Ameliorative effect of vasopressin-(4–9) through vasopressin V1A receptor on scopolamine-induced impairments of rat spatial memory in the eight-arm radial maze

https://doi.org/10.1016/S0014-2999(01)01200-6Get rights and content

Abstract

In order to clarify the mechanism by which pGlu-Asn-Cys(Cys)-Pro-Arg-Gly-NH2 (vasopressin-(4–9)), a major metabolite C-terminal fragment of [Arg8]-vasopressin (vasopressin-(1–9)), improves learning and memory, we used several different drugs such as an acetylcholine receptor antagonist, a Ca2+/calmodulin-dependent protein kinase II inhibitor, vasopressin receptor antagonists and L-type Ca2+ channel blocker to disrupt spatial memory in rats. Moreover, we examined the effect of vasopressin-(4–9) on acetylcholine release in the ventral hippocampus using microdialysis. Vasopressin-(4–9) (10 fg/brain, i.c.v.) improved the impairment of spatial memory in the eight-arm radial maze induced by scopolamine, pirenzepine and Ca2+/calmodulin -dependent protein kinase II inhibitor. Pirenzepine, a vasopressin V1A receptor antagonist, and L-type Ca2+ channel blocker, but not a vasopressin V2 receptor antagonist, suppressed the effects of vasopressin-(4–9) on scopolamine-induced impairment of spatial memory. Moreover, vasopressin-(4–9) did not affect acetylcholine release in the ventral hippocampus of intact rats or of scopolamine-treated rats as assessed by microdialysis. These results suggest that vasopressin-(4–9) activates vasopressin V1A receptors on the postsynaptic membrane of cholinergic neurons, and induces a transient influx of intracellular Ca2+ through L-type Ca2+ channels to interact with muscarinic M1 receptors. The activation of these processes by vasopressin-(4–9) is critically involved in the positive effect of vasopressin-(4–9) on scopolamine-induced impairment of spatial memory.

Introduction

[Arg8]-vasopressin (vasopressin-(1–9)), a nine-amino-acid peptide secreted by the neurohypophysis traditionally associated with water balance and blood pressure modulation, has been shown to act as a neurotransmitter or a neuromodulator in the central nervous system Brinton and McEwen, 1989, Brinton et al., 1994. Numerous studies have shown that vasopressin-(1–9) affects many kinds of behavior, especially learning and memory Kovács and De Wied, 1994, De Wied, 1997, Landgraf et al., 1998. For example, it was reported that vasopressin-(1–9) administered systemically or centrally, facilitated the consolidation and retrieval processes of active (Engelmann et al., 1992a) or passive avoidance tasks (Burbach et al., 1983), and enhanced social recognition (Engelmann et al., 1996), the retention of a visual discrimination task (Paban et al., 1997) and working and reference memory in radial maze (Dietrich and Allen, 1997), and improved experimentally induced impairment of learning and memory Fujiwara et al., 1997, Hirate et al., 1997. Vasopressin-(1–9) in the central nervous system was also reported to interact with classical neurotransmitter systems Brinton and McEwen, 1989, Maegawa et al., 1992, to elicit electrophysiological effects Joëls and Urban, 1984, Tanaka et al., 1994, Omura et al., 1999, to stimulate second messenger systems (Nakayama et al., 2000), to change Ca2+ channel activity Brinton et al., 1994, Gouzenes et al., 1999 and to induce the expression of transcription factors Giri et al., 1990, Zhou et al., 1995. Although these actions of vasopressin-(1–9) seem to be mediated via the vasopressin V1 receptor subtype, the exact mechanisms of action of centrally released vasopressin-(1–9) in learning and memory are largely unclear. This is because vasopressin-(1–9) is rapidly degraded in the brain by membrane-bound aminopeptidases with a half-time of <1 min Burbach and Lebouille, 1983, Stark et al., 1989.

Burbach et al. (1983) explored the metabolites of vasopressin-(1–9) that enhance learning and memory, and showed that the main active metabolite of vasopressin-(1–9) produced by aminopeptidase was the carboxy-terminal 4–9 sequence [pGlu4, Cyt6] vasopressin-(4–9) (vasopressin-(4–9)), and that vasopressin-(4–9) and its derivative vasopressin-(4–8) were about 1000- to 10,000-fold more potent than vasopressin-(1–9) to affect consolidation and retrieval processes of passive avoidance. Vasopressin-(4–8), the cysteinyl methyl ester derivative of vasopressin-(4–9), has been studied behaviorally and biochemically in detail as a highly potent metabolite of vasopressin-(1–9) Lin et al., 1990, Du et al., 1998. These peptides were found to be more selective on learning and memory without affecting the regulation of water balance and blood pressure Burbach et al., 1983, Lin et al., 1990.

