Behavioral Consequences of Intracerebral Vasopressin and Oxytocin: Focus on Learning and Memory *

Neuroscience and Biobehavioral Reviews, Vol. 20, No. 3, pp. 341–358, 1996 Copyright 01996 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0149-7634/96 $32.00 + .00

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Behavioral Consequences of Intracerebral Vasopressinand Oxytocin: Focus on Learning and Memory* MARIO ENGELMANN,T’ CARSTEN T. WOTJAK,t INGA NEUMANN,t MIKE LUDWIG* AND RAINER LANDGRAFt rDepartment of Neuroendocrinology, Clinical Institute, Max Planck Institute of Psychiatry, Kraepelinstrasse 2, 80804 Munich, Germany and $Department of Physiology, Medical School, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK

ENGELMANN,M.,C. T. WOTJAK,I. NEUMANN,M. LUDWIGAND R. LANDGRAF.Behavioral consequences of intracerebral vasopressin and oxytocin: Focus on learning and memory. NEUROSCI BIOBEHAV REV 20(3)341-358, 1996.—Sincethe pioneering work of David de Wied and his colleagues, the neuropeptides arginine vasopressin and oxytocin have been thought to play a pivotal role in behavioral regulation in general, and in learning and memory in particular. The present review focuses on the behavioral effects of intracerebral arginine vasopressin and oxytocin,with particular emphasis on the role of these neuropeptides as signals in interneuronal communication. We also discuss several methodological approachesthat have been used to reveal the importance of these intracerebral neuropeptides as signals within signaling cascades. The hterature suggests that arginine vasopressin improves, and oxytoein impairs, learning and memory. However, a critical analysis of the subject indicates the necessity for a revision of this generalized concept. We suggest that, depending on the behavioral test and the brain area under study, these endogenous neuropeptides are differentially involved in behavioral regulation; thus, generalizations derived from a single behavioral task should be avoided. In particular, reeent studies on rodents indicate that sociallyrelevant behaviors triggered by olfactory stimuli and paradigms in which the animals have to cope with an intense stressor (e.g., foot-shock motivated active or passive avoidance) are controlled by both arginine vasopressin and oxytocin released intracerebrally. Copyright @ 1996Elsevier Science Ltd. Vasopressin Oxytocin Intraeerebral neuropeptide release Interneuronal communication Antagonist Learning Memory Behavior Hamsters Rats Voles

1. INTRODUCTION

blood stream after appropriate stimulation [AVP: e.g., osmotic challenge, hemorrhage; OXT: e.g., suckling, parturition (40)]. In addition to this well-characterized hypothalamic–neurohypophysial axis release (89) and projections from the PVN to the median eminence as part of the hypothalamic–pituitary–adrenal system (11), both peptides are released within the central nervous system and therefore may be regarded as neuropeptides. Exohypothalamic (e.g., originating from the PVN) as well as extrahypothalamic [e.g., originating from the bed nucleus of the stria terminals (BNST)] vasopressinergic and oxytocinergic fibers innervate other brain regions, such as the limbic areas [e.g., septum and hippocampus (32,189)]. Moreover, the finding that both AVP and OXT are released synaptically not only from axon terminals but also from

BEHAVIORAL PERFORMANCE, which is related causally to learning and memory, is controlled by highly specialized neuronal networks. Integrative components of these networks are substances that transfer information between neurons as neurotransmitters and/or neuromodulators. The structurally related nonapeptides arginine vasopressin (AVP) and oxytocin (OXT) belong to those signals known to take part in interneuronal communication. They are synthesized in magnocellular and parvocellular neurons, which are predominantly located within the paraventricular (PVN) and supraoptic (SON) nuclei. From these hypothalamic nuclei, axons run to the neurohypophysis where both peptides are released into the

*This paper is dedicated to our friend and scientific teacher Prof. Dr Armin Ermisch (1935–1995). ‘To whom correspondence should be addressed. 341

342 dendrites and somata of hypothalamic neurons (169) has substantially broadened our knowledge of the involvement of these neuropeptides in interneuronal communication. After their release into the respective brain target area, AVP and OXT mediate their central effects via the AVP V1 receptor subtype and the OXT receptor (53). Central actions include a variety of autonomic, endocrine and behavioral effects (13,53,172). The physiological involvement of AVP and OXT (and their receptors) in behavioral performance in general, and learning and memory in particular, is one of the most prominent and controversial issues in the field. Pioneering work on this topic was started 30 years ago by David de Wied and his colleagues in Utrecht (51). Since then many papers have been published on the effects of central and peripheral administration of these peptides, their receptor antagonists and their behaviorally potent fragments (7,53,118). However, several questions remain to be answered. Can AVP be regarded as a general memory-enhancing peptide in comparison to OXT, which is thought to be an amnestic, as claimed by Kovacs and Telegdy (119)? Is the intracerebral release of AVP involved causally in behavioral regulation? How do AVP and OXT administered peripherally influence learning and memory performance, and can these actions be dissociated from those of the neuropeptides released centrally? The latter question in particular has been the cause of conflicting discussion (93). Various studies have reported that intraperitoneal (i.p.) or subcutaneous (s.c.) injection of synthetic AVP or its analogues improves the performance of rats in active (26) and passive (25) avoidance behavior as well as in a paradigm for short-term olfactory memory (42). These findings were supported by studies in humans (200,214). In contrast, other authors reported that peripherally administered AVP failed to have a positive influence on learning and memory performance [e.g., passive avoidance (94,176), delayed matching to sample (9), human memory (75,76)]. While searching for the causes of these discrepancies, several authors reported that blockade of the pressure activity of AVP injected peripherally by specific antagonists also abolished the behavioral effects of the AVP treatment (22,137). Additional experiments showed that the peripherally injected peptide induced aversive effects and acted as an unconditioned stimulus (58,59,193). These findings suggest that AVP treatment may alter behavior without “directly” influencing learning and memory processes at the brain level (58-60,70,71,136,137,176). Thus, pharmacological studies using the peripheral route of administration usually allow only vague conclusions to be drawn about the sites of action of AVP and OXT [(56), but see (55) for a definite conclusion], especially since the contribution of circulating peptides to the interneuronal communication is negligible because of their restricted passage through the blood–brain barrier (68,69). In 1983 Mens and colleagues (143) demonstrated that only 0.002Y0 of s.c.-administered AVP or OXT reached the cerebrospinal fluid (CSF) within the first 10 min post-injection. This finding has been

ENGELMANN ET AL. confirmed by our own studies that show that intravenous injection of a cocktail of synthetic AVP and OXT failed to alter the concentration of these neuropeptides in push–pull perfusates from limbic brain areas (127). Considering that the concentration of AVP in the extracellular fluid of discrete brain areas is several orders of magnitude higher than that in plasma (130), the central pool of this neuropeptide should not be affected significantly by the alteration of peripheral peptide concentration. Nevertheless, in some studies very high doses of synthetic AVP or OXT were administered peripherally to create behaviorally effective concentrations within the brain. However, this increases the risk of interference with behavioral perfo~mance in learning and memory paradigms that are predominantly caused by effects on visceral inputs (137). Since the interpretation of data obtained from studies in which AVP and OXT were administered peripherally is in some respect uncertain in a physiological context, we next review the behavioral consequences of AVP and OXT administered or released intracerebrally, with a special focus on learning and memory. Using selected behavioral paradigms we demonstrate that generalization of AVP and OXT functions on learning and memory should be avoided. However, first we discuss methodological approaches to the monitoring and manipulation of the neuromodulatory potential of AVP and OXT. 2. EXPERIMENTAL APPROACHES TO REVEALING BEHAVIORAL EFFECTS OF INTRACEREBRAL VASOPRESSIN AND OXYTOCIN

