Review
Overview of cellular electrophysiological actions of vasopressin

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Abstract

The nonapeptide vasopressin acts both as a hormone and as a neurotransmitter/neuromodulator. As a hormone, its target organs include kidney, blood vessels, liver, platelets and anterior pituitary. As a neurotransmitter/neuromodulator, vasopressin plays a role in autonomic functions, such as cardiovascular regulation and temperature regulation and is involved in complex behavioral and cognitive functions, such as sexual behavior, pair-bond formation and social recognition. At the neuronal level, vasopressin acts by enhancing membrane excitability and by modulating synaptic transmission. The present review will focus on the electrophysiological effects of vasopressin at the cellular level. A large proportion of the experiments summarized here have been performed in in vitro systems, especially in brain and spinal cord slices of the rat. Vasopressin exerts a powerful excitatory action on motoneurons of young rats and mice. It acts by generating a cationic inward current and/or by reducing a potassium conductance. In addition, vasopressin enhances the inhibitory synaptic input to motoneurons. By virtue of these actions, vasopressin may regulate the functioning of neuronal networks involved in motor control. In the amygdala, vasopressin can directly excite a subpopulation of neurons, whereas oxytocin, a related neuropeptide, can indirectly inhibit these same neurons. In the lateral septum, vasopressin exerts a similar dual action: it excites directly a neuronal subpopulation, but causes indirect inhibition of virtually all lateral septal neurons. The actions of vasopressin in the amygdala and lateral septum may represent at least part of the neuronal substrate by which vasopressin influences fear and anxiety-related behavior and social recognition, respectively. Central vasopressin can modulate cardiovascular parameters by causing excitation of spinal sympathetic preganglionic neurons, by increasing the inhibitory input to cardiac parasympathetic neurons in the nucleus ambiguus, by depressing the excitatory input to parabrachial neurons, or by inhibiting glutamate release at solitary tract axon terminals. By acting in or near the hypothalamic supraoptic nucleus, vasopressin can influence magnocellular neuron activity, suggesting that the peptide may exert some control on its own release at neurohypophyseal axon terminals. The central actions of vasopressin are mainly mediated by receptors of the V1A type, although recent studies have also reported the presence of vasopressin V1B receptors in the brain. Major unsolved problems are: (i) what is the transduction pathway activated following stimulation of central vasopressin V1A receptors? (ii) What is the precise nature of the cation channels and/or potassium channels operated by vasopressin? (iii) Does vasopressin, by virtue of its second messenger(s), interfere with other neurotransmitter/neuromodulator systems? In recent years, information concerning the mechanism of action of vasopressin at the neuronal level and its possible role and function at the whole-animal level has been accumulating. Translation of peptide actions at the cellular level into autonomic, behavioral and cognitive effects requires an intermediate level of integration, i.e. the level of neuronal circuitry. Here, detailed information is lacking. Further progress will probably require the introduction of new techniques, such as targeted in vivo whole-cell recording, large-scale recordings from neuronal ensembles or in vivo imaging in small animals.

Introduction

The nonapeptide vasopressin acts both as a hormone and as a neuromodulator. As a hormone, its target organs include kidney, blood vessels, liver, platelets and anterior pituitary. In peripheral cells, vasopressin binds to three distinct receptors: (i) vasopressin V1A receptors, which trigger phospholipase-Cβ (PLCβ) activation and calcium mobilization, and are present in smooth muscle, liver and platelets. (ii) vasopressin V1B receptors, which are also coupled to PLCβ and are found in the anterior pituitary. (iii) vasopressin V2 receptors, which are coupled to adenylyl cyclase, and are present in the kidney (Barberis et al., 1998, Birnbaumer, 2000, Schoneberg et al., 1998, Thibonnier et al., 1998). Although with somewhat less potency, vasopressin can also bind to oxytocin receptors. Peripheral oxytocin receptors, present in the uterus and in the mammary gland, are coupled to a PLCβ (Arnaudeau et al., 1994, Ku et al., 1995, Phaneuf et al., 1995, Phaneuf et al., 1996).

In the brain, vasopressin exerts its effects mainly by binding to vasopressin V1A receptors (Barberis and Tribollet, 1996, Raggenbass, 2001, Tribollet, 1992). Recently, the presence of vasopressin V1B receptors in some central structures has also been reported (Hernando et al., 2001, Lolait et al., 1995, Stemmelin et al., 2005, Vaccari et al., 1998, Young et al., 2006). Central vasopressin plays a role in autonomic functions, such as cardiovascular regulation (Toba et al., 1998), temperature regulation (Roth et al., 2004) and neocortical water-flux modulation (Niermann et al., 2001) and is involved in complex behavioral and cognitive functions, such as sexual behavior (Smock et al., 1998), memory processes (Alescio-Lautier et al., 2000), pair-bond formation (Lim et al., 2004, Young et al., 1999, Young and Wang, 2004), fatherhood behavior (Kozorovitskiy et al., 2006), anxiety and depression (Bielsky et al., 2004, Holmes et al., 2003, Landgraf, 2005) and social recognition (Bielsky et al., 2004Bielsky et al., 2005, Keverne and Curley, 2004, Winslow and Insel, 2004).

