Christine Lebrun

Behavioral effects of peripheral administration of arginine vasopressin: a review of our search for a mode of action and a hypothesis ☆

In this review we present data summarizing our studies concerning the mechanism of action for the behavioral effects of peripheral arginine vasopressin (AVP) administration. We have demonstrated a clear performance improvement in a one trial appetitive task designed to measure the memory-learning process. This behavioral effect is blocked by peptide analogs which block the pressor response to AVP. From these data, and from other data obtained in aversively motivated tasks, we hypothesize that peripheral AVP injections induce effects of physiological-endocrinological origin and that these peripheral signals (e.g. vasopressor actions) alert and arouse the animal, thus helping to improve its association of environmental events. This hypothesis is similar to that proposed by others regarding peripheral hormones and memory and still leaves open the possibility that vasopressin in the brain acts independently of the above proposed action for peripherally derived vasopressin.

Angiotensin II induces a complex activation of transcription factors in the rat brain : expression of Fos, Jun and Krox proteins

We investigated the effects of intracerebroventricular injection of angiotensin II on neuronal immediate early gene-encoded protein synthesis in the brain of conscious rats. The expression of seven immediate early gene-encoded transcription factors (c-Fos, FosB, c-Jun, JunB, JunD, Krox-20 (Egr-2) and Krox-24 (NGFI-A, Egr-1, Zif/268) was assessed simultaneously. Angiotensin II (1, 10, 100 ng) induced a dose-dependent expression of c-Fos and Krox-24 in the subfornical organ, the median preoptic area and in the paraventricular nucleus and supraoptic nucleus of the hypothalamus, regions known to be involved in the central osmoregulatory and neuroendocrine actions of angiotensin II. FosB expression was induced four hours after icv injection of the highest dose of angiotensin II in the median preoptic area and paraventricular nucleus, c-Jun expression was restricted to the median preoptic area, subfornical organ and paraventricular nucleus, and JunB was only induced in the median preoptic area and subfornical organ. In these above mentioned regions, JunD exhibited a high basal staining, which was not visibly altered by angiotensin II. Krox-20 was not induced by angiotensin II. Intracerebroventricular injections of isotonic saline did not induce immediate early gene expression in any of the above brain areas. The angiotensin II-AT1 receptor antagonist, losartan, applied intracerebroventricular five minutes prior to angiotensin II, prevented the angiotensin II-induced immediate early gene protein expression. Losartan alone had no effects on immediate early gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Arginine Vasopressin, Stress, and Memory

Arginine vasopressin (AVP) has been shown to have several non-renal actions including the potentiation of learned avoidance behavior in rats and improvement in cognitive functioning in humans. Research in our laboratory has confirmed these behavioral effects in rats using both peripheral and central injection of AVP. We have begun to examine the physiological basis for these effects. Peripheral administration of a vasopressor AVP antagonist reversed the prolongation of extinction produced by peripherally administered AVP in both active and passive avoidance, but also reversed the aversive unconditioned effects of AVP. However, central administration of the vasopressor AVP antagonist reversed peripheral effects of AVP only at doses shown to act peripherally to reverse vasopressor effects of AVP. An osmotic stress in doses known to liberate endogenous AVP mimicked the behavioral effects of exogenously administered AVP, and this stress effect was reversed by the AVP antagonist. These results support our hypothesis of separate but parallel AVP systems in the pituitary and brain with a role in behavioral adaptation to certain types of stress.

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.

Increased Brain Transcription Factor Expression by Angiotensin in Genetic Hypertension

A stimulated brain renin-angiotensin system has been implicated in genetic hypertension. We compared the effects of an intracerebroventricular injection of angiotensin II (100 ng) on the expression of inducible transcription factors c-Fos, c-Jun, and Krox-24 in the brain of spontaneously hypertensive rats (SHR). in Wistar rats with nephrogenic hypertension induced by aortic banding, and in normotensive Wistar-Kyoto and Wistar rats immunohistochemically. Generally, the angiotensin II-induced transcription factor expression was strictly confined to four distinct forebrain areas: the subfornical organ, median preoptic area, paraventricular nucleus, and supraoptic nucleus. In SHR, the angiotensin II-induced c-Fos and c-Jun expressions were significantly enhanced compared with those in normotensive control strains as well as in secondary hypertensive Wistar rats. Krox-24 expression in the subfornical organ, median preoptic area, and paraventricular nucleus of SHR was also significantly increased compared with that in all control strains. In the supraoptic nucleus, significant differences could be discriminated between SHR and secondary hypertensive Wistar rats. Injection of isotonic saline or arginine vasopressin (100 ng) as controls did not induce any expression of c-Fos, c-Jun, or Krox-24. Our findings demonstrate an enhanced sensitivity of SHR to angiotensin II-induced transcription factor expression in distinct brain areas involved in central blood pressure and osmotic control that is independent of blood pressure.