As already mentioned, behavioral performance is controlled by complex neuronal networks. As depicted in the information theory (141), interneuronal communication in these networks may be considered to consist of numerous sender–receiver assemblies where changes in sender or receiver sites, or both, are likely to occur. In a single sender–receiver assembly, the sender (in this case a neuropeptidergic neuron) increases the release of the signal (e.g., a neuropeptide acting as a neurotransmitter/neuromodulator) after an appropriate stimulus. Subsequently, mechanisms can be induced that allow the receiver site (i.e., a target neuron) to respond more sensitively to the signal. Both AVP and OXT can be regarded as signals within this type of signaling system in the brain. The following experimental approaches have been used to identify whether AVP and OXT are critically involved in different paradigms of learning and memory or behavioral performance in general: signal monitoring, signal reinforcement, signal reduction, sensitization of the receiver and desensitization of the receiver (Fig. 1). 2.1. Signal Monitoring Measurement of the release of endogenous neuropeptides concomitantly with behavioral testing provides essential information about neuropeptide involvement in the behavioral performance being

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studied. The initial attempts to quantify the secretory activity of neuropeptidergic neurons focused on changes in AVP and OXT concentrations in the CSF (125) and brain tissue (123,124). However, neither of these methods necessarily reflects the dynamics of intracerebral release (128). Therefore, in vivo push–pull perfusion, microdialysis (128) and soon computer-assisted real-time imaging techniques are thought to be more reliable approaches to the investigation of the signal function of these neuropeptides. Microdialysis has at least proven to be a suitable tool for monitoring the intracerebral release patterns of AVP and OXT in freely moving animals (66,155). 2.2. Signal Reinforcement The classical approach to determining the importance of an endogenous neuropeptide for learning and memory performance is to reinforce its signal function by increasing its concentration in the extracellular fluid of the entire brain, circumventricular areas or of a distinct brain area. Typically, the synthetic peptide is infused into the intracerebroventricular system (i.c.v.) with the expectation that it can be distributed easily throughout the brain to the target neurons via diffusion within the CSF and extracellular fluid. Direct infusion of the synthetic peptide into discrete brain areas represents a more selective administration. Direct infusion reduces possible interfering effects and thus confines the action of the peptide to the area of

interest in the brain and allows the quantification of its biologically active concentration. However, a disadvantage of both i.c.v. and local administration is that they often cause, at least transiently, local pharmacological concentrations. Thus, physiological concentrations (including temporal and spatial fluctuations) can hardly be achieved. This increases the risk of unspecific interactions with other neurotransmitter/neuromodulator systems. Another disadvantage is the necessity for substance administration immediately before or after the behavioral test, which usually causes additional stress to the animals. Furthermore, acute tissue irritation may occur with pressure microinjections into distinct brain areas. To circumvent these problems, a microdialysis administration technique was recently developed that allows substance administration by simply adding it to the dialysis medium and, after passage through the semipermeable membrane, delivery into the surrounding tissue based on its concentration gradient. With this technique peptides can be administered locally concomitantly with behavioral testing without causing intracranial pressure effects, which might disturb the animal’s behavior (63-65). Because substances can be administered continuously in this way for various time intervals (from minutes up to several hours), this approach may mimic release patterns within the brain more closely than a local injection. Thus, this technique, although invasive, allows an improved experimental access to learning- and memory-related processes in the brain

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TABLE 1 SELECTED STIMULI EVOKING INTRACEREBRAL RELEASE OF ARGININE VASOPRESSIN (AVP) AND OXYTOCIN (OXT) WITHIN HYPOTHALAMIC AND LIMBIC BRAIN AREAS IN RATS (DATA OBTAINED FROM IN VIVO MICRODIALYSIS AND PUSH-PULL PERFUSION STUDIES)

Stimulus Peripheral osmotic stimulation Local, intracerebral osmotic stimulation Intracerebral electric stimulation Parturition

Suckling

AVP Area of release (Ref.)

OXT Area of release (Ref.)

Septum (45,132) Hippocampus (132) SON (139) Septum (66) PVN (130) SON (130) Septum (45,157)

Septum (132) Hippocampus (132) SON (152) PVN (90) SON (155) Septum (157)

Septum (131) Hippocampus (131) PVN (155) SON (155) Septum (151) PVN [unchanged (155)] SON [unchanged (155)] Hippocampus (151) PVN (155) SON (147,155) Septum (131) Hippocampus (131)

PVN = paraventricular nucleus; SON = supraoptic nucleus.

during behavioral tests, particularly if the animals are trained repeatedly (e.g., in active avoidance or spatial navigation tests). Despite the use of refined administration techniques, it still remains difficult to answer questions regarding appropriate dosage. Therefore, the reinforcement of the signal by experimental stimulation that triggers the release of the respective endogenous neurotransmitter/neuromodulator appears to be more helpful. Stimuli that evoke the release of either AVP or OXT within discrete brain areas are shown in Table 1. In particular, peripheral osmotic stimulation (45,132) or, more recently, direct osmotic stimulation of selective brain nuclei (90,130) has been used to trigger the release of AVP within discrete brain areas and simultaneously to monitor peptide release and its behavioral consequences (66). In this context it should be mentioned that depending on the brain region and the functional state of the animal AVP and OXT may display positive feedback actions on their own central release, as shown in vitro (133,171) and in vivo (149,150,153,218). These actions to amplify further the signal on local receptors may contribute to a potentiated behavioral impact of the neuropeptide released locally. Considering the increasing importance of the application of molecular biological methods, there is a theoretical possibility of reinforcing the signal (i.e., to increase the release of the neuropeptide) by central administration of mRNA, which is subsequently translated into the corresponding amino acid sequence. However, in the case of AVP only a single paper has

