Arginine vasopressin and a vasopressin antagonist peptide: Opposite effects on extinction of active avoidance in rats

Systemic injection of arginine vasopressin (AVP) (1 μ/rat) significantly prolonged extinction of a pole-jump, active avoidance response in rats; lateral ventricular injection of 1000-fold less AVP (1 ng/rat) produced similar results. A new AVP analogue, [1-deaminopenicillamine-2-(O-methyl)-tyrosine]arginine vasopressin (dPTyr-(Me)AVP), is known to antagonize behavioral and vascular effects of exogenous AVP at molar ratios of 5:1. At a dose of 100 μ/rat (subcutaneously) dPTyr-(Me)AVP produces, by itself, a behavioral effect opposite to that of exogenous AVP, namely a facilitation of extinction. Injections of dPTyr-(Me)AVP into the lateral ventricle were ineffective except at a dose of 10 μg/rat. These results confirm previous reports of the effect of vasopressin on delaying extinction of avoidance behavior, but suggest a site of action distant from the lateral ventricle.     

Vasopressin levels in peripheral blood and in cerebrospinal fluid during passive and active avoidance behavior in rats.

Vasopressin (AVP) levels were measured in plasma and cerebrospinal fluid (CSF) of rats during acquisition and retention of a passive avoidance response. Only 5 min after the onset of the retention session a significantly higher level of AVP was found in plasma of animals which displayed a long latency, as compared with the levels of animals which showed a weak passive avoidance response (short latencies), or no passive avoidance behavior at all (controls). Moreover no changes in plasma AVP levels were found in plasma of rats submitted to acquisition or extinction of an active avoidance response. It is suggested that, although an elevated plasma AVP level is associated with strong retention of a passive avoidance response the peripheral circulation as well as the CSF are of minor importance for the transport of this neuropeptide to its site of behavioral action.     

Vasopressin pressor antagonist injected centrally reverses behavioral effects of peripheral injection of vasopressin, but only at doses that reverse increase in blood pressure

Previous work in rats (Ader, R. and De Wied, D., Psychon. Sci., 29 (1972) 46-48) has established that subcutaneously (s.c.) injected arginine vasopressin (AVP) prolongs extinction of active avoidance and that this effect could be prevented by pretreatment with the vasopressin antagonist analog [1-deaminopenicillamine, 2-(O-methyl)tyrosine]-beta-arginine vasopressin (dPtyr(Me)AVP). The purpose of the present study was to determine if peripherally administered AVP acts via a peripheral blood pressure effect or by a direct action in the central nervous system. We therefore tested the effects of the antagonist injected intracerebroventricularly (i.c.v.) on the prolongation of active avoidance and on blood pressure effects of s.c. injected AVP. The antagonist (i.c.v.) blocked the behavioral effects of systemically injected AVP only at dose sufficient to block the peripherally mediated pressor response of systemically administered AVP. The results show that peripherally injected AVP acts on peripheral systems and support our hypothesis that the peripheral visceral action of AVP contributed significantly to its behavioral action.     

Central injections of arginine vasopressin prolong extinction of active avoidance

Behavioral and physiological effects of arginine vasopressin (AVP) were examined following intracerebroventricular (ICV) injection in the rat. ICV injections prolonged extinction of active avoidance at doses of 1.0 and 10.0 ng/rat and this effect was blocked by peripheral injection of the vasopressor antagonist of vasopressin [dPtyr(Me)AVP] at a dose of 30 micrograms/kg (SC). However, 1.0 ng of AVP ICV failed to alter systemic blood pressure and also failed to produce taste aversions in a one or two bottle test. Results suggest that central AVP has a central action independent of systemic changes in blood pressure, but that the receptor mediating this action is functionally similar to the AVP V1 (vasopressor) receptor.     

The effect of chronic vs. acute injection of vasopressin on animal learning and memory

The effect of chronic and acute treatment with DDAVP, a vasopressin analog, was studied in 2 month old male rats, using an active avoidance test in a shuttle box. The experiment lasted 6 weeks: an acquisition period of 4 weeks and an extinction period of 2 weeks. Rats were treated one hour before behavioral testing 3 times a week for 6 weeks with either DDAVP 20 micrograms/rat/day for the whole period (chronic group) or with DDAVP for the first week and again once only on the first day of the extinction period (acute group) or with saline. Chronic treatment with DDAVP resulted in better acquisition and in a marked retardation of extinction compared with the acute treatment group. These results were obtained both in normal rats and in rats pretreated at age 5 days of life with intracisternal 6-OH dopamine.     

