findings suggest that LVP, N and AAVP influence memory retrieval processes. The effect of LVP on memory retrieval was antagonized by the simultaneous administration of AAVP (0.01 mcg/kg, s.c.) or mecamilamine (5 mg/kg, s.c.), but not by hexamethonium (5 mg/kg, s.c.), atropine (0.5 mg/kg, s.c.) or methylatropine (0.5 mg/kq, s.c.). On the contrary, the effect of N was only prevented by mecamilamine (5 mg/kg, s.c.). These results suggest a modulatory role of vasopressin on the activity of central cholinergic nicotinic mechanisms which are critical for memory retrieval.     

Effects of vasopressin on histamine H(1) receptor antagonist-induced spatial memory deficits in rats.

The effects of [Arg(8)] vasopressin on histamine H(1) receptor antagonist-induced memory deficits were investigated using the eight-arm radial maze performance test in rats. Pyrilamine and diphenhydramine as well as scopolamine induced memory deficits characterized by increases in the number of total errors, reference memory errors and working memory errors. [Arg(8)] vasopressin improved not only scopolamine--but also pyrilamine--and diphenhydramine-induced memory deficits, although a high dose of [Arg(8)] vasopressin was needed to antagonize pyrilamine-induced memory deficits. The effects of pyrilamine on the brain [Arg(8)] vasopressin content were studied, and the hippocampus [Arg(8)] vasopressin content was shown to be decreased after pyrilamine injection. From these observations, it seems likely that [Arg(8)] vasopressin participates in not only the cholinergic system but also the histaminergic system in spatial memory.     

Management of vasodilatory shock: defining the role of arginine vasopressin

The rationale for an arginine vasopressin (argipressin) infusion was put forward after it was discovered that patients in shock states might have an endogenous arginine vasopressin deficiency. Subsequently, several investigations impressively demonstrated that arginine vasopressin can successfully stabilise haemodynamics even in advanced vasodilatory shock. We report on physiological and pharmacological aspects of arginine vasopressin, and summarise current clinical knowledge on employing a continuous arginine vasopressin infusion in critically ill patients with catecholamine-resistant vasodilatory shock of different aetiologies. In view of presented experimental evidence and current clinical experience, a continuous arginine vasopressin infusion of approximately 2 to approximately 6 IU/h can be considered as a supplemental strategy to vasopressor catecholamines in order to preserve cardiocirculatory homeostasis in patients with advanced vasodilatory shock. Because data on adverse effects are still limited, arginine vasopressin should be reserved for patients in whom adequate haemodynamic stabilisation cannot be achieved with conventional vasopressor therapy or who have obvious adverse effects of catecholamines that result in further significant haemodynamic deterioration. For the same reasons, arginine vasopressin should not be used as a single, alternative vasopressor agent instead of catecholamine vasopressors. Future prospective studies will be necessary to define the exact role of arginine vasopressin in the therapy of vasodilatory shock.     

The improvement of memory retention and retrieval of a novel vasopressin fragment analog NC-1900

The effects of a novel vasopressin (AVP) fragment analog NC-1900 (pGlu-Asn-Ser-Pro-Arg-Gly-NH2 acetate) were studied on the performance of memory retention and retrieval in mice. NC-1900 of one time application of 1 hr after the acquired trial (electric shock) extended the latent period of passive avoidance task 21 days after the acquired trial. Though the extended response was also recognized with AVP4-9, the potency was approx. 1/1000 of NC-1900. The potentiation wasn't recognized with vasopressin. NC-1900 showed a significantly high correct answer after 21 days after the last trial in the search task. While, V1 antagonist Pmp1-Tyr (Me)2-AVP shortened the latent period of passive avoidance task. On the other hand, NC-1900 extended the reaction latency 21 days after the acquired trial by the application 1 hr before the retention trial. Though this improvement of memory retrieval was recognized with vasopressin and AVP4-9, the potency was 1/100-1/1000. NC-1900 improved the retrieval 24 h after the CO2 exposure. V1 antagonists Pmp1-Tyr-Me2-AVP or Deamino-Pen1, O-Me-Tyr2-AVP, and PMA had no effects on the retrieval 21 days after the acquired trial. These results suggest that NC-1900 may have the memory retention and retrieval potentiating action, and that phospholipase C-protein kinase C system may be involved in the former action, and the latter action not be involved.     