reported success and physiological relevance with this approach (103). In animals that are transgenic for the AVP gene, an increased AVP secretion into the periphery and/or within the hypothalamus and other brain areas has been reported (38,146). Unfortunately, there are no behavioral data available concerning these animals. 2.3. Signal Reduction The first and most prominent animal model used to investigate behavioral consequences of signal reduction is the Brattleboro rat (10,190), which lacks endogenous, biologically active AVP because of a point mutation within the AVP precursor gene (178). Another attempt has been made to monitor the effects of a reduced signal transmission by comparing the behavior of female and male and of castrated and sham-operated rats (24,20). The vasopressinergic immunoreactivity within distinct limbic brain areas (e.g., septum, central nucleus of the amygdala, BNST) depends on male sexual steroids (46,48,49,210,212) and thus shows pronounced sex differences (50). However, one must bear in mind that behavioral alterations are not necessarily caused by the mere reduction of endogenous AVP, because a variety of autonomic and endocrine parameters may additionally be changed in these animal models. Further approaches to reducing the amount of are biologically active endogenous neuropeptides central administration of AVP or OXT antisera (208) or antisense oligodeoxynucleotides. The latter are thought to hybridize with the mRNA coding for the respective neuropeptide, thus terminating the translational process (16). This translational arrest has shown behavioral impact (184), although the precise mechanisms of action remain obscure in most cases (154). 2.4. Sensitization of the Receiver Sensitization of V1 receptors is a well-characterized phenomenon that follows repeated treatment with AVP or successive treatment with OXT and AVP (35,168). Although these studies suggest that only relatively high doses of the neuropeptide induce sensitization, it cannot be excluded entirely that any study that uses repeated intracerebral administration of AVP will be accompanied by such processes at the receptor site. In this context, we refer to possible interactions between AVP and OXT at the same receptor subtype (54,168). Additionally, there are indications that AVP receptors in the Brattleboro rat are probably more sensitive than those in normal rats (182,183). 2.5. Desensitization of the Receiver The receiver can be desensitized by reducing the number of free binding sites for the endogenous ligand. The development of peptide receptor antagonists in the early 1980s allowed a more or less selective blockade of specific receptor subtypes (122). However, antagonists have to be applied in pharmacologically high enough doses to ensure efficiency in blocking the

CENTRAL VASOPRESSIN AND OXYTOCIN AND BEHAVIOR receptor sites; the former being in competition with the endogenous ligand, which normally shows a higher affinity. A possible consequence is that the antagonists may also bind to related receptor subtypes and induce a variety of intrinsic effects. In particular, the frequently used VI receptor antagonist @CH,),Tyr(Me) AVP cross-reacts with the OXT receptor even though it is highly selective between the VI and V2 receptor subtype (54). Within the hippocampus, both VI and OXT receptors are regulated by glucocorticoids, because adrenalectomy causes a significant decrease in B~.x of AVP (159,177) and in the density of OXT binding (138). Furthermore, in contrast to the AVP receptor (192), intracerebral OXT receptor density appears to be dependent on gonadal steroids (44,160,202). As a novel tool, the antisense targeting technique enables the selective down-regulation of a receptor subtype (e.g., AVP Vl) in a distinct brain area and at the same time makes it possible to monitor the consequences on molecular and cellular events as well as on behavioral performance (129,140). According to Vanderwolf and Chain (203), research in learning and memory can best be pursued on the basis of studies of animal behavior and cellular approaches to brain function.

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arousal, emotion and motivation make synergistic- and coordinated- rather than separate contributions to the behavioral performance. Learning and memory, in close and dynamic context with the central functions already mentioned, involve acquisition and the preservation of new information about the world that surrounds the subject. According to the neuronal theory (203), the basis for learning and memory is neuronal plasticity, which allows the central nervous system to tune interneuronal communication in acquired (and intrinsic) circuits (19,165,196,205). To guarantee an adequate behavioral response to defined stimuli from the internal and external world, it is essential that new and relatively stable patterns of interneuronal communication are generated at the cellular level. All central functions that are related closely to the determination of behavior depend substantially on the primary activation of neurochemical pattern of limbic, cortical and hypothalamic neurons. Intracerebral neuropeptides such as AVP and OXT form major components of these operating mechanisms. In this context it is important to note that behavioral changes caused by individual experience and peptide effects may all depend on the same, or at least similar, neuronal mechanisms (203). 3.1. Active Avoidance

3. EFFECTS OF AVP AND OXT ON BEHAVIORAL PARADIGMS DIRECTLY RELATED TO LEARNING AND MEMORY

We are just beginning to understand the causal relationship between the temporally and spatially differentiated pattern of intracerebral AVP/OXT release and subsequent ligand–receptor interactions and the behavioral performance of the animal. Because generalized interpretations are almost impossible, it is challenging methodologically to verify these relationships clearly under physiological conditions and after central peptide administration. Before we discuss the behavioral impact of AVP and OXT in this sense, we must admit that our subdivision of this discussion into behaviors that are (Section 3) and that are not (Section 4) related directly to learning and memory is to some extent arbitrary. For example, although the induction of pair bonding in an American vole species could be interpreted as a kind of learning and memory, we refer to it as a behavioral paradigm that is related predominantly to intrinsic rather than acquired circuits (203) and, therefore, not directly related to learning and memory (see 4.2). This is not only a problem of definition, but also reflects the difficulty in clearly relating AVP and OXT effects to certain central functions which in concert determine behavioral performance. Therefore, with consideration of previous controversies, we will not attempt to draw any premature conclusions in terms of peptide effects on “arousal” or “memory”. Rather we will consider behavioral regulation to be a plastic pattern that includes arousal, attention, emotion, motivation, learning and memory. In other words, behavioral tests that are specific for memory in the synaptic plasticity sense (203) do not exist, and cognitive functions such as

In active avoidance paradigms (e.g., shuttle box or pole-jumping), the animals have to learn to associate a conditioned stimulus (e.g., light or tone signal) that precedes by several seconds an unpleasant or even painful event (e.g., foot shock), called the unconditioned stimulus. An acquired behavioral performance is displayed by the correct association between these two stimuli by the presentation of the conditioned stimulus alone, which then allows the animal to avoid the unconditioned stimulus. Acquisition is measured when both stimuli are present. Extinction is evaluated in well-trained animals (quote of errors less than 20Yo) by the exclusive presentation of the conditioned stimulus. Whereas Ibragimov (96) reported an improved acquisition of an active avoidance response after administration of AVP agonists 60 min before each session, Bohus and co-workers (26) showed that i.c.v. injections of synthetic AVP immediately after each learning session had no effect. The latter study was confirmed by our experiments in which AVP was delivered via a microdialysis probe into the septum during the last two out of three test sessions. Under these conditions, AVP treatment did not affect the acquisition of pole-jumping avoidance (65). In addition, peripheral osmotic stimulation, which triggers central AVP release, failed to alter acquisition in this learning paradigm (65). Attempts to reveal the importance of endogenous AVP included both methods of signal reduction and desensitization of the receiver. Although i.c.v. injection of AVP antiserum improved the performance in this paradigm (26), it was impaired by septal administration of the AVP V1 antagonist D(CH2)~Tyr(Me)AVP and a combined V2/Vl antagonist (65).

