Introduction : Previous studies have
described a peculiar stretching and yawning
syndrome (SYS) in various mammals following
injection of peptides possessing ACTH or
intermedin (MSH) activity into the cerebrospinal
fluid. The sites of action of these peptides
were thought to be hypothalamic structures
located close to the wall of the third
ventricle. More recently, reports have been made
concerning the induction of a dramatic display
of sexual excitement following similar
treatments in male rats and rabbits. Preliminary
studies (Haun and Haltmeyer, unpublished
observations) have indicated that
intraventricular injections of ACTH 1-24 could
stimulate LH release and gonadal steroid
secretion in addition to sexual excitement in
male and female rabbits.
Initially, this study was designed to test
the effects of intraventricular injections of
ACTH 1-24 on LH release, and to investigate
electrophysiological changes in the areas of the
brain thought to be associated with this event.
Since, under these conditions, ovulation was
induced but only limited behavioral observations
could be made, a second series of experiments
were designed to (1) determine temporal
relationships of LH release with behavioral
changes, and (2) compare these with changes
occurring after injection of a smaller fragment
of ACTH, namely ACTH 4-10, and LH-releasing
hormone (LHRH), a peptide known to cause release
of LH. [...]
Discussion : When given alone or
preceded 1 h earlier by infusion of saline,
intraventricular infusions of ACTH 1-24 into
estrogen-primed rabbits induced ovulation and/or
LH release in the majority of animals tested. In
contrast, when ACTH 1-24 infusion was preceded
by cardiac puncture bleedings at 1 and 2 h in
addition to injection of saline, ovulation and
LH release were inhibited. Under the same
conditions the ability of ACTH 1-24 to promote
SYS and sexual excitement was also reduced.
Thus, it appears that the non-specific stress of
bleeding prior to the ACTH 1-24 infusion
resulted in an increased threshold of
responsiveness to intraventricular ACTH.
Recently, Sawyer referred to earlier unpublished
studies with Saul in which electrical
stimulation of the amygdala under acute
stereotaxic conditions was ineffective in
inducing ovulation, whereas such stimulation in
the unstressed chronically implanted rabbit was
highly successful. Also, Ellendorff et al.
reported that surgical stress in combination
with amygdala stimulation in the proestrus rat
would block cyclic ovulation, but in chronically
implanted rats under otherwise similar
conditions ovulation was not inhibited. The
above results, as well as those reported in this
study, suggest that a central nervous response
to a particular stimulus may be altered by
non-specific stress. Whether these effects are
due to direct changes in neural responsiveness,
or indirectly through the feedback of adrenal
secretions remains to be determined.
Glucocorticoids have been reported to alter
brain electrical activity, oppose the effects of
ACTH on conditioned avoidance behavior and
inhibit LH release.
Any suggestions as to how ACTH 1-24 might
cause a release of LH must at this time be
purely speculative. Nevertheless, since
catecholamines are, in general, stimulatory to
LH release, and, in particular, norepinephrine
infused into the third ventricle of rabbits
activates LH release, it could be suggested that
ACTH 1-24 stimulates central adrenergic pathways
responsible for LH release. Similarly, altering
the norepinephrine-serotonin balance in rats by
treatment with p-chlorophenylalanine and
pargyline has been reported to stimulate sex
behavior. Our dosages of ACTH 1-24 and ACTH 4-10
were suggested by the work of Bertolini et al
and are admittedly in the pharmacological
range.
The induction of SYS reported here in female
rabbits is similar to that described earlier in
males indicating that there is little or no sex
difference in this behavioral response to ACTH
1-24. On the other hand, noticeable sexual
excitement in the female rabbit was much less
dramatic than that described for the male. This
may reflect a real sex difference in response to
ACTH 1-24 or it may be merely that sexual
excitement in the singly caged female is more
difficult to assess than in males. Since LHRH
bas been shown to stimulate sexual behavior in
estrogen-primed ovariectomized rats it seemed
possible that the sexual behavior we were
observing might be due to rejease of LHRH and,
therefore, not a direct effect of ACTH 1-24 on
behavior. Since infusion of large quantities of
LHRH caused a substantial release of LH without
a noticeable effect on behavior, this
explanation seems unlikely.
It is of interest that compounds with similar
structurai relationships to the naturally
occurring ACTH molecule, e.g., ACTH 1-24 ,
a-MSH, Li, also exert similar effects on the
induction of SYS and sexual excitement. Natural
ACTH, ACTH 1-24 , and a-MSH as well as a smaller
fragment of ACTH, e.g., ACTH 4-10 can also
influence the extinction of conditioned
avoidance response in rats. Although the number
of observations is rather limited, the
intraventricular infusions of 10 ug ACTH 4-10
(approximately 3 times the amount of ACTH 1-24
on a molar basis) did not induce ovulation and
were less effective in causing LH release or
inducing SYS and sexual excitement. This
suggests that although some stimulating activity
may be retained on the shorter molecule, the
additional amino acid residues on the ACTH 1-24
are necessary for maximum hormonal and
behavioral responses. As in the case of ACTH
1-24, bleedings prior to the injection of ACTH
4-10 suppressed both behavioral and hormonal
changes.
Although saline infusion was essentially
without effect on LH release, a few animals
showed a slight rise in serum LH levels 30 min
after infusion. Since ventricular expansion has
been reported to elevate plasma LH in the rat'5,
it may be that these animals experienced acute
ventricular expansion at the time of infusion. A
similar physical effect may also have induced
the SYS and sex behavior seen in 1 of the 9
animals infused with saline.
The site of action of these peptide hormones
is unknown. Areas adjacent to the third
ventricle have immunoreactive ACTH
concentrations much greater than those found in
plasma. Also, hypothalamic areas lining the
third ventricle were, with the exception of the
caudate nucleus, the most sensitive sites in the
brain for induction of SYS in the cat. These
investigators proposed that these hypothalamic
areas were connected with the reticular system
to maintain an aroused state (as determined by
cortical EEG patterns) since drugs known to
block the reticular system suppressed the SYS.
In the present study, no definite changes in
sleep-wake EEG patterns were observed following
ACTH infusion. However, electrode sites in the
LPO-diagonal band and PPO areas were found to
respond to intraventricular ACTH 1-24 with
elevated MUA activity. Whether these changes are
related to behavior, hormone release, or some
other CNS response is not known. Obviously more
detailed studies will be needed before anything
conclusive can be said about either the site(s)
of action of these peptide molecules on the
central nervous system or the possible
physiological implications of their
actions