Preventive effect of cholecystokinin octapeptide on experimental amnesia in rats

The effect of intracerebroventricular (ICV) administration of cholecystokinin octapeptide (CCK-8) on electroconvulsive shock (ECS)-induced amnesia in passive avoidance response was studied in rats. In normal rats, CCK-8 in doses from 1 ng to 1 microgram had no effect on the response when injected before the training trials, immediately after foot shock or before the first retention test. However, proglumide, a CCK-8 receptor blocker, induced marked amnesia when injected in doses from 0.1 to 10 micrograms before the training trials and in doses of 1 and 10 micrograms before the first retention test, though not subsequent to foot shock. ECS given immediately after the foot shock caused amnesia in the 24 hr and 48 hr retention tests, which could have been prevented by CCK-8 injected in doses of 10 ng to 1 microgram prior to the training trials, of 10 ng to 1 microgram following ECS and of 0.1 and 1 microgram before the first retention test. In addition, the effects of CCK-8 and proglumide became pronounced following chronic ICV infusion, using an osmotic minipump, for 7 days at a dose of 1 ng/day and 10 ng/day, respectively. The amnesia induced by proglumide was not affected by arginine vasopressin (AVP), while AVP in doses of 10 ng and 100 ng given 30 min before the training trials prevented ECS-induced amnesia. The antiamnesic effect of AVP was abolished by simultaneous administration of proglumide. On the other hand, AVP-antiserum produced marked amnesia which could be antagonized by CCK-8. However, the antiamnesic effect of CCK-8 was not suppressed by AVP-antiserum.(ABSTRACT TRUNCATED AT 250 WORDS)     

Behavioral effects of intraventricularly administered vasopressin and vasopressin fragments

Vasopressin is involved in memory processes. A single subcutaneous injection of arginine-8-vasopressin (AVP) increases resistance to extinction of a pole jumping avoidance response. This effect can also be achieved after a single intraventricular administration of much lower amounts than after systemic injection. The covalent ring of AVP, pressinamide (PA), is also highly active following intraventricular administration while the C-terminal part prolyl-arginyl-glycinamide (PAG) is less active. These results indicate that the covalent ring of vasopressin contains the essential requirements for the behavioral effect of this neurohormone. A second activity site however may be present in the C-terminal portion of the molecule.     

D-Pen2-[D-Pen5]enkephalin impairs acquisition and enhances retention of a one-way active avoidance response in rats.

We reported previously that D-Pen2-[D-Pen5]enkephalin (DPDE), a delta-opioid receptor selective analog of Leu-enkephalin, impairs acquisition of an automated jump-up avoidance response in rats and acquisition of a one-way active avoidance response in mice. In the present study we investigated the effects of DPDPE on one-way avoidance conditioning in rats. The rats received two escape-only trials on day 1 and eight additional training trials on day 2. DPDPE (1.16 micrograms/kg IP) administered prior to training on day 2 impaired acquisition of the avoidance response. On the other hand, DPDPE (0.332 microgram/kg IP) administered following presentation of the two escape-only trials on day 1 significantly enhanced retention, as measured by improved one-way active avoidance performance on day 2. These results indicate that activation of delta-opioid receptors by DPDPE has a modulatory effect on acquisition and retention of aversively motivated performance.     

Arginine vasopressin facilitates reversal learning in albino, but not hooded rats

Male Holtzman albino and Long-Evans hooded rats were administered one microgram of arginine vasopressin (AVP) or a placebo each day after the acquisition trials of a visual white-black discrimination. Animals were then trained in the reversal of the discrimination. Performance was assessed by the number of trials to criterion during acquisition and reversal. Treatment with AVP resulted in significantly fewer trials to criterion during reversal learning in Holtzman albino rats, but did not influence reversal learning in Long-Evans hooded rats. These results provide evidence that AVP may have differential actions on memory processes in different strains of rats.     