Delayed effect of the vasopressin metabolite VP4-8 on the social memory of sexually naive male rats

RATIONALE: Endogenous vasopressin is involved in the social memory of the male rat and administration of exogenous vasopressin improves social memory. These findings are mainly based on studies using sexually experienced males that were tested in the social recognition test. OBJECTIVE: The present study was aimed to establish whether the modulation of social memory by vasopressin fragments depends on the sexual experience of the male rat. For this purpose, the social discrimination test was used, since this test is more suitable than the social recognition test for measuring social memory in sexually naive males. METHODS: Male rats were tested in the social discrimination test and treated subcutaneously with the vasopressin metabolite [pGlu4,Cyt6]vasopressin-(4-8) (VP4-8). VP4-8 shares with vasopressin the effects on memory processes but lacks the peripheral effects of vasopressin. RESULTS: VP4-8 (1 microgram/kg) acutely improved the social memory of sexually experienced male rats, confirming previous reports. However, in sexually naive males VP4-8 failed to improve social memory in doses ranging from 0.1 microgram/kg to 1 microgram/kg. Instead, 1 microgram/kg VP4-8 or 6 micrograms/kg desglycinamide-vasopressin were found to exert a delayed effect in sexually naive rats. This delayed effect resulted in an improved social memory 2 days after administration. CONCLUSIONS: Vasopressin sensitisation is discussed as a possible underlying mechanism of the observed delayed effect of vasopressin fragments. It is concluded that in male rats sexual experience can influence the modulation of social memory by vasopressin.     

Role of neuropeptides in antidepressant and memory improving effects of venlafaxine

The aim of this study has been to investigate the effects of vasopressin and oxytocin on antidepressive and memory improving effects of venlafaxine. Male Wistar rats weighing 180-200 g were used in the study. Venlafaxine (20 mg/kg) was administered po 30 min before the test once, and for 7 and 14 days in the chronic experiments. Oxytocin (1 microg/kg) ip and vasopressin (1 microg/kg) sc were administered only once on the test day, 60 min before the tests. The animals were subjected to Porsolt's test for testing antidepressant activity, and their memory functions (working and spatial memory) were evaluated in the maze test and Morris Water Maze test. Antidepressant effects of venlafaxine could be observed already after single drug administration and the effect was maintained during 7 days of drug administration. Oxytocin also exhibited antidepressant activity, and concurrent administration of venlafaxine and oxytocin helped to maintain antidepressant activity of venlafaxine. Vasopressin was devoid of antidepressant action, yet concurrent administration of vasopressin and venlafaxine did not suppress antidepressant activity of the latter. In the chronic experiment, there was no shortening of passive swimming time. Venlafaxine improved memory in the labyrinth test and in the spatial memory test, whereas oxytocin did not affect memory of the tested animals. Joint administration of venlafaxine and oxytocin did not produce memory improving effect observed after administration of venlafaxine only. Vasopressin improved memory and joint administration of venlafaxine and vasopressin maintained the memory improving effect induced by vasopressin. The regulatory role of neuropeptides and new antidepressant drugs, e.g. venlafaxine in mood status and memory functions may depend on the interactions between monoaminergic and neuropeptidergic systems.     

Opposite effects induced by low and high doses of apomorphine on single-trial passive avoidance learning in mice

The effects of apomorphine (0.0125-1 mg/kg, SC), a dopamine (DA) agonist, on passive avoidance learning were assessed in mice which received brief and long foot-shocks in a training test. At low doses, apomorphine stimulates DA autoreceptors. With a shock of brief duration, apomorphine at a low dose (0.05 mg/kg), enhanced the avoidance learning when it was administered 20 min before the training test or the retention test. At high doses, apomorphine stimulates postsynaptic DA receptors. With a shock of long duration, apomorphine at a high dose (1 mg/kg), impaired the avoidance learning when it was administered 20 min before the training test or the retention test. However, apomorphine (0.05 and 1 mg/kg) given immediately after the training test did not have any effect on the avoidance behavior with shocks of either brief or long durations. Apomorphine-induced enhancement of passive avoidance learning was antagonized by sulpiride, but not by haloperidol. These results show that apomorphine induced the opposite effects on the passive avoidance learning depending on the dose or on the reinforcement intensity and suggest that the central DA system may play an important role in modulating memory processes.     

Time variables affecting the permanence of amnesia produced by combined cycloheximide and electroconvulsive shock treatments

Mice pretreated with saline or cycloheximide were trained in a multiple-trial avoidance apparatus. Electroconvulsive shock (ECS) was administered at various intervals following training. The animals were retrained either one day or about one week later. Both transient and permanent memory deficits were observed. Presence and type of memory deficit were dependent upon time of ECS treatment, time of retraining and whether the animals received saline of cycloheximide prior to original training. A possible relationship between the results observed and reported effects of training on macromolecular synthesis in the brain is discussed.     

