Department of Psychology,
University of Florida, Gainesville,
USA.
Rudolf Magnus Institute for
Pharmacology, University of Utrecht, The
Netherlands.
The induction of excessive grooming by
intraventricular administration of ACTB1-24 was
studied in rats with lesions in midbrainlimbic
structures. Such areas have been reported to be
implicated in mediating ACTH-induced effects on
avoidance behavior, sexual excitement or
stretching and yawning. Electrolytic lesions in
the septal complex, the anterior
hypothalsmic/preoptic area,the mammillary
bodies, the amygdala, the posterior thalamus and
dorsal or ventral hippocampus did not interfere
with ACTH-induced excessive grooming. Lesioning
of the hippocampal complex by aspiration led to
an inhibition of excessive grooming depending on
the degree of hippocsmpal da-Age. hmygdala and
hippocsmpal lesions enhanced the display of
stretching and yawning activity after treatment
with the peptide. The data indicate differences
in the neural substrates mediating the effect of
ACTH on extinction of conditioned avoidance
behavior, excessive grooming, sexual excitement
and stretching and yawning.
It is now well known that ACTB/MSH/LPH
peptides influence the activity of the central
nervous system. The effects of these hormone
fragments are often measured by changes in
performance in learning tasks, both during
acquisition and extinction (1,2) and lesions in
structures related to limbic systems seem to
alter some of their effects (3).
Intraventricular administration of peptides
derived from ACTH/MSH/LPH induces excessive
grooming which in most instances is followed by
a stretching and yawning syndrome (SYS)
(4,5,6,7,8,9,10). Some authors suggest that in
addition to SYS, intraventricular application of
these peptides also induces sexual arousal in
rabbits (6,11,12,13) and rats (14). This is
characterized by recurrent episodes of penile
erections accompanied by copulating movements.
However, the male does not seek to copulate with
either male or receptive female partners (14)
and it is therefore questionable whether indeed
the elicited penile erections reflect sexual
excitement. Damage to the preoptic area
auppressed ACTH-induced penile erection leaving
SYS activity unaltered (15).
The behavioral significance of the grooming
response is not entirely established. Grooming
in rodents is sometimes interpreted as
representive of "displacement activities"
(16,17), but other investigators think of
grooming as collateral act, i.e. behavior
associated with, but not part of, a
goal-directed activity (18,19,20). While
feedback from the peiiphery is usually important
for the development and maintenance of
integrated movement repertoire like grooming
(17) there is evidence for a strong internal
control of grooming (21).
Since excessive grooming and SYS begin at
different times after peptide-injection and
there are discrepancies between effectiveness of
various peptides in inducing grooming and/or
SYS, it is likely that different neural
substrates exist for these two behaviors (7,8).
In the present paper, the induction of excessive
grooming induced by intraventricular
administration of ACTh1.24 is studied in rats
with lesions of brain areas which have been
reported to be implicated in mediating
peptide-induced effects on avoidance behavior,
sexual excitement or SIS.
Discussion
The present paper aimed to study the effects
of brain lesions on the induction of the
excessive grooming produced by intraventricular
injection of ACTH12. The lesions were made in
brain regions that have been implicated in
mediating other behavioral effects of ACTE by
previous reports.
Extinction of a conditioned avoidance
response in rats is delayed by peripheral or
intraventricular administration of peptides
derived from the N-terminus of ACTH (1,26).
Implantation studies as well as lesion
experiments, revealed that the posterior
thalamic area (including the n.
parafascicularis) and the rostral septal region
are involved in the expression of these
peptide-induced behavioral changes (3,27,28,29).
In addition, after intraventricular
administration of a radioactively labeled
ACT1h-g-analog, high uptake of the peptide was
restricted to va*ious dorsal-medial septal
nuclei (30). In this study no suppression of
excessive grooming or STS was found after the
septal lesion. In fact, tendency towards
enhanced grooming was noted. Although little
signs of the so-called septal syndrome
(viciousness, rage-like behavior,
over-reactivity to stimuli; 31) was noted, a
tendency to display enhanced grooming activity
when compared to sham lesioned groups may be
related to their known increased reactivity to
stimulation (e.g. 32,33). Furthermore, both
ACTh1_2z and D-Phe7J ACTH-10 induced excessive
grooming and STS in rats bearing lesions in the
posterior thalamic area including the n.
parafascicularis. These data indicate
differences in the neural substrates of
ACTH-induced excessive grooming end ACTEinduced
delays in the extinction of avoidance
responses.
Micro-injections of ACTH1-2j1 (20 ig/5 ul)
into different regions of the cat brain have
shown that SYS can be most easily elicited from
the hypothalamic areas liming the third
ventricle (34). It is of interest that in the
squirrel monkey, injecting ACTE in the medial
preoptíc region or MSH into the septal
area results in episodes of SYS, scratching, and
penile erection. Such injections were
ineffective when placed in the ventromedial
hypothalamus or prmnammillary region (35). In
cats, injection of ACTH1-21 into the manunillary
bodies induced SYS within 7 min. This was the
shortest latency found in all brain locations
studied (34). In this study rats with lesions in
the manreillary bodies displayed more SYS.
Therefore in rats the maninillary region can not
be the site of SYS inducing activity of
ACTH1_24.
Despite the importance of the anterior
hypothalamic and preoptic regions for sexual
behavior, the present results raise questions
about the importance of these areas for grooming
and SYS. In female rabbits, intraventricularly
injected ACTh1-21 increased multiple finit
activity in the area of the lateral diagonal
band of Broca and the periventricular preoptic
area (6). There is a rise in serum LE as a
result of ACTE infusion (6,13), but sexual
behavior seemed not to depend on this raised LE
level (6). Lesions of the preoptic/hypothalamic
areas are ineffective in suppressing
ACTH-induced excessive grooming and SYS.