Neurohypophyseal peptide levels in CSF and plasma during passive avoidance behavior in rats

Levels of vasopressin (AVP), oxytocin (OXT), and neurophysin (NP) in CSF and plasma of rats were determined during acquisition and retention of passive avoidance behavior. None of the levels of neurohypophyseal peptides in CSF were changed either during the adaptation period, or during acquisition or the retention of this behavior. Moreover, no differences were found in hormone levels in CSF of the various groups of rats subjected to different shock intensities during the acquisition trial. The marked differences in individual latencies of nonavoiding rats, and the differences in latencies due to a different shock intensity applied during the learning trial were not reflected by changes in CSF hormone levels. Neither AVP nor NP levels in plasma were affected by the different shock intensities applied, when measured at 20 min after the learning trial. In contrast, a decrease in plasma OXT levels was observed after application of a shock intensity of 0.25 mA during the learning trial. During retention of the passive avoidance response plasma levels of AVP, OXT and NP were not different from the levels found in the nonshocked groups. It is suggested that under the conditions used in this study the CSF is apparently not involved in the distribution of neurohypophyseal peptides to their possible sites of behavioral action in the brain.     

Acquisition of avoidance reaction in rats with different social experience in youth

The acquisition of both active and passive avoidance response, the extinction of the former and the retention of the long-term memory trace of the latter were studied in 30- and 90-day-old male rats of the Wistar strain. The rats were in 3 groups which had had a different history between 15 and 30 days of age: (1) normally weaned rats lived from birth in a cage together with mother and siblings, i.e. under usual laboratory breeding conditions; (2) prematurely weaned rats lived under the same conditions for the first 15 days; after this period, their mother was removed from the cage; (3) community-reared rats had the same history up to 15 days of age; then they began to live in a community (5 connected cages) in contact with both young and adult rats from other cages. Ninety- day-old male rats acquired an active avoidance response at the same rate irrespective of their history in youth but 30-day-old rats were relatively slower if they had been prematurely weaned. Among both normally and prematurely weaned 30-day-old rats, the extinction was slower than in community-reared rats of the same age. Passive avoidance response was acquired by all rats at the same rate irrespective of their history and age. The long- term memory trace was always more stable in adult rats than in young ones.     

Effects of angiotensin and vasopressin V(1) receptors on water and sodium intake induced by injection of vasopressin into lateral septal area

The specific arginine(8)-vasopressin (AVP) V(1) receptors antagonist (AAVP) was injected (20, 40 and 80 nmol) into the lateral septal area (LSA) to determine the effects of selective septal V(1) receptor on water and 3% sodium intake in rats. Was also observed the effects of losartan and CGP42112A (select ligands of the AT(1) and AT(2) ANG II receptors, respectively) injected into LSA prior AVP on the same appetites. Twenty-four hours before the experiments, the rats were deprived of water. The volume of drug solution injected was 0.5 microl. Water and sodium intake were measured at 0.25, 0.5, 1.0 and 2.0 h. Injection of AVP reduced the water and sodium ingestion vs. control (0.15 M saline). Pre-treatment with AAVP (40, 80 and 160 nmol) did not alter the decrease in the water ingestion induced by AVP, whereas AAVP abolished the action of AVP-induced sodium intake. Losartan (40, 80 and 160 nmol) did not alter the effect of AVP on water and sodium intake, whereas CGP42112A (20, 40 and 60 nmol) at the first 30 min increased water ingestion. Losartan and CGP42112A together increased the actions of AVP, showing more pronounced effects than when the two antagonists were injected alone. The results showed that AVP inhibited the appetites and these effects were increased by the AAVP. The involvement of angiotensinergic receptors in the effects of AVP is also suggested.     

Effect of desglycinamide-lysine vasopressin (DG-LVP) on sexually motivated T-maze behavior of the male rat

Desglycinamide lysine vasopressin (DG-LVP), a vasopressin analog which has been found to facilitate the maintenance of active and passive avoidance behavior, influences the retention of a sexually motivated choice behavior of male rats in a T maze. A higher percentage of rats receiving DG-LVP after each acquisition session shows a correct choice during free-choice retention trials. The total number of correct choices is also higher than in the controls. Copulation reward after a correct choice is an essential requisite for acquiring the choice response and retention effect of DG-LVP. Male rats which were prevented from copulating with the receptive female goal rat or which were presented with another male in the goal box did not acquire the response, and their behavior was not influenced by DG-LVP. Response latencies were never affected by the peptide. It is concluded that the long-term effect of vasopressin on learned behavior is of a rather general nature and is most probably due to facilitated memory consolidation processes.     

