Department of Psychology,
Bowling Green State University
abstract
The effects of centrally administered
ACTH(1-24) and ACTH(4-10) on isolation-induced
distress vocalizations (DVs) were assessed in
the presence or absence of social cues (mirrored
and plain environments). A dose-response
analysis indicated that ACTH(1-24) at doses of
0.5 nM and above increased DVs relative to
controls when the animals were tested in
mirrored or social environments which reduce
baseline levels of calling. This effect,
however, was short-lived (approx. 15 min). When
tested again 1 hr after injection, the treated
animals did not differ from controls.
ACTH/MSH(4-10) had no effect on vocalization
when the animals were tested immediately after
injection, but marginally increased calling when
animals were tested an hour later. In addition
to vocalization changes, ACTH(1-24) induced
squatting when animals were isolated in the test
boxes, and yawning, head shaking, wing
flapping and preening when animals were reunited
after testing. ACTH(1-24)-treated chicks also
exhibited longer latencies to close their eyes
when they were held in the cupped hands of the
experimenter. Taken together, the results
suggest that ACTH(1-24) induces a central state
of arousal in chicks that resembles
fear/anxiety.
ALTHOUGH a large number of behavioral
changes have been observed following both
central and peripheral administration of
adrenocorticotropin (ACTH) (6,7), the central
integrative functions mediated by this
neurochemical system remain ambiguous. Initial
investigations in this field found that ACTH, as
well as several shorter fragments of the
peptide, could induce a stretching and
yawning syndrome in cats, dogs, and
monkeys (9), and a stereotyped, albeit
sequentially normal, grooming pattern (10). In
male rabbits, ACTH yielded prominent episodes of
sexual excitement consisting of penile
erections, copulatory movements, and
ejaculations (3), accompanied by elevated plasma
luteinizing hormone (LH) and testosterone (12).
More recent work indicates' that this peptide
system can promote regeneration within the
nervous system (20). Although these diverse
effects, including the demonstrated interactions
with many neurochemical systems, especially
dopamine and opioid ones, have now been
extensively documented (7), the only coherent
conceptual scheme presently available is that
the central role of this neurochemical system is
congruent with its peripheral role, namely
promoting preparation of the animal to respond
to and cope with stress (22). Indeed, it is well
known that stress can produce a diversity of
behavioral changes ranging from increased
grooming behavior to increased sexual
behavior.
The diverse behavioral changes that have
been observed following central ACTH
administration may represent a relatively
unitary change in the emotive/affective tone of
the nervous. system. Indeed, very dramatic
fear-like flight has been obtained by
administration of high levels of this peptide
into the periventricular gray of the midbrain
(13), which may suggest that the basic role of
this system is to change levels of emotionality
and/or arousal within the nervous system. The
fact that ACTH-induced grooming (which is
commonly obtained at much lower doses than
flight) also relies on periventncular circuits
(21) suggests that the grooming may be a symptom
of mild emotional arousal whereas flight is a
symptom of more intense arousal, perhaps of the
same type. From the perspective that brain ACTH
systems may modify a specific type of
emotionality, it was deemed desirable to analyze
the effects of this peptide on a very clear and
concrete emotional response that all
warm-blooded social vertebrates are known to
exhibit-the production of distress vocalizations
(DVs) in response to social separation. In the
following study we measured the effects of
centrally administered ACTH(l-24) and
ACTH/MSH(4-1O) on the separation distress
response of young chicks. The responsivity of
this emotional system to a large variety of
other agents, especially opioids, is documented
elsewhere.
The possibility that separation distress
circuitry may be responsive to changes in
central ACTH levels is suggested by the massive
arousal of the pituitary-adrenal system of
primates in response to maternal separation (4),
and the ability of corticotropin releasing
factor (CRF) placed into the fourth ventricle
region to promote the emission of isolation
calls, at least in young domestic chicks (17).