Bertolini had previously reported that a lesion
in the preoptic area suppressed ACTH-induced
penile erection but not SYS (15). Furthermore,
castration of rabbits and rats suppresses
ACTH-induced penile erection leaving SYS
activity unaltered (14) and does not interfere
with ACTH-induced excessive grooming (7). Only
occasionally is penile erection seen during
grooming of the genital area and a detailed
analysis of the ACTH-induced behavior revealed
no difference at all between male and female
rats (Gispem et al., in preparation). Therefore,
it seems that excessive grooming and SYS are
independent of penile erection in the rat.
Rippocampal lesions do not affect grooming
in the rat when observed in the familiar
environments like the home cages (36,37).
However, observations by Oades and Isaacson (38)
indicate that hippocampal lesions almost
completely eliminated grooming in a relatively
unfamiliar open field. The hippocampus also
seems to be an important structure for ACTE
effects on the CNS. Damage to the dorsal
hippocampus has been found to interfere with the
affect of ACTE on the extinction of am avoidance
response (39). In freely moving dogs, peripheral
treatment with ACTE4-10 shifted the hippocampal
theta activity to lower frequencies (40).
In rats, the peripheral administration of
ACTH-10 produced a shift to higher frequencies
when hippocampal theta was induced by
stimulation of the reticular formation (41).
Administration of ACTR increased unit activity
in the dorsal hippocampus (42). Segal (43) has
reported that iontophoretically applied ACTR
inhibited unit firing in the hippocsmpus end
also antagonized the inhibitory effects of
norepinephrine in about 50% of the hippocampal
neurons tested. In this study, extensive damage
to the dorsal hippocampus reduced ACTH-induced
grooming activity and extending of the lesions
to the posterior-ventral site further decreased
this response. In both instances a markedly
display of SYS activity was observed. The
decrease in grooming can not be accounted for by
increased amounts of SYS. Smaller electrolytic
lesions in the posterior dorsal part of the
hippocsmpus did not interfere with grooming
activity but small lesions of the ventral
hippocampus did. The near total
hippocampectomized rats had greatly reduced
grooming but little SYS activity was observed in
these animals. It would appear that damage to
the ventral hippocampus or total hippocampectomy
suppressed ACTH-induced grooming. Lesions of
these regions produce enhanced locomotor
activity in the open field while lesions of the
dorsal hippocampus do not (25).
The low level of grooming in the total
hippocampal lesion group is not likely due to
interference with the ventricular system since
in two rats with cannulae in the fourth
ventricle, grooming was still eliminated. The
fourth ventricle is at some distance from the
area of brain damage. Injection of the peptides
in the fourth ventricle can produce the same
amount of grooming as injection into the
interventricular foremen (Brakkee, Weyman and
Gispen, in preparation). it is unlikely that a
general debilitation of condition would have
caused the absence of grooming and SYS in
ACTH-injected hippocampally lesioned rats since
all lesioned rats were gaining weight at the
time of testing.
Prom the dissociation of the effect of
ACTh1..2t treatment on grooming and SYS in rats
with lesions in the mammillary bodies, the
amygdale or the dorsal/ ventral hippocampus, it
is likely that the peptide-induced effects on
grooming and SYS depends on different neural
substrates. This is further supported by (a) the
difference in onset latencies between grooming
and SYS (immediately vs 30-40 mm), (b) the
induction of grooming but absence of SYS by
LP1161_91 (8) and (c) the elicitation of
grooming by injection of ACTH1_2t4 into
substantia nigra without the induction of SYS
(44; Gispen, Colbern and Cools,
unpublished).
The mechanism by which ACTR induces
excessive grooming and SYS is unclear. In regard
to excessive grooming, there is presumptive
evidence for involvement of dopeminergic
pathways since ACTH1214 injections into
substantia nigra can induce excessive grooming.
ilaloperidol injections into the caudate can
block this response (44).
Systemically administered haloperidol at a
low, but behaviorally effective dose, fails to
affect grooming and may even facilitate
peptide-induced grooming (Colbern, Isaacson and
Gispen, in preparation) while large doses will
attinuate the grooming response (44). A
presumptive relationship between forebrain BA
systems and hippocampal activity has been
established by Fish (45) who found that animale
with near total hippocampal destruction seemed
to be more resistant to dopaminergic blocking
agents than control animals in several
behavioral situations. Other behavioral changes
usually found after hippocampal destruction are
compatible with the idea that the lesion
enhances the effectiveness of the ascending BA
system. The present results would suggest that
the ventral hippocampus is most important to
these effects and that fibers may pass through
the finbria-fornix system to other brain
regions. This would explain the progressively
smaller behavioral effects after aspiration
lesions of middle and dorsal portions of the
structure. The smaller electrolytic lesions of
the dorsal and ventral hippocampus that did not
transect the structure would be presumed to have
interrupted too few of these fibers to produce
an effect on the peptideinduced behavior.
Projections to the hippocampus from the
medial septal nuclei do not seem to be necessary
for the ACTH-induced grooming since none of the
septal lesions, including those specifically
directed at the medial septal area, influenced
grooming or SYS.
The analysis of neural systems related to
SYS seems more complicated and, at the moment,
difficult to interpret. Projections from
amygdala and ventral hippocampus reach area of
the ventromedial nucleus of the hypothalamus and
it would be tempting to consider this nucleus as
part of a neural system related to SYS. However,
the elimination of SYS by total destruction of
the hippocsmpus and the effects produced by
lesions of the manriillary bodies are not
explicable on this basis. Further research is
needed to clarify the nature of the
peptide-sensitive systems related to SYS.