The present review will focus on the electrophysiological effects of vasopressin at the neuronal level. A large proportion of the experiments summarized here have been performed in in vitro systems, especially in brain and spinal cord slices of the rat. Data published up to about 2000 have been previously reviewed (Raggenbass, 2001), and will not re-reviewed here in their entirety.

Section snippets

Vasopressin as an activator of motoneurons

A pioneering study showed that vasopressin could directly enhance the excitability of spinal motoneurons (Suzue et al., 1981). Since then, the action of vasopressin on motoneurons has probably become the most thoroughly studied and best characterized effect of the peptide at the cellular level. During development, vasopressin V1A receptors are abundantly expressed in brainstem and spinal motor nuclei (Barberis and Tribollet, 1996, Liu et al., 2003, Tribollet et al., 1991, Tribollet, 1992). By

Vasopressin and the amygdala: a partnership with oxytocin

The amygdala contains high amounts of vasopressin and oxytocin receptors (Tribollet et al., 1988, Veinante and Freund-Mercier, 1997). At least part of these receptors are functional, since extracellular recordings, performed in brain slices, showed an excitatory action of vasopressin on about half of the neurons located in the central nucleus, and an inhibitory action only in a minority of them (Lu et al., 1997). The excitatory effect, which was suppressed by a vasopressin V1A receptor

Vasopressin and lateral septum: direct and indirect effects

The lateral septal area is rich in vasopressin V1A receptors (Freund-Mercier et al., 1988b, Tribollet et al., 1988, Tribollet, 1992). In addition, the lateral septum is densely innervated by vasopressinergic axons, originating mostly from the bed nucleus of the stria terminalis and the amygdala (Caffe et al., 1987). Recent genetic and behavioral studies have evidenced that vasopressin V1A receptors expressed in this area play a determinant role in promoting social recognition (Bielsky et al.,

Vasopressin and autonomic functions

Central vasopressin is capable of influencing a variety of autonomic functions (see above). In particular it can modulate cardiovascular parameters such as blood pressure and heart rate (Toba et al., 1998). Little is known about the sites of action and the neuronal mechanisms by which the peptide exerts these regulatory roles. One such site is probably the spinal cord. Previous studies have shown that vasopressin, by stimulating vasopressin V1A but not V2 receptors, can depolarize lateral horn

Vasopressin and the supraoptic nucleus: autoregulation?

Ultrastructural evidence indicates that dense core vesicles are present in the soma and dendrites of supraoptic magnocellular neurons and that exocytose can occur (Pow and Morris, 1989). In vivo and in vitro studies have shown that the vasopressin concentration in the extracellular compartment of the supraoptic nucleus is higher than in the plasma and can vary in response to a variety of stimuli (reviewed in Ludwig, 1998). In addition, in vivo studies suggest that vasopressin, by acting at or

A role for central vasopressin V1B receptors?

As stated above, several studies have reported the presence of vasopressin V1B receptors in some central structures (Hernando et al., 2001, Lolait et al., 1995, Stemmelin et al., 2005, Vaccari et al., 1998). In addition, central effects of vasopressin possibly mediated by vasopressin V1B receptors have been recently reported by several groups. The vasopressin V1B receptor antagonist SSR149415 appears to exert anxiolytic- and antidepressant-like effects (Griebel et al., 2002, Stemmelin et al.,

Central vasopressin and signal transduction

As summarized above, peripheral vasopressin V1A receptors are coupled to G proteins of the Gq/11 class, and receptor stimulation by agonists activates PLCβ. This in turn triggers the production of inositol-1,4,5 trisphosphate, which releases Ca2+ from intracellular stores, and diacylglycerol, which activates PKC (Birnbaumer et al., 1992, Thibonnier et al., 1998). What is the intracellular signal activated by central vasopressin? Few studies have attempted to determine the transduction pathway

Conclusions and perspectives

Recent studies on the mechanism of action of vasopressin, performed at the cellular level or at the level of local neuronal circuitry, have revealed a recurrent theme. Vasopressin appears to exert its effects, at least in some central nervous structures, in a dual, apparently paradoxical manner: (i) by acting postsynaptically, it causes excitation in a specific neuronal population; (ii) by acting indirectly, it causes inhibition in this same neuronal population. This is the case for VII and XII

Acknowledgements

The author's work cited in this review was supported in part by the Swiss National Science Foundation and the Fondation Carlos et Elsie de Reuter, Geneva, Switzerland. I thank Dr. Isabelle Reymond-Marron for performing the experiment described in Fig. 3 and Dr. Eliane Tribollet for reading the manuscript and offering insightful comments.

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