Physiology&Behavior.Vol. 55, pp. 145-149, 1994 0031-9384/94 $6.00+ .

00
Printedin the USA. Copyright© 1993PergamonPressLtd.

Microdialysis Administration of Vasopressin Into

the Septum Improves Social Recognition in
Brattleboro Rats

M A R I O E N G E L M A N N * A N D RAINER L A N D G R A F t 1

*University of Leipzig, Department of Biosciences, Zoological Institute, D-04103 Leipzig, Germany

-?Max Planck Institute of Psychiatry, Clinical Institute, D-80804 Munich, Germany

Received 16 F e b r u a r y 1993

ENGELMANN, M. AND R. LANDGRAF.Microdialysisadministration of vasopressin into the septum improvessocialrecognition

in Brattlebororats. PHYSIOL BEHAV55(1) 145-149, 1994.--The role of septal argininevasopressin(AVP) in a social recognition
test was investigatedin both homozygousBrattleboro(HO-DI)and normal Long-Evansrats. To do this, the duration of investigation
of conspecificjuveniles by untreated adult males of both rat strains was measured before and after inter exposure intervals of 30
and 120 min. Additionally,a microdialysisadministration technique was used to administer synthetic AVP (0.2 or 2.0 ng) or its
V I receptor antagonist d(CH2)5Tyr(Me)AVP (5.0 ng) into the mediolateral septum concomitantly with the behavioral test.
Untreated HO-DI rats showed an impaired social recognition compared with untreated Long-Evans rats. A similarly impaired
performance was observed after V 1 receptor antagonist treatment of Long-Evans rats. Microdialysisadministration of synthetic
AVP, on the other hand, significantlyimproved social recognition in both rat strains. The data suggest that endogenous AVP in
the septal brain area is critically involved in the acquisition, storage, and/or recall of olfactory cues in rats.

Microdialysis Vasopressin V~ receptor antagonist Socialrecognition Olfactorylearning Long-Evans rat

Brattleboro rat

THE ability to recognize conspecific individuals by using olfac-
tory cues seems to be a fundamental prerequisite for social be-
havior in rodents (12). It has been reported that adult males of
different rat strains are able to store information about che-
mosensory signals released from a conspecific juvenile for at
least 30 min; after 120 min, however, this kind of social rec-
ognition is extincted (3,15,35). Other studies have revealed that
central (14,27) and peripheral (15) administration of the neu-
ropeptide arginine vasopressin (AVP) or its analogs (31) as well
as stimulation of the release of the endogenous peptide (4) im-
proves social recognition in rats. Direct injection of a selective
AVP V 1 receptor antagonist into the lateral septum, on the other
hand, interferes with juvenile recognition (14), indicating that
endogenous AVP released within this brain area is causally in-
volved in this type of behavior.
In 1962, Valtin et al. (39) described a hypothalamic diabetes
insipidus in an inbred rat strain (Brattleboro) spontaneously
arising from Long-Evans litter rats. One of the main character-
istics of Brattleboro rats is that homozygous animals (HO-DI)
are not able to synthesize biologically active AVP in their hy-
pothalamic nuclei due to a frameshift mutation in the corre-
sponding gene (33,34). Therefore, HO-DI rats were used as
models to investigate the role of endogenous AVP in behavioral
performance [see (1) for review]. The results of these studies,
however, are controversial. Whereas some authors found no sig-
nificant differences between normal (i.e., animals that do not
suffer from diabetes insipidus) and HO-DI rats (13,42), others
reported an impaired behavioral performance in HO-DI animals
[at least in some behavioral tests (2,6-9)]. Synthetic AVP given
peripherally, on the other hand, has been shown to improve the
behavioral performance of HO-DI rats (16).
Because of bidirectional diffusion through the membrane,
synthetic peptides can be perfused through a microdialysis probe
and delivered locally into the extracellular space of a discrete
brain area. In two recent studies, this technique has been used
for administering peptides into the mediolateral septum con-
comitantly with behavioral tests. Whereas chronic implantation
of the probe and its subsequent perfusion with artificial CSF per
se did not interfere with the behavior of rats in pole-jumping
avoidance and the Morris water maze, AVP and its antagonists
added to the perfusion medium were shown to induce differential
effects on behavior (19,20).
In the present study, we describe a) the behavioral perfor-
mance of HO-DI rats in the social recognition test compared

Requests for reprints should be addressed to Dr. Rainer Landgraf, Max Planck Institute of Psychiatry, Clinical Institute, Kraepelinstrasse2-10,
D-80804 Munich, Germany.