Arginine vasopressin in fever: a still unsolved puzzle

(1) Administration of arginine vasopressin (AVP) in the ventral septal area (VSA) or intracerebroventricularly (i.c.v.) is thought to attenuate lipopolysaccharide (LPS) or prostaglandin (PG) E₂ fevers in rabbits and rats by acting on the V₁ receptor. (2) We found that the fever response of rabbits to intravenous LPS (200 ng/kg) or intra-VSA PGE₂ (500 ng) was not attenuated but enhanced by intra-VSA AVP (5 μg); a pharmacological analysis showed that this fever-enhancing effect was mediated by the V₂ receptor. (3) The febrile response of rats to intraperitoneal (50 μg/kg) or i.c.v. (100 ng) LPS was unaffected by i.c.v. AVP (2.5–100 ng). (4) The role of AVP in fever should be re-examined.     

Effects of peripherally injected vasopressin and des-glycinamide vasopressin on the extinction of a spatial learning task in rats

An elevated eight-arm radial maze was employed to study the effects of neuropeptide administration on the spatial learning abilities of food-deprived rats. Following 18 days of reinforced training, each animal was briefly exposed to the maze with no food available in any of the eight food-cups. Immediately after this preliminary trial, animals were injected with a single subcutaneous dose of either saline, arginine vasopressin (AVP: 1.0 or 5.0 micrograms/kg), or an AVP analog with only weak endocrinological activity, des-gly-arginine vasopressin (DG-AVP: 1.0, 5.0 or 10.0 micrograms/kg). Additional extinction trials were conducted at 2, 4, 6 and 8 h post-injection. These tests consisted of individually placing an animal on the empty maze and recording the number of arms chosen in a 5-min period. In this situation, animals learn that food is no longer present in the maze and, consequently, extinguish responding. Vasopressin potentiated this radial maze extinction behavior while DG-AVP produced behavioral results directionally opposite to those predicted by a memory facilitation hypothesis. In a subsequent experiment, vasopressin had no effects on unconditioned locomotor activity measured 2 and 4 h post-injection. These results suggest that: vasopressin improved the learning that occurred during extinction of conditioned appetitive behaviors, these vasopressin effects on conditioned behavior were independent of any unconditioned, sedative or non-specific actions of the peptide, and peripheral endocrinological responses may be necessary to demonstrate memory-enhancing effects following peripherally administered AVP.     

Cardiovascular effects of neuropeptide Y in the nucleus tractus solitarius of rats: relationship with noradrenaline and vasopressin

The central haemodynamic effects of neuropeptide Y (NPY), both alone and together with either noradrenaline (NA) or vasopressin (AVP), have been investigated by microinjecting synthetic peptide into the nucleus tractus solitarius (NTS) of anaesthetized rats. NPY alone elicited dose-dependent changes in blood pressure (BP) and heart rate (HR); 470 fmol inducing a pressor response, and 4.7 pmol a fall in BP. The hypotensive response to 20 nmol NA was significantly modified by both simultaneous and prior injection of an ineffective dose (47 fmol) of NPY. Prior injection of a similar dose of NPY also modified the NTS pressor effect of 10 ng AVP. A relationship between the action of AVP and NPY in the NTS was further indicated by the finding that prior injection of an ineffective dose of AVP (1 ng) reduced the hypotensive response to 4.7 pmol NPY, and by the demonstration of contrasting effects of 4.7 pmol NPY in AVP-deficient Brattleboro rats compared to parent strain LE rats. These results, taken together with the recent localization of NPY-like immunoreactivity in the NTS, suggest a role for NPY in central cardiovascular control. In addition, NPY has been shown to exhibit functional interactions with both an amine neurotransmitter and a neuropeptide present in the NTS of rats.     