Vasopressin potentiation in the performance of a learned appetitive task: reversal by a pressor antagonist analog of vasopressin

Rats were tested in a simple one-trial water-finding task for the effects of arginine vasopressin (AVP) on performance of an appetitive task. On the training day, each animal was exposed for 5 min to a novel open-field environment that contained a water-tube located in an alcove set into one of the walls of the enclosure. Immediately upon removal from the enclosure, the animals received a subcutaneous injection of either AVP (1 microgram/rat) or vehicle solution. When water-deprived and tested 48 hr later, vasopressin-treated rats found the water tube reliably faster than controls. In other groups of animals, this potentiation in learned performance was prevented by concurrently treating the rats with a vasopressin analog having potent pressor antagonist properties. These results are consistent with the notion that vasopressin may play a role in memory consolidation, but peripheral visceral factors may mediate this action.     

CR 2249: a New Putative Memory Enhancer. Behavioural Studies on Learning and Memory in Rats and Mice

The effects of S-4-amino-5-[4,4-dimethylcyclohexyl)amino]-5-oxopentanoic acid (CR 2249), a new entity selected from a new series of glutamic acid derivatives, has been investigated in different paradigms for screening nootropics. CR 2249 ameliorated the memory retention deficit produced by scopolamine in step-through-type passive avoidance in rats and by electroconvulsive shock in step-down-type passive avoidance in mice. CR 2249 was also capable of improving performance in behavioural tests of learning and memory in the absence of cholinergic hypofunction or cognitive deficit. The activity was determined using different passive and active avoidance behavioural test procedures on rats. CR 2249 was active only when given 45 min before training and did not show any effect when administered immediately after the learning training or before the retention trial. No changes in the general behaviour or motor activity of the animals were observed, indicating that CR 2249 effects cannot be attributed to sensory-motor deficit. Microdialysis experiments have shown that CR 2249 significantly increased noradrenaline release in the hippocampus of freely moving rats and reduced 3,4-dihydroxyphenylglycol efflux. These effects have led us to hypothesize that CR 2249 memory effect might be mediated by a direct or indirect action on noradrenergic transmission. These behavioural results suggest that this new agent has clinical application in memory disorders.     

Role of serotonin in memory: facilitation by alaproclate and zimeldine

The effects of alaproclate and zimeldine on memory retrieval were examined in male Swiss Webster mice using a one-trial inhibitory avoidance task. All drugs were administered IP prior to the retention test 24 h after training. Both drugs were found to facilitate memory retrieval significantly in a dose-and time-dependent fashion that could not be explained in terms of non-specific effects of the drug (illness, lack of motility, etc.) at the time of the test. The temporal effects of alaproclate and zimeldine on memory closely followed their course of concentration of the drug within the blood stream. The facilitation of retrieval induced by alaproclate and zimeldine was blocked by the putative serotonergic receptor agonist quipazine but not blocked by the antagonist cyproheptadine. Pretreatment with quipazine alone in a group of animals trained to a shock level which normally results in high levels of suppression was not sufficient to produce memory impairment, suggesting that quipazine was probably antagonizing the facilitative effects of alaproclate and zimeldine directly, rather than overriding the facilitation through an indirect action on retrieval in general. The present results lend further support to the suggestion that serotonin plays a significant role in memory.     

Vasopressin During Cardiopulmonary Resuscitation and Different Shock States

Vasopressin administration may be a promising therapy in the management of various shock states. In laboratory models of cardiac arrest, vasopressin improved vital organ blood flow, cerebral oxygen delivery, the rate of return of spontaneous circulation, and neurological recovery compared with epinephrine (adrenaline). In a study of 1219 adult patients with cardiac arrest, the effects of vasopressin were similar to those of epinephrine in the management of ventricular fibrillation and pulseless electrical activity; however, vasopressin was superior to epinephrine in patients with asystole. Furthermore, vasopressin followed by epinephrine resulted in significantly higher rates of survival to hospital admission and hospital discharge. The current cardiopulmonary resuscitation guidelines recommend intravenous vasopressin 40 IU or epinephrine 1mg in adult patients refractory to electrical countershock. Several investigations have demonstrated that vasopressin can successfully stabilize hemodynamic variables in advanced vasodilatory shock. Use of vasopressin in vasodilatory shock should be guided by strict hemodynamic indications, such as hypotension despite norepinephrine (noradrenaline) dosages >0.5 mug/kg/min. Vasopressin must never be used as the sole vasopressor agent. In our institutional routine, a fixed vasopressin dosage of 0.067 IU/min (i.e. 100 IU/50 mL at 2 mL/h) is administered and mean arterial pressure is regulated by adjusting norepinephrine infusion. When norepinephrine dosages decrease to 0.2 microg/kg/min, vasopressin is withdrawn in small steps according to the response in mean arterial pressure. Vasopressin also improved short- and long-term survival in various porcine models of uncontrolled hemorrhagic shock. In the clinical setting, we observed positive effects of vasopressin in some patients with life-threatening hemorrhagic shock, which had no longer responded to adrenergic catecholamines and fluid resuscitation. Clinical employment of vasopressin during hemorrhagic shock is experimental at this point in time.     