145
 146
with that of animals from the Long-Evans (litter) strain and the
effects of microdialysis administration of synthetic AVP or a V1
receptor antagonist into the mediolateral septal brain area on
the juvenile recognition abilities of both rat strains.
METHOD
Animals
Adult male rats, formerly used as breeders, were used in this
study (350-450 g b.wt.; HO-DI: Breeding colony of the Academy
of Sciences of the Czech Rep., Prague, n = 12; Long-Evans:
University of Leipzig breeding colony, n = 10). The rats were
housed individually in plastic cages (25 × 43 X 23 cm) and kept
under controlled laboratory conditions with food and water ad
lib. Juveniles (age: 20-27 days; housed in groups of 5-6) of both
sexes of the respective rat strain were used as social stimuli.
Behavioral Procedure
All experiments were performed over a period of 2 weeks.
Behavioral testing took place during scotophase ( 1800-0600 h)
of the photoperiod in a weakly illuminated room; each adult rat
was tested in its home cage. Each session consisted of two 5-
min exposures of a juvenile separated by a 30- or 120-min in-
terval (inter exposure interval, IEI). The second exposure was
performed either with the same (sj) or a different juvenile (dj).
During each exposure, a trained observer measured the total
investigatory behavior of the adult by typing preset keys on the
keyboard of an IBM-computer. Investigatory behavior was de-
fined as direct action of the adult towards the juvenile rat, in-
cluding anogenital sniffing, licking, hunting, pawing, and close
pursuing.
Microdia(vsis Implantation
After investigating their untreated behavioral performance
during the first week (2 sessions: IEI 30 min sj; IEI 30 min dj;
for the Long-Evans rats an additional session: IEI 120 rain sj),
the rats were implanted under anesthesia (Pentobarbital, Spofa,
Czech Rep.; 1 ml/kg b.wt.) with a microdialysis probe into the
brain directed towards the mediolateral septum [implantation
coordinates: 0.2 mm anterior to bregma, 2.0 mm lateral to mid-
line, angle of 23 ° to avoid damage to the sagittal sinus (28)].
The probe was fixed to the skull using dental acrylic and two
stainless steel screws.
Starting the next day (but not less than 30 h after implan-
tation), the microdialysis probes were perfused at a flow rate of
3 #l/min during the social recognition test. The perfusion started
5 rain before the first exposure and lasted in total 30 min. The
perfusion fluid was either artificial CSF [aCSF; for composition
see (24)] or aCSF containing different doses of synthetic AVP
or the V l receptor antagonist d(CH2)5Tyr(Me)AVP. Taking into
account the in vivo efllux out of the perfusion medium into the
surrounding brain tissue, it was estimated that approximately
0.2 ng AVP, 2.0 ng AVP, and 5.0 ng V1 receptor antagonist,
respectively, was delivered into the septum during the 30-min
dialysis interval (20) during which (i.e., 5 min after its start) the
first 5-rain exposure occurred.
After the experiment, the rats were killed by an overdose of
ether, the brains removed, and fixed in Bouin's fluid. For his-
tological verification of the microdialysis site, sections were made
and examined with a dissecting microscope.
Statistics
Results are expressed as means + SEM. For statistical eval-
uation, the total investigation durations of each rat strain were
ENGELMANN AND I.-\NDGRAI-
submitted to a two-way randomized block ANOVA (main tac-
tors: sessions x exposures); for differences between the rat strains
a two-way ANOVA (rat strain × exposures) with repeated mea-
sures on the last factor was used. The individual group com-
parisons were made by employing Newman-Keuls or Tukey
(HSD) test. Differences were considered significant ifp < 0.05.
Besides the presentation of raw data, time spent in social
investigation will be expressed in this paper as the ratio of in-
vestigation duration [RID, investigation duration of the second
exposure divided by investigation duration of the first exposure
(29)]. This method of presentation has been chosen to exclude
the day-to-day variations in baseline of performance within and
between the rat strains.
RESUIAS
A total of 12 HO-DI and I0 Long-Evans rats were implanted
with a microdialysis probe. The results presented here show only
the performance of those animals in which histological verifi-
cation confirmed a correct localization of the tip of the micro-
dialysis probe in the mediolateral septum (see Fig. IA, B) and,
moreover, in which the microdialysis probe worked correctly
during all sessions (Brattleboro, n = 10; Long-Evans, n = 9).
During all successful perfusion sessions the behavior of the an-
imals was assessed to be normal, as reflected by drinking, eating,
grooming, exploring, investigating or resting.
Untreated Sessions
Data for the duration of social investigation for both untreated
rat strains are presented in Fig. 2.
The investigation duration of the first exposures (IEI = 30
min) of HO-DI rats was significantly higher than that of Long-
Evans rats, F( 1, 17) = 12.80, p = 0.0023. Furthermore, as shown
in Fig. 2, homozygous rats of the Brattleboro strain investigated
the same juvenile with the same duration during the second
exposure [IEI = 30 min: overall main factor interaction: F(5,
45) = 4.67, p = 0.0016]. This behavioral performance was
comparable with that which could be measured by exposing a
different juvenile, indicating that HO-DI rats are not able to
recognize the same juvenile after 30 min. In contrast to the HO-
D1 animals, Long-Evans rats [overall main factor interaction:
A B
FIG. 1. (A) Schematic diagram showingthe localizationof the tip of the
microdialysis probes in the mediolateral septum of Long-Evans rats
(hatched dots). Localizationsrostral or caudal (max. 0.5 mm) have been
shifted into the coronal plane shown. The dotted area demonstrates the
tip of the probe outside the septum in one animal. (B) A representative
coronal section used to reconstruct the localization of a microdialysis
probe in the brain.
VASOPRESSIN A N D SOCIAL R E C O G N I T I O N 147