In a previous study (Fujiwara et al., 1997), we also found that vasopressin-(4–9) administered by i.c.v. injection and its newly synthesized analogue, l-Pyroglutamyl-l-asparaginyl-l-seryl-l-prolyl-l-prolyl-l-arginylglycinamide (NC-1900, Hirate et al., 1997), in which the cysteine residue of vasopressin-(4–9) was replaced by serine, at a dose in the fentogram range, improved the scopolamine-induced impairment of spatial memory in an eight-arm radial maze, and were about 1000–10,000 times as potent as vasopressin-(1–9), with its smaller fragments being much less active. In addition, the scopolamine-induced disruption of spatial memory was found to be improved by the microinjection of vasopressin-(4–9) into the ventral hippocampus but not into the dorsal hippocampus. Our results thus suggested that the hexapeptide containing the 4th to 9th amino acids (H-Asn-Cys(Cys)-Pro-Arg-OH) and the 6th amino acid (Cys–Cys bond) found in the structure of vasopressin-(1–9) were important for its effects and that the ventral hippocampus was the region where vasopressin-(4–9) exerted its effect. However, the mechanisms by which vasopressin-(4–9) improves learning and memory have not yet been clarified, because the vasopressin-(4–9) binding site remains questionable Brinton et al., 1986, Jurzak et al., 1993, Nakayama et al., 2000, in spite of numbers of behavioral studies about learning and memory enhancement by vasopressin-(4–9) Dietrich and Allen, 1997, Tanabe et al., 1999. The purpose of the present study was to clarify the mechanisms by which vasopressin-(4–9) improves learning and memory. We therefore used several different drugs such as an acetylcholine receptor antagonist, Ca2+/calmodulin-dependent protein kinase II inhibitor, vasopressin receptor antagonists and an L-type Ca2+ channel blocker to disrupt spatial memory of rats and examined the interaction between vasopressin receptor and muscarinic receptor. We also examined the effect of vasopressin-(4–9) on acetylcholine release in the ventral hippocampus, using microdialysis.

Section snippets

Animals and housing

Male Wistar, rats weighing 200–250 g, were obtained from Kyudo (Saga, Japan), and were housed in groups of four to five animals per cage, in a room with the temperature controlled at 23±2 °C and a relative humidity of 60±10% with the lights on from 7:00 am to 7:00 pm. The animals were allowed a restricted food intake (10–12 g/day, CE-2, Crea Japan, Tokyo, Japan). Their body weight was maintained at approximately 80% of their weight under free-feeding conditions during the experimental period.

Effects of vasopressin-(4–9) on scopolamine-induced impairments of spatial memory

All animals performed successfully in the maze within a maximum of 20 days. When the rats underwent cannula implantation and drug injection, they were re-trained and it was confirmed that they maintained their previous performance level.

As shown in Fig. 1, after scopolamine (0.5 mg/kg, i.p.), the number of correct choices decreased significantly while that of errors increased. Vasopressin-(4–9) (10 fg/brain, i.c.v.) reversed the decrease in the number of correct choices and the increase in

Discussion

In the present study, we found that vasopressin-(4–9) administered by i.c.v. injection, even at the very small dose of 10 fg, improved the scopolamine-induced impairment of spatial memory of rats in the eight-arm radial maze in agreement with our previous report (Fujiwara et al., 1997). Moreover, we examined whether vasopressin-(4–9) could improve the impairment of spatial memory induced by pirenzepine, a muscarinic M1 receptor antagonist, in rats. The results demonstrated that

Acknowledgements

Part of this study was supported by a Grant-in Aid for Scientific Research from the Japanese Ministry of Education, Science and Culture. We thank Otsuka Pharmaceutical for the kind gift of OPC-31260, as well as Dr. K. Hirate and Dr. Y. Ohgami for helpful discussion and skillful technical assistance.

References (47)

  • P.R. Giri et al.

    Arginine vasopressin induces the expression of c-fos in the mouse septum and hippocampus

    Mol. Brain Res.

    (1990)
  • K. Hirate et al.

    No. 302, a newly synthesized [pGlu4, Cyt6]AVP(4–9) analogue, prevents the disruption of avoidance behavior

    Behav. Brain Res.

    (1997)
  • K. Iwasaki et al.

    The disruption of spatial cognition and changes in brain amino acid, monoamine and acetylcholine in rats with transient cerebral ischemia

    Brain Res.

    (1996)
  • M. Joëls et al.

    Arginine–vasopressin enhances the responses of lateral septal neurons in the rat to excitatory amino acids and fimbria–fornix stimuli

    Brain Res.

    (1984)
  • C. Lin et al.

    Cysteinyl methyl ester of AVP(4–8), a potent agonist on the maintenance of passive avoidance in rats

    Peptides

    (1990)
  • H. Maegawa et al.

    Arginine–vasopressin fragment 4–9 stimulates the acetylcholine release in hippocampus of freely-moving rats

    Life Sci.

    (1992)
  • K. Mishima et al.

    The scopolamine-induced impairment of spatial cognition parallels the acetylcholine release in the ventral hippocampus in rats

    Jpn. J. Pharmacol.

    (2000)
  • Y. Nakayama et al.

    Pharmacological characterization of a novel AVP4–9 binding site in rat hippocampus

    Brain Res.

    (2000)
  • T. Omura et al.

    Intracellular pathways of V1 and V2 receptors activated by arginine vasopressin in rat hippocampal neurons

    J. Biol. Chem.

    (1999)
  • V. Paban et al.

    Effects of arginine8–vasopressin administered at different times in the learning of an appetitive visual discriminative task in mice

    Behav. Brain Res.

    (1997)
  • H. Stark et al.

    In vivo conversion of vasopressin after microinjection into limbic brain areas of rats

    Peptides

    (1989)
  • S.E. Tan et al.

    Inhibitory avoidance learning alters the amygdala calcium/calmodulin-dependent protein kinase II activity in rats

    Brain Res.

    (1997)
  • S. Tanabe et al.

    Effects of arginine–vasopressin fragment 4–9 on rodent cholinergic systems

    Pharmacol. Biochem. Behav.

    (1999)
  • Cited by (26)

    • Sex differences of oxytocin and vasopressin in social behaviors

      2021, Handbook of Clinical Neurology
      Citation Excerpt :

      How long-term intervention influences mature cerebral function is also a question that remains to be solved. Current studies have shown that VP has a memory-enhancing effect (Mishima et al., 2001; Barsegyan et al., 2015; Hicks et al., 2015). The most relevant brain region for this effect is the hippocampus (Alescio-Lautier et al., 2000).

    View all citing articles on Scopus
    View full text