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OXT has been reported to impair slightly the acquisition of active avoidance behavior if applied either i.c.v. after each session (26) or directly into the hippocampus 60 min before each session (96). After i.c.v. injection of an OXT antiserum, animals with a reduced signal function of the neuropeptide showed an improved acquisition of this type of behavior (26). There has been more interest focused on the extinction period than on the acquisition period in active avoidance behavior. An increased resistance to extinction has been reported after i.c.v. administration of AVP (26,52,113) immediately after acquisition session(s) as well as after intrahippocampal injections of AVP agonists 1 h before each extinction session (96). In contrast, AVP antiserum administered i.c.v. immediately before the test situation increased the rate of extinction (26). This supports the idea ‘of a causal involvement of the endogenous neuropeptide in the resistance to extinction of learned behavior. Intracerebroventricular injection of the covalent ring of the AVP molecule (AVP<) induced effects similar to the native peptide, whereas the C-terminal section was less effective in increasing the resistance to the extinction of this type of behavior (52). Furthermore, stimulation of the intracerebral release of the peptide by i.p. injection of hypertonic saline after the last acquisition session was also reported to inhibit the extinction in pole-jumping avoidance behavior. A peripherally injected V1 receptor antagonist was potent in blocking this effect (114). These findings suggest that the reinforcement of the central AVP signal is responsible for the behavioral effects of hypertonic saline. Intracerebroventricular OXT treatment slightly increased the extinction of pole-jumping avoidance behavior (26) in a manner similar to direct application into the ventral hippocampus (96). OXT antiserum administered i.c.v. caused the opposite effect, which the authors interpreted as an amnestic action of the endogenous neuropeptide (26). 3.2. Passive Avoidance Passive avoidance procedures are based on behavior that drives the animal from an unpleasant to a pleasant environment. For instance, an environment that is brightly illuminated or open and elevated is unpleasant for rats. In contrast, a pleasant environment is dark and complies with the inborn inclination of the rats for thigmotaxis. A typical experiment consists of two sessions interspersed with intervals that range from hours to days. In the first session (acquisition), the animal is put into the unpleasant compartment of the test apparatus. Normally, naive animals leave this compartment quickly and enter the pleasant compartment, where they immediately receive a punishment (e.g., electrical foot-shock). In the second session (retention), the experimental subject is exposed again to the unpleasant compartment and latency is measured. Latency is the time that the animal takes to enter the originally preferred compartment (now associated with the aversive stimulus). A high latency reflects the correct association of the dark compartment with the punishment, whereas a short latency reflects the extinction of the correct association.

ENGELMANN ET AL. The actions of AVP administered into various brain areas were studied in a series of experiments by de Wied, Bohus, KOV5CSand co-workers. They found an improvement in passive avoidance after i.c.v. injection of the neuropeptide (25,26,54) in the dorsal and ventral hippocampus (120), the gyrus dentatus (115), the dorsal raphe (115,116,120) and the dorsal septal nuclei (115). No effects were observed after AVP administration into the locus coeruleus or the central amygdaloid nucleus (116). In this context, it should be mentioned that Sahgal and co-workers (176) failed to find any effect on passive avoidance after i.c.v. AVP administration. Further studies showed that the AVP fragments 4–8 and 5–8 were more effective in increasing the latency to enter the pleasant chamber in the retention test than was the complete peptide after injection either i.c.v. (33,54) or into several “AVPsensitive” brain areas (120). The effects of AVP administered i.c.v. were blocked by pretreatment with antagonists for the Vl, V2 and OXT receptors (54). Moreover, the OXT receptor antagonist blocked the effects of the i.c.v. AVP fragment 4-8 (54). Stimulation of AVP release by i.p. hypertonic saline improved the retention, an effect that was blocked by peripheral V1 antagonist treatment (18). This again suggests a causal involvement of endogenous AVP in the mediation of behavioral effects of hypertonic saline. AVP antiserum injected immediately after the training session either i.c.v. (26,207,208), into the dorsal hippocampus (117) or into the dorsal raphe nucleus (206) impaired the retention in passive avoidance. Microinjection into the lateral habenular region attenuated the retention in passive avoidance with only preretention treatment (206). To ascertain the importance of the endogenous neuropeptide in this paradigm, the levels of AVP in CSF after the learning trial (125) and the AVP content in different brain areas were found to be altered after the retention test (123,124). This was seen as an indication of the causal involvement of endogenous AVP in this behavioral test, but based on these findings, conclusions about release processes are rather limited (128). In contrast to AVP, treatment with OXT either i.c.v. (25,26,54) or into discrete brain areas [gyrus dentatus, dorsal raphe nucleus (115)] impaired passive avoidance. Like the AVP fragment, the OXT fragment 4-8 administered i.c.v. was more potent than the complete peptide (54). An OXT and a V1 antagonist administered via the same route blocked the effects of OXT and its fragment (54). However, administration of the neuropeptide into the dorsal septal nucleus improved passive avoidance (115). This finding contradicts the suggestion that OXT may act as a general amnestic peptide in this behavioral test. OXT antiserum administered into either the dorsal hippocampus, the dorsal raphe nucleus or the lateral habenular region did not affect passive avoidance (206), whereas i.c.v. OXT antiserum induced an improvement (26). 3.3. Social Recognition In their natural environment, Norway (or Brown) but not house (or black) rats prefer direct bodily contact

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with conspecifics (194), which allows the animals to recognize scents from each other. It has been shown that by means of this olfactory evaluation, members of Norway rat cohorts are able to identify each other individually. In the last few years, interest has been focused on the involvement of endogenous AVP and OXT in this kind of olfactory memory by using the social memory or social recognition test. This procedure, which was introduced by Thor and Holloway (198) and refined for laboratory use by Dantzer and co-workers (42), is impressive in its simplicity and ethnological relevance. Each test session consists of two exposures of a given nonspecific juvenile to the experimental subject. During each exposure, which lasts for 4-5 rein, the social investigative behavior of the experimental subject towards the given juvenile is monitored. Under the assumption that a non-familiar (i.e., not previously exposed) juvenile would be a more attractive stimulus for investigation than a familiar (i.e., previously exposed) juvenile, the ratio between the investigation duration during the first and second exposure to a given juvenile serves as an indicator of memory for the juvenile’s typical odor. In male rats of different rat strains it has been shown that this juvenile-related olfactory memory lasts no longer than 45 min. However, as an internal standard a 30-min inter-exposure interval is usually chosen. After about a 120-rnin interval, a complete extinction of this kind of short-term memory is to be expected. Modifications of this procedure have been described (67,88). The shortterm lasting ability to recognize juveniles enables the investigation of both memory-improving and memoryimpairing substances. Substances that are expected to improve social memory would be injected during the 120-min inter-exposure interval with the expectation of a decrease in the investigation duration of the same juvenile. In contrast, substances that are thought to interfere with juvenile recognition would be administered during a 30-min inter-exposure interval with the assumption that the treatment abolishes the differences in investigation duration.

Intracerebroventricular treatment with AVP improved this kind of short-term memory in a dosedependent manner for at least 120 min (135) without affecting investigatory behavior towards conspecifics per se (61). As shown by microinjection (43,167) and microdialysis administration studies (64), the lateral septal brain area appears to be a sensitive site in which the neuropeptide acts in a wide range of doses. Administration of the AVP 4-8 fragment into this brain area also improved the behavioral performance, although it showed no potentiated action (166). Administration of AVP into the medial preoptic area, however, failed to induce detectable effects (166). Intraperitoneal injection of hypertonic saline, which was used to stimulate central AVP release, improved social recognition in adult male rats; again, this effect could be blocked by peripheral administration of a V1 receptor antagonist (23). We were able to demonstrate using the microdialysis technique in this behavioral model that the amount of endogenous AVP released in response to direct osmotic stimulation within the SON area is correlated significantly with the behavioral performance of the same animal in this behavioral test (66) (Fig. 2A). Administration of a V1 receptor antagonist into either the SON, the septum or into the central nucleus of the amygdala interfered with the memory improvement induced by osmotic stimulation of the SON, whereas V1 receptor antagonist administration into the SON under basal conditions (i.e., without additional stimulation) failed to show any effect (66). Furthermore, a similarly stimulated AVP release by direct osmotic stimulation of the PVN was able to induce a similarly improved olfactory recognition performance (Engelmann, unpublished results) that suggests that AVP might particularly facilitate juvenile recognition if released simultaneously within several hypothalamic and limbic nuclei, In addition to the findings that behavioral performance can be improved by an increase in the concentration of AVP in the extracellular fluid of distinct

