haut de page
Dopamine agonist-induced yawning in rats: a dopamine D3 receptor mediated behavior
Collins G et al  





mise à jour du
1 septembre 2003
Brain Research
1974; 80; 1974; 291-301
Effects of intraventricular infusions of ACTH 1-24 and ACTH 4-10 on LH release, ovulation and behavior in the rabbit 
David M. Baldwin, Charles K. Haun And Charles H. Sawyer
 Departments of Anatomy, University of California and University of Southern California Medical
Schools and UCLA Brain Research Institute, Los Angeles (U.S.A.)


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 Preliminary studies (Haun and Haltmeyer, unpublished observations) have indicated that intraventricular injections of ACTH 1-24 could stimulate LH release and gonadal steroid secretion in addition to sexual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