investigation duration [sec] RID Long-Evans

14o : BratUeboro Long-Evans
## ## 1.6 I
12o~ ~ i _ 1.4 "k~

ih ,.
T [
:IIEI 0.6I
0.4
0.0 0.2
ng AVP/rat

o.~~ IEI = 120 min

~sl ~dl 305j 30dj 120sJ

IEI
Ist exposure ~ 2nd expoeure
FIG. 2. Investigation durations (means + SEM) of untreated HO-DI (n
= 10), and Long-Evans rats (n = 9). The inter exposure interval (IEI)
was 30 rain or 120 min; sj = exposure of the same juvenile during first
and second exposure; dj = exposure of a different juvenile during second
exposure. ##p < 0.01 compared with the first exposure of the Long-
Evans rat strain, Newman-Keuls test; **p < 0.01 compared with the
corresponding first exposure, Tukey test.
F(8, 64) = 4.70, p = 0.0001] showed a significant decrease in
the investigation duration during the second exposure of the
same juvenile after an IEI of 30 rain (p < 0.01, Tukey test; Fig.
2). Using a different juvenile during the second exposure con-
firmed that this behavior reflects juvenile-specific recognition.
After an IEI of 120 min and exposure of the same juvenile,
however, no significant difference between the investigation du-
rations of both exposures could be observed, indicating an ex-
tinction of social memory (Fig. 2).
Treated Sessions
Implantation of a microdialysis probe into the mediolateral
septum and its perfusion with aCSF failed to cause any alterations
FIG. 4. Effect of microdialysis administration of AVP (0.0 ng, 0.2 ng)
into the mediolateral septum of Long-Evans rats (n = 9). The inter
exposure interval (IEI) was 120 min. Overall mean investigation duration
during the first exposure: 45.3 _+ 4.7 s. **p < 0.01 (difference between
both exposures, Tukey test); for further details see Fig. 3.
in the behavioral performance of either rat strain compared with
performance in untreated sessions (Fig. 2 vs. Figs. 3 to 5, aCSF).
HO-DI rats, administered with both doses of AVP (0.2 ng or
2.0 ng) via the microdialysis probe showed a significantly lower
investigation duration during the second exposure of the same
juvenile (p < 0.01 both, Tukey test, Fig. 3). Exposure of a dif-
ferent juvenile demonstrated this effect to be juvenile-specific
recognition (Fig. 3) as behavioral performance in this case was
comparable with that ofaCSF-perfused or untreated Long-Evans
rats (Figs. 2, 4, and 5).
Administration of AVP into the septum of Long-Evans rats
via the microdialysis probe improved their social recognition
even after an IEI of 120 min and, again, this effect was juvenile-
specific (Fig. 4). Administration of the V1 receptor antagonist
into these animals, on the other hand, interfered with their ability
to recognize the same juvenile, which, in contrast to that of
aCSF-perfused animals, does not reflect a statistically significant
difference between the exposures (IEI = 30 min; Fig. 5). A com-
parable failure to recognize juveniles has also been observed in
untreated or aCSF-perfused HO-DI rats (Figs. 2 and 3).