Existing work also indicates that the
pro-opiomelanocortin (POMC) system (14) of the
brain can modify DVs in both directions. The
opioid-mimetic segments of POMC can markedly
attenuate DVs (18), while centrally administered
a-MSH has recently been found to increase DVs,
especially when testing is conducted in the
presence of social cues (such as mirrors or
other animals) which normally tend to reduce the
baseline levels of crying (1). Since a-MSH and
the carboxy terminal of ACTH share the same 13
amino acids, and because the two peptides
typically yield similar behavioral effects (6),
we anticipated the ACTH( l-24) fragment, which
shares the biological effects of the complete 39
amino acid peptide, to yield a comparable
pattern of results. Accordingly, in the
following study we contrasted the effect of
intracerebroventricular (1CV) administration of
ACTH(l-24) on the separationinduced DVs of young
chicks to that of the ACTH(4-1O) segment which
possesses little adrenocortical activity, but
which is known to have a variety of social
effects of its own (5). Other behaviors of the
chicks following ACTH( l-24) treatment were also
assessed in this experiment, including postural
and locomotor effects, and the response of the
chicks to contact comfort.
DISCUSSION
The patterns of vocalization changes
following central ACTH(I-24) administration
closely resemble those obtained previously with
ct-MSH (1). ACTH(I-24) elevated DVs, especially
when animals were tested either in pairs or in
mirrored environments. This ACTH(I-24) effect
was biphasic, with the initial elevation of DVs
followed by a phase of diminished DVs. Neither
of these effects were simulated by
ACTH/MSH(4-10).
Besides the vocalization and other
behavioral effects observed in the present
series of experiments, central ACTH( l-24)
administration also yielded a sustained
squatting posture which seemed identical to that
produced by a-MSH (1), which suggests that a
fear-like central state, which should promote
freezing and hiding, had been instigated. During
the period of time that the most intense
squatting was observed, DV rates were reliably
reduced below baseline levels. In general these
observations suggest that the type of emotional
effect evoked by central ACTH( l-24) activity
resembles anxiety and fear. This would be
consistent with the observations of Jacquet (13)
that flight can be evoked by massive doses of
ACTH administered to the periventricular region.
These outwardly distinct behavior patterns may
not be contradictory since low levels of fear
typically induce freezing while high levels of
fear precipitate flight. Also, since grooming is
commonly observed in animals placed into
situations that provoke mild anxiety, in
combination with the fact that grooming induced
by ACTH requires periventricular gray tissue
(21) through which basic fear circuits appear to
pass, further affirms that a diversity of
behavioral effects produced by ACTH and MSH
peptides may be mediated via this type of
emotional change. From such a perspective, one
would predict that heightened ACTH activity in
the brain would normally be perceived as
aversive by humans and other animals.
To our knowledge, there is no compelling
evidence indicating how heightened central ACTH
activity changes affective experiences. In
humans, peripheral ACTH injections appear to
promote positive emotional states (8,11), but
there is no evidence that these effects are
mediated directly via brain ACTH receptive
systems. Animal data with brain reward systems
indicate that central ACTH(I-24) injections
reduce self-administration of stimulants (15)
and these investigators suggested that this may
be due to the ACTH(I-24) partially fulfilling
the hedonic needs of the animal, obviating the
need for further self-administration of
rewarding chemicals. Of course, it is equally
plausible that the reduced behavior was due to
the reduced intensity of the reward or the
behaviorally suppressive effects of another type
of emotional arousal such as fear. Clearly,
there are two distinct viewpoints regarding the
hedonic effects of central ACTH circuits, and it
is possible that the effects are biphasic, with
low doses promoting a desirable level of arousal
and higher doses promoting a state of arousal
that is aversive. To the extent that present
data permit hedonic interpretations, we believe
the existing spectrum of results is more
consistent with the conclusion that ACTH
promotes aversive rather than pleasurable states
of the central nervous system.