Vasopressin and A1 noradrenaline turnover during food or water deprivation in the rat

In the present study, we have examined in Wistar rats the effects of food or water deprivation of 3 days on the hypophyso-adrenal axis, vasopressinergic system and activity of A1 noradrenergic brain stem cell group, which is involved in the control of the hypothalamic neuro-endocrine activity. Levels of adrenocorticotropic hormone (ACTH) and vasopressin (AVP) were determined by radio-immunoassay, and corticosterone level was determined by fluorimetric method. Plasma levels of ACTH and corticosterone were greatly increased in both groups of rats. In water-deprived rats, plasma AVP (13.83 +/- 1.63 vs. 3.03 +/- 0.23 pg/ml) and osmolality levels were significantly elevated with a marked decrease of AVP hypophysis content (272 +/- 65 vs. 1098 +/- 75 ng/mg protein), but not in food-deprived rats in which osmolality did not change and AVP remained stocked (2082 +/- 216 ng/mg protein) in the hypophysis without release in the plasma (1.11 +/- 0.23 pg/ml). These observations indicated that both food-deprivation and water-deprivation stimulated the pituitary adrenal axis thereby suggesting a stress state. AVP production is stimulated both by fluid and food restriction but is secreted with differential effects: during food restriction AVP secretion is limited to supporting the hypothalamic pituitary-adrenal system.     

Memory effect of caerulein and its analogs in active and passive avoidance responses in the rat

The memory effects of caerulein (CER) and its analogs ([des-Gln2]-CER and [Leu5,Nle8]-CER) were compared with that of cholecystokinin octapeptide (CCK-8) using active and passive avoidance responses in rats. In the active avoidance test, single subcutaneous (SC) injection of CER and its analogs immediately after the learning trials at doses of 10 and 100 ng/kg prevented extinction of learned task for 10 days, and at a dose of 1000 ng/kg for at least 15 days, but the effect of CCK-8 was somewhat weaker. In the saline control group, the number of responses decreased after 5 days. In the passive avoidance response, electroconvulsive shock (ECS)-induced amnesia was partially prevented by CCK-8 at doses of 100 and 1000 ng/kg SC, while CER and its analogs at doses of more than 100 ng/kg totally prevented the ECS-induced amnesia. Intraperitoneal administration of scopolamine caused complete amnesia which was also partially prevented by CCK-8, while CER could totally prevent the amnesia following SC injection of 2 micrograms/kg. These results indicate that CER and its analogs are more effective than CCK-8 for preventing experimental amnesia.     

Differential effects of DGAVP on acquisition and extinction of active avoidance behavior

DGAVP facilitates consolidation and retrieval of active and passive avoidance behavior. In this study it was tested whether the long-term behavioral effects of DGAVP are the consequence of an initial increase in behavioral arousal during the learning phase. Animals that were preestimated in an open field test to be low active showed a lower number of conditioned avoidance responses (CAR's) during acquisition and extinction of a shuttle-box task than high active rats. DGAVP was administered 40 min prior to the 1st acquisition session. The immediate effect of DGAVP was a shift in the bell-shaped curve of the relation between arousal and performance (13); an increase in acquisition performance was observed with a low dose of DGAVP (0.1 microgram), while a decrease was found with a high dose of DGAVP (1 microgram). A dose-dependent inhibition of extinction was found in both low and high active animals. These results suggest an immediate effect of DGAVP on the rate of acquisition behavior, which may be a direct consequence of its arousing properties, and a long-term effect on extinction, indicating the formation of memory traces specific for vasopressin-related neuropeptides.     

Vasopressin release in response to hypovolaemia in the conscious rat and the effect of opioid and aminergic receptor antagonists.

Conscious rats were given i. p. polyethylene glycol (PEG) or dextran injections to compare their efficacy in inducing moderate hypovolaemia. Dextran was found unsuitable, producing large variability in the plasma vasopressin (AVP) concentrations. Putative neurotransmitters involved in the AVP response to hypovolaemia and in basal release were examined using opioid, and beta-adrenoceptor and dopamine receptor-blocking agents. A dose of PEG was chosen to produce a decrease in blood volume of approx 14.5% giving plasma AVP concentrations of 19.0 +/- 4.6 pmol/l. Naloxone and phenoxybenzamine failed to influence AVP release under both hypovolaemic and basal conditions. Prazosin also failed to influence the AVP response. In contrast propranolol elevated the plasma AVP concentrations in both conditions. Haloperidol enhanced basal AVP release but did not influence release during hypovolaemia. Guanethidine pretreatment partially blocked the response to hypovolaemia, but did not affect basal plasma AVP. Thus it appears that aminergic pathways have an inhibitory influence on AVP release under hypovolaemic and basal conditions. However, endogenous opioids do not appear to contribute significantly to the hypovolaemic response.