RID Brattleboro
1.6 RID Long-Evans
1.4 3.4

3.0
1.2

1.0
/ 0.2 2.0 2.6

0.0

I!
0.2 2.2
0.8 ng AVP/rat
1.8

0.6
1.4
0.0
0,4 1.0 - -

0.2 IEI = 3 0 m i n 0,6

ee 0.0 5.0
ng V1 antagonist/rat
FIG. 3. Effect of microdialysis administration of different doses of AVP 0.2

(0.0 ng, 0.2 ng, 2.0 ng) into the mediolateral septum of HO-DI rats (n
= 10) on the ratio of investigation duration (RID, investigation duration
of the second exposure divided by investigation duration of the first
exposure). Overall mean investigation duration during the first exposure:
119.1 + 6.0 s. Black columns represent the exposure of the same juvenile,
the hatched column that of a different juvenile during the second ex-
posure; the inter exposure interval (IEI) was 30 min. Values are means
+ SEM; **p < 0.01 (difference between both exposures, Tukey test).
IEI = 3 0 min
FIG. 5. Effect of administration of the VI receptor antagonist (0.0 ng,
5.0 ng) via microdialysis into the mediolateral septum of Long-Evans
rats (n = 9). The inter exposure interval (IEI) was 30 min. Overall mean
investigation duration during the first exposure: 39.7 + 4.6 s. **p < 0.01
(difference between both exposures, Tukey test); for further details see
Fig. 3.
148
DISCUSSION
The present study was undertaken to investigate the behav-
ioral performance of homozygous Brattleboro rats, compared
with that of the Long-Evans strain, in a social recognition test
with particular respect to the importance of septal AVP. More-
over, the feasibility of microdialysis as a method to deliver pep-
tides into the septum during the behavioral test was examined.
The social recognition test has been reported to be a highly
sensitive indicator for the action of AVP within the septal brain
area. Excess of this peptide within the septum due to adminis-
tration of synthetic AVP improves social recognition (14,32).
Blockade of the action of endogenously released peptide by in-
jection of specific antagonists, on the other hand, interferes with
the juvenile recognition of adult male Wistar rats (14). The pres-
ent paper provides the first evidence that homozygous rats of
the Brattleboro strain have an impaired social recognition, which
is comparable with that of normal Long-Evans rats after septal
V 1 receptor antagonist administration via a microdialysis probe
(Figs. 2 and 5}. The hypothesis that the inability to recognize a
juvenile is causally related to the lack of endogenous AVP in
the septum of HO-DI rats is supported by the finding that mi-
crodialysis administration of synthetic AVP was able to improve
social recognition in this rat strain up to the performance of
untreated or aCSF-treated Long-Evans rats (IEI = 30 min; Figs.
2, 3, and 5). Likewise, a further rise in septal AVP of Long-
Evans rats due to the administration of synthetic AVP via the
microdialysis probe resulted in a significantly improved behav-
ioral performance, indicating that social recognition may be
manipulated over a relatively wide range. In all experimental
groups, the use of different juveniles during the second exposure
proved behavioral changes in response to synthetic AVP to be
juvenile-specific, i.e., peptide treatment appeared not to alter
the nonspecific desire of the adult to explore and to interact with
a conspecific juvenile.
Electrophysiological studies have shown that AVP treatment
causes an increase in the firing rate of neurons in hippocampal
slices from HO-DI rats (17). Using autoradiographical tech-
niques, highly specific AVP binding sites have been demonstrated
in the septal brain area of this rat strain (37). Probably mediated
via these receptors, AVP is able to stimulate the postreceptor
response, i.e., the phosphoinositol hydrolysis, in the septum of
homozygous Brattleboro rats (36). These results indicate that in
HO-DI rats the neuronal substrate is still (or even more) sensitive
to AVP. This is supported and extended further by the finding
that both sensitivity and density of septal AVP receptors seem
to be independent of the absence or presence of endogenous
AVP during early postnatal development (38).
Diabetes insipidus produces a variety of changes in endocri-
nological parameters ( 10,39-41 ), causes alterations in the content
of several neurotransmitters in various brain areas (21), and
causes changes in c4os regulatory mechanisms (22). All of these
alterations possibly contribute to the significantly different in-
vestigation duration during the first exposure between untreated
Long-Evans and HO-DI rats (Fig. 2). Whereas an involvement