348 brain areas (e.g., by administration of the synthetic peptide or stimulation of its local release), several studies have reported that under “unstimulated conditions” the endogenous peptide is involved causally in social recognition. Local administration of AVP antiserum into the dorsal septum interfered with juvenile recognition abilities of adult male rats after a 30-min inter-exposure interval (209). Moreover, behavioral performance was impaired by administration of both VI and V2 antagonists into the septal brain area (43,64,167). The importance of the VI receptor subtype in the vasopressinergic transmission in the septal brain area was confirmed in our recent study (129) in which we used a more selective approach to discriminate between AVP and OXT receptors in a slightly modified version of the social recognition paradigm. Chronic infusion of an AVP V1 receptor antisense oligodeoxynucleotide (oligo) into the septum caused a reduced receptor density within this brain area and impaired juvenile recognition. Moreover, i.c.v. administration of the synthetic peptide failed to improve the juvenile recognition abilities of animals treated in this way. While control infusions of artificial CSF or a scrambled sequence oligo did not influence the behavioral performance, the administration of the sense oligo sequence (complementary to antisense) influenced social memory differentially. Sense oligotreated rats were able to recognize a previously exposed nonspecific juvenile after a 30-min interexposure interval, but they behaved like antisensetreated animals by failing to respond to i.c.v. AVP with an improved juvenile-related memory. The suggestion that sense treatment also interfered with the expression of the VI receptor gene was confirmed by receptor autoradiography, which showed an intermediate binding capacity between controls and antisensetreated animals (129) (Fig. 2B). Adult male Brattleboro rats behaved like V1 antagonist- or antisense oligo-treated animals as indicated by their failure after 30 min to recognize a previously exposed nonspecific juvenile (64). This impaired performance is probably caused by a lack of central AVP because administration of the synthetic peptide into the septum via microdialysis improved their behavioral performance (64). Other studies focused on the steroidsystem in rodents. vasopressinergic dependent Manipulation of the vasopressinergic innervation by male rat castration caused a temporary disruption of social recognition for up to 7 days after operation, followed by an insensitivity to a VI antagonist (24). Implantation of a capsule filled with testosterone restored this sensitivity (24). After chronic i.c.v. infusion of AVP with an Accurel collodion mini-device, castrates behaved like sham-operated males in their response to familiar juveniles. Chronic administration of an AVP V1 receptor antagonist had the opposite effect in intact male rats (21). These results confirm the hypothesis of an essential role for androgen-dependent vasopressinergic neurotransmission in social recognition in male rats (41). Interestingly, female rats display an ability to recognize a nonspecific juvenile that lasts about twice as long as that in males and appears to be independent of vasopressinergic transmission (20).

ENGELMANN ET AL. OXT injected into the lateral part of the septal brain area has been reported to improve juvenile recognition abilities in adult male rats (167). However, because this effect was blocked neither by an OXT antagonist nor by V1 and V2 antagonists, the authors concluded that this neuropeptide might act via an unknown receptor type (167). Similarly, although direct administration of OXT into the medial preoptic area within a wide dose range improved social recognition, the effects could not be blocked by pretreatment with a specific OXT antagonist. Despite this controversy, it was concluded that the medial preoptic area is a sensitive brain area for the action of OXT in rat social recognition (167). However, the endogenous neuropeptide may be involved in this behavioral performance because local administration of OXT antiserum into the ventral, but not dorsal hippocampus improved juvenile recognition abilities of adult male rats in the 120-min interexposure interval. OXT antiserum failed to induce discernible effects when administered into the dorsal septum (209). 3.4. Morris Water Maze (MWM) The MWM enables the measurement of spatial navigation abilities of animals by the absence of local cues (148). This is achieved by submerging a platform target in a circular pool below the water surface, thus forcing the rats to use extramazial cues to navigate to the non-visible target. The relatively low temperature of the water (approx. 21°C) serves as an aversive stimulus for the animals to search intensively for the target. A typical experiment that investigates the identification of the target’s spatial location consists of two to five sessions in which the rats are released into the water at different starting positions. The time required and the distance covered by the animal from the starting position to the target serve as indicators of the precision with which the animal can locate the target. Direct administration of AVP via microdialysis into the septal brain area interfered with the acquisition in this test in each of the three training sessions. The V1 receptor antagonist, however, administered into the same brain area by the same experimental approach, navigation (63). spatial failed to influence Experiments that have investigated the performance of homozygous male Brattleboro rats showed that animals of this rat strain performed significantly worse in the first session than animals of the Long–Evans strain; in sessions 2 and 3, however, they performed similarly to the controls (62). Taken together, these results suggest that endogenous AVP that interacts with the V1 receptor subtype after its release—at least within the septal brain area—does not appear to be involved causally in this behavioral performance. This conclusion was confirmed by data obtained in an experiment in which testosterone treatment that had been used to restore steroiddependent vasopressinergic innervation in senescent male Brown Norway rats failed to improve learning in the MWM (87).

CENTRAL VASOPRESSIN AND OXYTOCIN AND BEHAVIOR 3.5. Conditioned Taste Aversion (CTA) The CTA paradigm is based on the well-known ability of rats to associate sickness behavior with a previous food consumption that prompts the rat to avoid eating this particular kind of food. The most interesting features of this paradigm are that the delay between the presentation of the conditioned stimulus (preferred food or solutio,n, e.g., sweetened milk) and the unconditioned stimulus (peripherally applied poison) can last for up to 6 h and that the unconditioned stimulus can even be administered under narcosis (34). Furthermore, not all poisons are potent enough to evoke a CTA. AVP administered i.c.v. either chronically or acutely failed to induce a CTA when paired with a new food (30,113). Chronic treatment with a VI receptor antagonist, however, increased the extinction of CTA (30). In contrast to normal female Long–Evans rats, which extinguished a learned CTA significantly more rapidly than did males of the same strain, homozygous Brattleboro rats showed no sexually dimorphic extinction of an acquired CTA. Therefore, Brot and coworkers (31) hypothesized that normal AVP levels are necessary for observation of the expression of sexually dimorphic behavior. 3.6. RetrievaVRelearning in a Food-reinforced Go/No-go Discrimination The go/no-go discrimination task allows the measurement of food-rewarded visual discrimination capacities in rodents (7). The animals are exposed to two runways of different colors, one of which contains the reinforcing food reward. After their start at one end, the time taken by the animals to reach the other end of the runway with or without the reward is used as a measure for the learning and memory performance. In the acquisition period, the time that the animals take in the rewarded runway decreases (go), whereas the time in the non-rewarded increases (no-go). Retrieval/retention is tested under similar conditions on different days. AVP microinjections in mice either i.c.v. (6) or into the hippocampus (144) improved retrieval and relearning. In contrast, lesioning the medial amygdala results in not only a disappearance of hippocampal AVP fibers in the CA1 and CA2 but not CA4 and gyrus region, but also an impairment in this behavioral performance. This impairment was partially reversible after microinjection of AVP into the hippocampus. In a follow-up study, the same authors reported that local pretreatment with a beta-adrenergic antagonist interfered with the retrieval and relearning effect of intrahippocampal AVP injections, whereas an alpha-adrenergic receptor antagonist potentiated the AVP effects (145). Binding of endogenous AVP released within the hippocampus by an AVP antiserum failed to affect the retrieval (6) or to cause an impairment in the food reinforced go/no-go discrimination paradigm (144). Blockade of the vasopressinergic transmission by local administration of a V1 receptor antagonist into the hippocampus also caused a deterioration in both retrieval and relearning (8).