The role of vasopressin in vasodilatory septic shock

Septic shock that requires therapy with adrenergic agents is associated with high rates of mortality. Inappropriately normal or low serum concentrations of vasopressin contribute to the development of hypotension during sepsis. We critically evaluated the role of administering exogenous vasopressin to patients with septic shock. A computerized search of MEDLINE from January 1966--December 2003 and a manual search of relevant journals for abstracts were conducted. Eleven retrospective, six prospective cohort, and four prospective randomized studies were identified. Most studies evaluated short-term infusions of vasopressin at 0.08 U/minute or less as add-on therapy in patients requiring adrenergic agents. The results show that starting vasopressin in patients with septic shock increases systemic vascular resistance and arterial blood pressure, thus reducing the dosage requirements of adrenergic agents. These effects are rapid and sustained. Substantial enhancement of urine production, likely due to increased glomerular filtration rate, was shown in several studies. A few studies demonstrated clinically significant reduced cardiac output or cardiac index after vasopressin was begun, necessitating cautious use in patients with cardiac dysfunction. Vasopressin was associated with ischemia of the mesenteric mucosa, skin, and myocardium; elevated hepatic transaminase and bilirubin concentrations; hyponatremia; and thrombocytopenia. Limiting the dosage to 0.03 U/minut or less may minimize the development of these adverse effects. Vasopressin 0.03 U/minute or less should be considered if response to one or two adrenergic agents is inadequate or as a method to reduce the dosage of adrenergic agents. At present, vasopressin therapy should not be started as first-line therapy. Additional studies are needed to determine the optimum dosage, duration, and place in therapy of vasopressin relative to adrenergic agents. A multicenter, comparative study of vasopressin 0.03 U/minute as add-on therapy is under way and should provide mortality data.     

Transient diabetes insipidus after discontinuation of therapeutic vasopressin

The use of vasopressin for the treatment of septic shock is increasing. Few reports of fluid and electrolyte complications of this therapy have been reported. A neurologically impaired, 53-year-old man with a history of syndrome of inappropriate antidiuretic hormone developed apparent transient diabetes insipidus and acute hypernatremia after being treated with vasopressin. He was treated for presumed septic shock with intravenous vasopressin 0.01-0.10 U/minute. His blood pressure did not improve with this therapy, and his course was complicated by hyponatremia during the vasopressin infusion. Discontinuation of the infusion was followed by a profound (8.4 L) diuresis and rapid onset of hypernatremia (serum sodium concentration increased from 132 to 157 mEq/L over 8 hrs). Although urine osmolality was not measured during the patient's diuresis, the rapid changes in serum sodium concentration can be explained only by an inappropriate water diuresis. The diuresis ceased when the vasopressin infusion was resumed. We concluded that these findings are most consistent with transient diabetes insipidus. The safety and efficacy of intravenous vasopressin have not been established in patients with septic shock and underlying disorders of water homeostasis. The drug may have diminished vasoconstrictive effects in this patient population. Careful monitoring of water and sodium balance is warranted in all patients treated with vasopressin for septic shock.     

Alteration of cardiovascular, neurogenic, and humoral responses to acute hypovolemic hypotension by administered prostacyclin

Acute hypovolemia induced by bleeding (5 ml/300 g body weight) halothane-anesthetized (0.8% in oxygen) rats is attended by hypotension, bradycardia, and increases in plasma renin, vasopressin, and catecholamine levels. Infusion of prostacyclin (PGI2, O.03 microgram/kg.min) to acutely hemorrhaged rats enhanced recuperation of heart rate, and potentiated the sympathetic response and vasopressin release without altering blood pressure of plasma renin concentration (PRC). Bleeding of bilaterally adrenal demedullated, splanchnicectomized rats resulted in prolonged hypotension and increased plasma levels of vasopressin and renin; epinephrine in the plasma was not detectable, and plasma norepinephrine concentration was not increased after hemorrhage. Prostacyclin infusion to the demedullated, splanchnicectomized rats had no effect on heart rate but enhanced blood pressure recovery after hemorrhage; in this experimental group, PRC was markedly elevated but prostacyclin had no effect on plasma vasopressin or catecholamine concentrations. In rats exposed to severe bleeding, resulting in a nonreversible shock and high mortality, PGI2 infusion after the bleeding increased the survival rate without effect on blood pressure, heart rate, or circulating levels of vasopressin and catecholamines. This study suggests that prostacyclin, through stimulation of the sympathoadrenal axis, enhances heart rate recuperation and vasopressin release in response to acute hemorrhagic shock. Furthermore, prostacyclin may stimulate renin secretion in sufficient amount to compensate for the inadequate sympathetic response during hemorrhagic shock. It is also shown that prostacyclin improves the survival rate to severe hemorrhage without overt hemodynamic or sympathetic effects.     