of endogenous AVP in this behavioral difference remains hy-
pothetical, effects on social recognition after AVP or V 1 receptor
antagonist administration into the rat septum should primarily
be the result of changed interactions between the exogenous or
endogenous neuropeptide and its septal receptors. Because mi-
crodialysis administration during behavioral testing is virtually
stress free and, additionally, provides the advantage of mimicking
AVP release patterns in the septum better than intraperitoneal
or intracerebroventricular neuropeptide injections prior to or
EN(;EI.MANN AND I ANI)GRAF
after the behavioral lest session, efl:ects of other endogenous pa-
rameters or pathways should be comparatively low. The precise
mechanisms ofseptally acting AVP, however, remain to be clar-
ified. Septal release of AVP in response to a variet~ of stimuli
has been shown in vitro (11,26) and in vivo (23.25).
As shown in Fig. 5, administration of the V 1 receptor antag-
onist resulted in a nonsignificant increase in the ratio of inves-
tigation duration. This tendency is mainly due to one animal
that showed a RID of 11. There was, however, no reason to
discard this individual value in terms of localization of the mi-
crodialysis probe or the behavioral pertbrmance shown by this
rat in the other sessions. The failure of the V 1 receptor antagonist
delivered into the septum (5 ng during the 30-min interval) to
significantly influence the investigation duration has recently
been confirmed by a preliminary study on Wistar rats (RID
1.1. #z - 10; Engelmann, unpublished results). Future studies
will locus on increasing the amount of the antagonist. In this
particular case, the animals are expected to behave more like
HO-DI rats during the second exposure, thus t'urther increasing
the RID.
The untreated Long-Evans rats did not behave differently
from males of the Wistar [Engelmann, unpublished results,
(5,15)] or Sprague-Dawley strains (3). Despite a number of pa-
pers reporting no differences between normal Long-Evans and
homozygous Brattleboro rats in terms of behavioral parameters
[see (1) tbr review], the results of the present paper are clear.
The fact that the present study includes rat strains from two
different sources could not explain the observed differences be-
tween homozygous Brattleboro and Long-Evans rats. Pilot
studies using HO-DI rats from other breeders confirmed the
impaired juvenile recognition regardless of the inbred rat strain
used (Engelmann, unpublished results). Theretbre, the lack of
central AVP in HO-DI rats seems to be responsible tbr the im-
paired acquisition, storage, and/or recall of olfactoD' cues. This
hypothesis is supported by the findings of Brito ct al. (9) who
reported that the behavioral performance of HO-DI rats is im-
paired in olfacto U discrimination but not in other tasks. In this
context, it is noteworthy that HO-DI animals show a lower be-
havioral performance only in those tests in which a critical in-
volvement of endogenous AVP could be confirmed, tn fact, in
the Morris water maze, in which septal endogenous AVP seems
not to be involved (19), the pertbrmance of homozygous male
Brattleboro rats did not differ from those of the Long-Evans
strain (18). The results of the present paper confirm and extend
the findings of Dantzer et al. (14) on Wistar males. The finding
that AVP injections into the medial preoptic area failed to affect
social recognition (30) supports the hypothesis that the septum
in particular seems to be involved in this behavioral performance.
Taken together with other findings, our results point toward
the conclusion that AVP in the septal brain area is differentially
involved in behavioral performance. Using the same adminis-
tration protocol, AVP had no effect on acquisition in pole-
jumping avoidance (20), but interfered with spatial memor2y(19).
The social recognition test, on the other hand, has been proven
to be an appropriate model for revealing the essential role of
septal AVP in learning and memory processes of rats.
ACKNOWLEDGEMEN'IS
The authors wish to express their thanks to Dr. Jan Bures(Academy
of Science, Institute of Physiology, Prague, Czech Rep.) for supplying
the Brattleboro rats and for the opportunity to work in his laboratory.
The V I receptor antagonist was a generous gift of Dr. M. Manning,
Toledo, OH. This work was supported by VW-Stiftung(167301).
VASOPRESSIN A N D SOCIAL R E C O G N I T I O N
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