344 4. EFFECTS OF AVP AND OXT ON BEHAVIORAL PERFORMANCE NOT DIRECTLY RELATED TO LEARNING AND MEMORY

In addition to affecting behavioral performance that falls into the category of learning and memory, the neuropeptides AVP and OXT also play a role in other types of behavior. However, although these other behaviors are of similar complexity they tend to be stereotyped. In this section we focus on several types of affiliative behavior that bring conspecifics into close proximity for the purpose of forming social bonds. Here, in contrast to learning and memory, the importance of the two neuropeptides can be attributed to their signal function in interneuronal communication within a neuronal network that is mainly fixed (intrinsic circuits) rather than plastic (acquired circuits) (203). 4.1. Sexual and Maternal Behavior in Rats and Sheep OXT, but not AVP, seems to play a major role in the sexual behavior of male and female rats and in maternal behavior, as recently reviewed by Carter (37) and Argiolas and Gessa (13). There are only a few indications of a possible probably inhibitory role of endogenous AVP in female sexual receptivity (188) and male sexual behavior (186). In female rats, sexual receptive behavior after priming with estrogen and progesterone was facilitated by infusion of OXT into the cerebral ventricles (15,179) or directly into the medial preoptic area (36), whereas central infusion of an OXT antagonist reduced lordosis behavior (217). In male rats, penile erection could be induced with OXT administered i.c.v. (14) or directly into the PVN (142), whereas central infusion of an OXT antagonist markedly reduced male sexual interest, as measured by declines in the number of mounts, intromissions and ejaculations (12). It should be noted, however, that high doses of OXT (pg range) inhibited sexual behavior (13,191), which the authors interpreted as evidence of a possible role of central OXT in male postcopulatory sexual satiety. Thus, OXT released intracerebrally into limbic or hypothalamic brain regions may initially facilitate sexual interest, whereas high levels of endogenous OXT may inhibit it (37). In addition to estrogen and prolactin, intracerebral OXT appears to be crucially involved in the onset of maternal behavior, as first demonstrated by Pedersen and Prange after i.c.v. infusion of OXT into nulliparous, ovariectomized female rats primed with estradiol benzoate (164) and also confirmed by other investigators in rats (72) and sheep (107). However, conflicting results regarding the induction of maternal behavior by central infusion of OXT also exist. A possible explanation may be differences in the rat strain and in the experimental protocol used (27,74,162,174). These conflicting results add to the debate about the effects of synthetic versus endogenous AVP on behavioral parameters already mentioned. The onset of maternal behavior around parturition may be more consistently affected by blocking the action of endogenous OXT by central

350 administration of an OXT antagonist or of OXT antisera or by lesions of the PVN as the main source of central OXT. In this context it should be emphasized that only the critical period during which this kind of affiliative behavior is induced, not the period for lactation, when maternal behavior is established, seems to depend on OXT released within the brain (73,98,153,161,204). Important evidence for a role of central OXT pathways in the onset of maternal behavior comes from studies in sheep. Infusion of OXT into the cerebral ventricles was shown to induce maternal behavior in non-pregnant, nulliparous ewes (107), and there are increased levels of endogenous OXT in the CSF (108) and in specific brain regions such as the BNST, the preoptic area, the olfactory bulb and the substantial nigra (29,109–111) at a time when maternal behavior is induced either as a consequence of normal parturition or in response to vagino-cervical stimulation in steroid-primed ewes (112). In addition, OXT immunoreactivity and OXT mRNA levels within these brain regions are at their highest immediately after parturition (29), which the authors interpreted as being associated with the induction of peripartum maternal behavior. It is of interest to note that vagino-cervical stimulation, which produces a marked increase in the intracerebral release of OXT, induced maternal behavior in steroid-primed ewes (112). A variety of limbic brain regions may be involved in or ovarian steroid-induced maternal postpartum behavior, and a remarkable overlap exists between the neuronal circuits thought to be involved in maternal behavior on the one hand and the demonstration of OXT immunoreactivity, local OXT release and OXT binding sites on the other. Recently, by local infusion of OXT or AVP antagonists, Pedersen and co-workers demonstrated the involvement of endogenous OXT in the ventral tegmental and medial preoptic areas and, to a lesser extent, also of AVP in the medial preoptic area in the postpartum activation of maternal behavior in Sprague–Dawley rats. Interestingly, OXT binding in these areas was increased at parturition (163). Although until recently the SON was thought to project exclusively to the neurohypophysis and not to play an important role in behavioral regulation, administration of an OXT antagonist bilaterally into the SON after delivery of the first pup not only resulted in a slower parturition process, but also had marked effects on the occurrence of maternal behavior and lactation: nestbuilding and grouping of pups in the nest were reduced, and more pups were without milk 24 h after parturition, which could also be explained by both impaired maternal behavior and inhibition of the onset of lactation (149,153). It is known that hypothalamic OXT is needed for the structural reorganization of the central OXT system necessary for lactation (195) and for the positive feedback activation of OXT cells (126,150). The results showing an involvement of local OXT within the SON in behavioral regulation are of interest in conjunction with the findings already mentioned that stimulation of local release of AVP within the SON is accompanied by septal peptide

ENGELMANN ET AL. release and is correlated with the ability of adult male rats to recognize nonspecific juveniles (66) (Fig. 2A). Thus, administration of an OXT antagonist into the SON during parturition not only reduces local release of OXT within the SON, known to be enhanced at parturition (155), but also somehow affects release within limbic regions. A differentiated pattern of OXT and AVP release within the latter (ventral septal area, dorsal hippocampus) has recently been shown around parturition (131,156), but the involvement of this release in reproduction-related behaviors needs further study. No effect on maternal behavior was observed after intra-SON infusion of the OXT antagonist in established lactation (150). 4.2. Social Behavior in Voles Another aspect of central AVP and OXT involvement in affiliative behaviors has recently been described in prairie and montane voles, two closely related species with dichotomous systems of social organization. Whereas the montane vole is polygamous, spends little time in contact with conspecifics and does not show paternal care, the prairie vole is monogamous and rather social, and both sexes show high levels of parental care (180,181). In prairie voles, induction of strong pair bonding after mating is accompanied by an increase in paternal responsiveness, both of which were shown to depend on intracerebral AVP (212,216). Injections of AVP into the lateral septum of sexually inexperienced prairie vole males enhanced their paternal responsiveness, whereas blockade of vasopressinergic neurotransmission by local injection of a VI antagonist had the opposite effect (212). Furthermore, 3 days of male–female cohabitation increased the activity of intracerebral, and especially septal, AVP projections in males but not in females, as evidenced by an increase in the number of AVP mRNA-labeled cells in the BNST, the main source of septal AVP (17), and a decrease in AVP immunoreactivity in the septum (213). Although there is still no direct evidence for increased release of AVP within the septum, and the above-mentioned limitations in interpreting alterations in immunoreactivity have to be considered (see Section 2), these results were taken as a possible indication of increased septal AVP release in the male prairie vole caused by mating/cohabitation (213). Castration resulted not only in a reduction in immunoreactivity in the BNST, the medial amygdala and consequently the lateral septum but also in a reduction in paternal behavior (211). Testosterone replacement prevented the behavioral effects (211). In contrast, administration of synthetic OXT to males failed to induce any detectable behavioral effects (99,215). Whereas in the male prairie vole AVP clearly plays a prominent role in affiliative behavior, in females of this species central OXT seems to dominate in the mediation of such behavior. The latter is illustrated by the finding that i.c.v. injections of AVP failed to produce a partner preference in female prairie voles (99). The fact that i.c.v. V1 receptor antagonist treatment failed to block a partner preference in females is

