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mise à jour du
9 septembre 2009
Effects of ACTH(1-24) and ACTH/MSH(4-10)
on isolation-induced distress vocalization
in domestic chicks
Panksepp J, Normansell L.
Department of Psychology, Bowling Green State University


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.
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.