ADH and related peptides: effect of pre- or posttraining treatment on puromycin amnesia

The peptide Z-Pro-Leu-Gly-NH2 attenuated puromycin-induced amnesia in mice when administered 5 days prior to training, while arginine vasopressin, lysine vasopressin and cyclo(Leu-Gly), were effective when given 24 hr before training. The activity of all peptides to inhibit puromycin-induced amnesia decreased as the interval after training and before peptide administration increased, suggesting that the peptides influence memory processes rather than generalized arousal mechanisms.     

Does DGAVP influence memory,attention and mood in young healthy men?

The influence of an increasing dose of the vasopressin-like peptide DGAVP (desglycinamide-arginine-vasopressin) on memory was investigated in two groups of ten healthy male volunteers to provide information about the hypothesis of improvement of memory by vasopressin. At the same time we evaluated the effect of DGAVP on mood, alertness or sleepiness in a double-blind placebo-control design. The treatment group received at 9.15 a.m. intranasally a daily increasing dose from 0.1 mg at day 1 to 10.0 mg at day 5. DGAVP did not significantly affect any measure of memory or alertness. DGAVP did, however, produce a significant increase in concentration level and mood. The results of the present study provide no support for the vasopressin theory of memory improvement; rather, the results direct the attention to attention modulating effects.     

Role of corticotropin-releasing factor, vasopressin and the autonomic nervous system in learning and memory

Learning and memory are essential requirements for every living organism in order to cope with environmental demands, which enables it to adapt to changes in the conditions of life. Research on the effects of hormones on memory has focused on hormones such as adrenocorticotropic hormone (ACTH), glucocorticoids, vasopressin, oxytocin, epinephrine, corticotropin-releasing factor (CRF) that are released into the blood and brain following arousing or stressful experiences.Most of the information have been derived from studies on conditioned behavior, in particular, avoidance behavior in rats. In these tasks, an aversive situation was used as a stimulus for learning. Aversive stimuli are associated with the release of stress hormones and neuropeptides. Many factors play a role in different aspects of learning and memory processes. Neuropeptides not only affect attention, motivation, concentration and arousal or vigilance, but also anxiety and fear. In this way, they participate in learning and memory processes. Furthermore, neuropeptides such as CRF and vasopressin modulate the release of stress hormones such as epinephrine. In turn, systemic catecholamines enhance memory consolidation. CRF and vasopressin are colocalized in neurons from the nucleus paraventricularis, which project to nuclei in the brainstem involved in autonomic regulation. The objective of this paper is to discuss the role of CRF, vasopressin, and the autonomic nervous system (ANS) in learning and memory processes. Both CRF and vasopressin have effects in the same direction on behavior, learning and memory processes and stress responses (release of catecholamines and ACTH). These neuropeptides may act synergistically or in a concerted action aimed to learn to adapt to environmental demands.     

Effects of the novel compound NIK-247 on impairment of passive avoidance response in mice

The effects of NIK-247 [9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)-quinoline monohydrate hydrochloride] were studied on a model involving various types of drug- and electroconvulsive shock (ECS)-induced amnesia. The step-down type passive avoidance task in mice was used for comparison of the effects with those of tacrine, a 4-aminopyridine derivative which has an antiamnesic action. NIK-247 administered pre- and post-training or pre-retention test (24 h after training) prevented the disruption of memory induced by cycloheximide administered immediately after training. In addition, NIK-247 protected from the amnesia induced by treatment with ECS, phencyclidine and picrotoxin immediately after training. Tacrine failed to protect from ECS- and PCP-induced amnesia at the doses effective on cycloheximide-induced amnesia. The results indicate that NIK-247 improves cognitive functions at different phases of the learning and memory processes such as acquisition, consolidation, and retrieval in drug- and ECS-induced amnesia. NIK-247 may produce its antiamnesic effects via the cholinergic and GABAergic neuronal systems.