CENTRAL VASOPRESSIN AND OXYTOCIN AND BEHAVIOR a further indication that the endogenous neuropeptide is probably not involved in this type of behavior (99). OXT administered centrally, but not peripherally, facilitated the formation of a partner preference in female prairie voles (99,215), an effect which may be triggered physiologically by central OXT release during mating. Pretreatment with a selective OXT antagonist blocked this facilitator effect of synthetic OXT, which suggests that intracerebral OXT receptors are involved. In this context it is of interest to note that the distribution of brain OXT and AVP receptors differs markedly in the two vole species, especially in limbic brain regions, there being, for example, a much higher OXT receptor density in the BNST and amygdala (thought to be involved in parental care) in the highly parental prairie vole (100,101). These differences in receptor distribution are probably linked with species-typical patterns of social organization. In the montane vole, which shows little affiliative behavior except after parturition, the induction of maternal behavior in the immediate post-partum period was associated with an increase in OXT receptors in specific brain regions, e.g., the amygdala, whereas in the prairie vole binding did not change at parturition (loo). 4.3. Flank Marking in Hamsters In contrast to Norway rats, which live in social communities, golden hamsters are known to be individualists. To scent mark their territory, hamsters use the secretion from glands located on their flanks (104,105). The behavioral pattern of flank marking in hamsters starts with grooming and wetting the fur in the area where the glands are located, and this is followed by rubbing the glands against edges and surfaces that are mainly vertical. The rigidity of the sequence behaviors indicates that this is a stereotypic pattern. It can be observed in both males and females, for example, after an animal has been exposed to scent marks of a nonspecific. Local injections of AVP or selective AVP V1 receptor agonists stimulated flank-marking behavior in the absence of additional olfactory stimuli if administered into discrete brain areas such as the lateral septum (102), hypothalamus (4,77,82,84,85) and periaqueductal gray (91). Castrated male hamsters, which have a reduced AVP content and fewer AVP-immunoreactive neurons in the anterior hypothalamic nucleus circulars and less flank-marking activity in the presence of conspecifics than normal male hamsters (78), had a response to microinjection of AVP into the anterior hypothalamus which was only 50~o of that of shamoperated animals (3). Testosterone replacement, however, normalized not only flank-marking activity (78) but also the response to AVP (3) in castrates. Female hamsters, which respond with a two-fold higher scent-marking activity than males to odors of males (5), require higher doses of AVP to be administered into the periaqueductal gray for flank-marking behavior to be triggered. Although there are no sex differences in AVP immunoreactivity within the medial preoptic area of the anterior hypothalamus, estradiol

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may influence the sensitivity or responsiveness of the neurons to AVP in this brain area, or both. Ovarectomized hamsters treated with estradiol responded to direct injections of synthetic AVP more sensitively than animals without estradiol replacement (95). Local injection of a selective AVP V1 receptor antagonist into the anterior hypothalamus suppressed scent marking (83) and aggression and reversed dominant/subordinate behavior (82). Furthermore, intraseptal administration of a V1 antagonist interfered with flank marking induced both by local injections of AVP (85) and by exposure to olfactory stimuli (102). In a more detailed study with an iodinated AVP V1 receptor antagonist, evidence was found that different limbic and mesencephalic brain areas, e.g., septum, amygdala and periaqueductal gray, may play an important role in neuronal circuits controlling flank marking (79). These results confirmed and extended findings obtained by lesioning of AVP-containing neurons with kainic acid (81). Studies employing lesions of either the anterior hypothalamus or the lateral septum not only confirmed the importance of these AVP-sensitive brain areas but also showed that magnocellular and steroid-dependent neurons may control this type of behavior (80). Infusion of OXT into the anterior hypothalamus (2) or the periaqueductal gray (91) was sufficient to induce flank marking but was less potent than AVP. Taken together, the results obtained in the flankmarking paradigm resemble those related to the role of the vasopressinergic system in social recognition in the rat. Therefore, the method introduced by Johnston (106), which, on the basis of flank marking, shows important characteristics of the social recognition procedure in rats, may be an interesting approach to investigating the importance of the endogenous neuropeptides in the formation of short-term olfactory memory in the hamster. 5. CONCLUSIONS

The present review focuses on the effects of centrally administered and released AVP and OXT on behavioral performance in general, and learning and memory in particular in mammals. These neuropeptides are excellent candidates for investigation of the behavioral consequences of peptidergic neurotransmission and neuromodulation because a large amount of information has been accumulated about their molecular biology (173), receptor subtypes (201), intracerebral pathways (47,189), release patterns (128) and receptor distribution (158,201,219). Moreover, several more or less specific receptor antagonists and antisera as well as new antisense technology provide tools to affect interneuronal communication by selectively reducing the interactions between the endogenous ligand and its receptors. Finally, improvements in the administration techniques, from pressure injections into the ventricle or brain tissue to administration via microdialysis probes, make it possible to monitor consequences on behavioral performance with little additional stress for the experimental animals.

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ENGELMANN ET AL. pole social Morris jumping recognition water maze avoidance— increased information transfer

(treatment with synthetic AVP)

decreased information transfer (treatment with VI antagonist)

FIG. 3. Effects of increased (by administration of svnthetic AVP) and decreased (by administrati& of an AVP VI re~eptor antago~ nist) vasopressinergic information transfer within the mediolateral septum in different learning and memory paradigms. In all cases the experimental animals were adult male rats that received the treatment concomitantly with behavioral testing. ~: Improved performance: ~: impaired performance; =: no significant influence on the animals’ behavior. (Data from Refs 63-65.)