Antogonism of effects of vasopressin (AVP) on inhibitory avoidance by a vasopressin antagonist peptide [dPtyr (Me) AVP]

After training in two different passive avoidance tasks, the platform box of Ader and De Wied (1972) and the Jarvik box of Jarvik and Kopp (1967), rats injected with vasopressin immediately following the training trial showed a significant enhancement of retention 24 hours later. This vasopressin effect was reversed by high doses of the vasopressor antagonist, dPtyr(Me) AVP. These results support the hypothesis that the visceral afferent signals may be involved in the apparent memory-enhancing effects of AVP, but the high doses of antagonist required suggest that factors other than a simple reversal of the pressor effects of AVP may be important.

Angiotensin II Induces the Expression of C-FOS mRNA in the Central Nervous System of the Rat

We have investigated the effects of intracerebroventricular injections of angiotensin II in conscious rats on the expression of c-fos messenger RNA (mRNA) in the caudate nucleus, hypothalamus, midbrain and brainstem using semi-quantitative polymerase chain reaction and Northern Blots. RNA analysis revealed the presence of c-fos transcripts in the midbrain and brainstem following icv injections of ANG II. ANG II (1, 10, 100 ng) induced a substantial increase in c-fos mRNA in the brainstem which was significant after 10 ng ANG II, and less after 100 ng. This effect was time-dependent being detectable within 15 minutes and maximal after 60 minutes. This ANG II-induced c-fos mRNA expression was totally inhibited by icv pretreatment with the ANG II-AT1 receptor antagonist, losartan. Our data show for the first time that stimulation of central periventricular AT1 receptors induces the expression of c-fos mRNA in the brain. Thus, ANG II, in addition to its short-term regulatory actions, can participate through transcription factors in neuroplastic processes.

EEG effects of subcutaneous and intracerebroventricular injections of arginine vasopressin in the rat

Several studies have suggested that arginine vasopressin (AVP) may act centrally as a neurohormone or neuromodulator to produce electrophysiological and behavioral effects. However, there are few reports of EEG effects of AVP in unanesthetized, behaving animals. In the present study the EEG effects of “behaviorally relevant” subcutaneous (SC) doses of AVP (6 μg/kg) known to raise blood pressure were compared to “behaviorally relevant” intracerebroventricular (ICV) doses (0.1–1.0 ng) and multiple “toxic” ICV doses (1.0 μg) of AVP. Central injections of toxic doses of AVP produced behavioral arrest, bodily barrel rolling, and EEG slowing, but did not induce electrographic signs of seizure activity. Comparison of the spectral characteristics of the EEG revealed some similarities in the distribution of power between SC and the 1.0 ng ICV dose; whereas ICV doses of 0.1 and 0.5 ng produced power distributions that were different from those seen following saline or SC doses of AVP. The similarities in EEG activity between SC injections and the 1.0 ng ICV dose suggest a common brain state may be induced by the two routes of administration in those dose ranges.

Central vasopressin pretreatment sensitizes phosphoinositol hydrolysis in the rat septum

Previous in vivo and in vitro studies have demonstrated that exposure of the brain to arginine vasopressin (AVP) can potentiate various responses to a second central challenge with AVP. To determine whether this sensitization is mediated by changes at the receptor level, we investigated the effects of AVP on the phosphoinositide metabolism in septal slices prepared from rats centrally pretreated with saline or AVP. Addition of vasopressin (10(-7) M, 10(-6) M) to septal slices from saline-pretreated rats failed to elicit a significant stimulation of inositol-1-phosphate (IP1). In contrast, AVP (10(-7) M) significantly stimulated IP1 release in septal slices prepared from rats pretreated intracerebroventricularly (i.c.v.) 24 h earlier with 10 or 100 ng AVP. Pretreatment with the same i.c.v. doses of AVP also induced a significant enhancement of the carbachol-induced stimulation of IP1 release, but i.e.v. pretreatment with carbachol did not stimulate the IP1 release in response to AVP. Our results suggest that a novel facilitation of phosphoinositide metabolism can be induced by central AVP pretreatment.