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mise à jour du
21 décembre 2009
Life Sciences
1977;21:393-402
 
Limbic-midebrain lesions
and acth-induced excessive grooming
 
D.Colbern , R.L.Isaacson , B.Bohus and W.H.Grspen
 
Department of Psychology, University of Florida, Gainesville, USA. 
Rudolf Magnus Institute for Pharmacology, University of Utrecht, The Netherlands.
 
 

Chat-logomini

 
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.