The only way to evaluate learning and memory abilities in animals and to characterize the physiological role of AVP and OXT is to monitor and analyse the behavior in highly reliable and ethnologically significant test paradigms. These should reflect either natural conflict situations or more artificial test designs. According to Vanderwolf and Cain (203), learned behavior represents a refinement and further development of instinctive behavior. Social identification, for instance, is an essential prerequisite for social communication between the members of rat cohorts (social recognition paradigm), whereas spatial navigation is a necessity for all rats that live in a city sewage system (MWM). Furthermore, the superior ability of rats to remember a poisonous food, which protects them from extinction by humans, has been adapted in the CTA paradigm. More artificial behavioral tests such as the shuttle-box or step-through active and passive avoidance tests focus on distinct cognitive functions and reflect the ability of the animals to handle sudden and dramatic changes in their natural environment. However, compared to the natural tests already mentioned, the interpretation of the results and their physiological significance remains more difficult (175). To account for the broad spectrum of behavioral skills, the learning and memory capabilities, and the emotionality of laboratory rats, a combination of different tests is recommended before final conclusions can be drawn about the role of defined neurotransmitters and neuromodulators in behavioral performance. An overwhelming number of more pharmacologically oriented studies focused on the involvement of AVP and OXT in the extinction of active avoidance and passive avoidance behavior. As a result, AVP has been implicated as a memory-improving peptide and OXT as an amnestic peptide (119). Nevertheless, the facts that Saghal and co-workers (176) failed to

replicate the effects of i.c.v.-injected AVP on passive avoidance and that rather conflicting results were reported for the acquisition period of active avoidance (see 3.1) indicate that such interpretations have to be reported with caution. In support of this interpretation, intracerebrally administered OXT impaired the extinction of active and passive avoidance (see 3.1 and 3.2) and improved social recognition (see 3.3). Recent studies that used either signal reinforcement or receiver desensitization showed conflicting results about the importance of oxytocinergic neurotransmission in the passive avoidance pa~adigm (54,115,206). We demon~trated that administration of the same dose of AVP via the same route (microdialysis) into the same brain area (septum) improved social recognition in adult male rats but impaired their navigation in the MWM. Similarly, the endogenous neuropeptide released within the septum appears to be essential for a normal performance in the social recognition paradigm (see 3.3), but it is less or not at all important in the MWM (see 3.4). Because the MWM is based on an aversive stimulation (cold water), these results have general implications for understanding the action of intracerebrally released AVP. Activation of the vasopressinergic system has been suggested to be involved causally in stress-handling of the organism in terms of an appropriate behavioral response because of the central role of the neuropeptide in the regulation of the HPA axis (118). However, this opinion does not agree with the HPA axis activation observed in the MWM (Plotsky and Engelmann, unpublished results). Because the failure to show a significant contribution of endogenous AVP in the respective behavioral performance cannot be attributed simply to a mismatch between the ligand and its receptor or to technical problems, the aforementioned results indicate that endogenous AVP released within the septum appears to be involved differentially in different behavioral tests. For example, the animal’s performance in the pole-jumping avoidance, the juvenile recognition procedure and the MWM is primarily independent of the stimuli underlying the procedure, regardless of whether or not it is aversive (Fig. 3). Clear indications of an essential role for the two neuropeptides come from findings that suggest that intracerebrally released AVP and OXT are involved in behavioral performance that is cued by olfactory signals and appears to be related causally to reproduction. Indeed, there is a remarkable congruence between the results in the social recognition paradigm in rats (see 3.3), partner preference and pair bonding in voles (see 4.2) and territory marking in hamsters (see 4.3). Despite significant inter-species variations between different rodent species in the magnocellular and parvocellular vasopressinergic systems, the results obtained so far indicate that predominantly sexual vasopressinergic neurons are steroid-dependent involved in these behavioral paradigms (41,212). Because reproduction belongs to the basic demands of living systems and olfactory signals are dominant stimuli of sexual behavior in rodents (197), it appears

CENTRAL VASOPRESSIN AND OXYTOCIN AND BEHAVIOR possible that a close coupling between olfactory cue acquisition and mating behavior was established during evolution and involved a sharing of the same neuronal circuits and neurotransmitters/neuromodulators. In this context, it is interesting to note that for the first time the social recognition paradigm in adult male rats provides evidence that indicates a significant correlation between the amount of AVP released intracerebrally and the density of its septal VI receptor subtype on the one hand and the behavioral performance of these animals on the other (Fig. 2). In particular, the findings that indicate a pivotal role for vasopressinergic neurotransmission/neuromodulation in the establishment of partner preferences in different species of American voles (see 4.2) appear to support the hypothesis of a pivotal role for the neuropeptide in the relevant behavioral processing of olfactory cues. The precise contribution of olfactory stimuli to this behavioral pattern needs further investigation. These examples which include maternal care suggest that AVP and OXT are involved synergistically in behavioral regulation regardless of whether or not they induce primary effects on cognitive parameters like arousal, attention and motivation. This behavioral synergism results finally in biologically adequate reproduction with all its facets, interindividual communication and organism homeostasis. Although numerous effects of the two neuropeptides on neuronal activity have been reported in vitro (28,39,57,86,96,121,170) and in vivo (126,199), the mechanisms of action of AVP and OXT on behavioral performance are largely unknown, and the effects on certain cellular functions cannot be necessarily related to the observed behavioral effects. The situation is further complicated by findings that indicate that AVP may act on V1 receptors of non-neuronal structures like glia cells (134) or cerebral microvessels (1,185,187), thus indirectly and probably synergisticommunication. interneuronal influencing cally Furthermore, it must be mentioned that the central release of both peptides may be paralleled by peripheral release into blood (128). Plasma AVP and OXT, in turn, may induce metabolic and autonomic alterations that may support the effects triggered by the central neuropeptide. These synergisms at different levels suggest that the peptides themselves may provide the link between arousal, attention, emotion, learning, memory and behavioral performance, thus ensuring that relevant information is acquired and successful behavioral strategies are established and stored, reactivated under appropriate conditions,

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colored by motivation, changed with altered conditions, etc. All of our information about characteristics of the temporal and the spatial pattern of intracerebral release (128) fits with the hypothesis that AVP and OXT may play such a key role. However, the precise manner of information transfer in which the neuropeptides may be critically involved is an important question that remains to be answered. Although this is largely unknown with respect to intracerebrally released AVP and OXT, the experimental data concerning the most efficient administration time of the synthetic peptides (immediately before, during or after the behavioral test) suggest that the acquisition/early processing stage is more sensitive to the effects of the two neuropeptides than the storage or recall of information. This hypothesis, that suggests that AVP as well as OXT take part predominantly in the emotional evaluation of incoming information, is supported by the conclusion already mentioned concerning the importance of the two neuropeptides in reproductive behavior. However, we would like to state that we prefer to emphasize the concerted action of factors like arousal, emotion, motivation, learning and memory for behavioral regulation rather than to discuss them as more or less separated targets of neuropeptide action or as separate contributors to behavior. Consequently, it is almost impossible to design behavioral tests that unequivocally measure these factors independently. In this context, P. B. Medawar’s aphorism that “endocrine evolution might not be an evolution of hormones, but an evolution of the uses to which they are put” may point to an interesting direction for future research. Behavioral neuroscientist should keep in mind that they are working with transient neuronal systems rather than with optimized and stable creations. Each behavioral paradigm described in this review reflects complex behavioral facilities. However, our review focuses on a selected topic of the phenomenon under study, and a generalization of the findings should be avoided. In 1991 Mayer and Baldi asked: “Can regulatory peptides be regarded as words of a biological language?” (141) and discussed this with respect to gastrointestinal peptides with the help of the information theory. Two years later this question is being asked again with respect to neuropeptides and the limbic system (92). One aim of the present review was to demonstrate that AVP and OXT are key words of such a language. However, as shown in this review, in the case of learning and memory they seem to code for “as well as” rather than for “yes” or “no”.

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