ACTH-induced excessive grooming in the rat

Observations indicate that certain forms of environmental manipulations also lead to excessive grooming, and stressors seem to fall into two classes: those that produce excessive grooming after their termination and those that do not.

Abstract

Excessive grooming is a remarkable behavioral response for several reasons. Probably the most important is that it represents an almost unique behavioral assay for the injection of the longer ACTH fragments. Fractions of a microgram of ACTH1–24 or ACTH1–16 produce extensions of grooming bout duration to an extent that the animal does little else during the entire observation period. The specificity of the response is remarkable, as well. Few other neuropeptides induce excessive grooming, and those that do (e.g. [7-d-phe]ACTH4–10) are only of limited effectiveness. Also of special interest is the limited number of brain regions in which lesions influence the response. Only two such regions have been found: the substantia nigra and the hippocampus. A link to naturally occurring events is now provided by the observations which indicate that certain forms of environmental manipulations also lead to excessive grooming. These are conditions of mild stress, the most completely studied being that of 'novelty'. While providing a connection to real world events, the study of stress-induced excessive grooming has also led to certain difficult questions. In the study of stress conditions that produce excessive grooming, only certain ones have been found to be effective. These include handling, noise, transport, novelty, the anticipation of footshock and water immersion. Of these, water immersion has the most pronounced effects. From our pharmacologic studies, water immersion produces a type of grooming that is distinctly different from either that produced by novelty or other mild stress conditions and also different from that produced by central ACTH administration. For example, the excessive grooming induced by water immersion is not reduced by either substantia nigra or hippocampal lesions, neither is it reduced by the systematic administration of clonidine. On the other hand, these treatments and procedures reduce both novelty and ACTH-induced excessive grooming. The stress procedures which do not induce excessive grooming also bear consideration. They include the exposure to ether fumes, bodily restraint, and electrical footshock. In fact, the latter reduces excessive grooming. Putting aside, for a moment, the effects of water immersion, stressors seem to fall into two classes: those that produce excessive grooming after their termination and those that do not. It seems to us that this could come about in two ways: (1) the stressors that do elicit grooming may produce a different type of distribution of ACTH release in the brain than those that do not; or (2) all stressors may produce ACTH release in a similar fashion, but those that fail to elicit grooming may also elicit antagonistic activity, possibly involving the brain monoamine systems. While there is little evidence to support a differential pattern of release as a consequence of different stress conditions, the possibility cannot be ruled out. The second possibility, the activation of incompatible neural systems by certain stressors, seems more likely. If this is the case, then it could be proposed that the amount of excessive grooming displayed by an animal is positively related to the amount of ACTH affecting certain brain regions involved with the production of excessive grooming, and negatively related to the activity in opposing systems. ACTH could reach the target areas of the central nervous system from the anterior pituitary (de Kloet and de Wied, 1980; Mezey, et al., 1978) or from central ACTH networks. Beagley (1976) felt that this electrical stimulation at higher intensities may have activated an excitatory system for grooming that did not achieve behavioral expression because of the simultaneous induction of an opposing, inhibitory process. He proposed that the grooming system, however, had a longer afterdischarge than the opposing processes. Thus, when inhibition or the competing response tendencies declined in activity, grooming would be observed. Bolles (1960) came to a similar conclusion. He had found that the induction of motivation for food or water by deprivation decreased grooming as did the induction of fear. He concluded that these 'motivational' procedures did not induce grooming directly but that grooming-occurred after the conclusion of goal-directed acts or highly motivated episodes, presumably when competing neural mechanisms declined in activity. The relatively high levels of excessive grooming seen after water immersion seem to be quite different in some aspects from either novelty- or ACTH-induced grooming. Their resistance to lesions effects and pharmacological intervention suggest a different component or mechanism has been involved. It may be that this is related to increased 'maintenance' grooming (an attempt to remove water from the fur), but if this were the case, it would be necessary to account for the fact that from 1 to 3 min of water immersion is necessary to induce the effect. Exposure to water for less than one min fails to elicit the effect. It is also difficult to explain why the soiling and disturbances of the fur in the restraint procedures fails to elicit a similar amount of grooming on the basis of a maintenance hypothesis. The involvement of opiate-sensitive systems in the grooming response is based on the ubiquitous blocking effect of naloxone on all excessive grooming, including that induced by water immersion. It is certainly not a response common to all of the known endogenous opiates since the enkephalins and some endorphin fragments are ineffective in producing excessive grooming. In fact, the excessive grooming induced by β-endorphin is qualitiatively different from that produced by ACTH. β-endorphin seems to activate the animals into more behavioral activities including grooming, while ACTH acts to extend the duration of grooming episodes. The neurochemical mechanism by which ACTH induces the grooming behavior is not understood. However, the recent isolation of an ACTH-sensitive protein kinase from rat brain synaptosomal plasma membranes suggests that ACTH may modulate trans-synaptic neuronal activities by altering the degree of phosphorylation of certain synaptic proteins. The insensitivity of this protein kinase to endorphins and the unique ACTH structure-activity correlation between the induction of excessive grooming and inhibition of protein phosphorylation support this notion. Since excessive grooming is found after the termination of several stressors, it is possible that it is related to restorative neural and chemical processes. ACTH could be thought of and acting as an initiating factor in the mobilization of the organism to meet the emergency situation while at the same time initiating processes aimed at re-establishing a stable, internal equilibrium. The grooming response, itself, has been considered to play a deactivating role in animal behavior (for example see Delius, 1970; Delius, et al., 1976; Jolles et al., 1979a). It is also possible to cast the behavioral observations into a related but different context which removes some of the objections that can be made to the view that grooming should only occur before relatively inactive states. This would be that excessive grooming is a correlate of a central state in which behavioral activation may be present but without concomittant demands for fight or flight. This central state may be correlated with a number of classes of responses and the ones selected for exhibition would depend on environmental opportunities, the animals past history and genetic predispositions. Grooming may occur after extremely arousing conditions. This suggests that these acts may be correlated with pleasurable experiences. The slow body stretching and paw extensions found in cats by MacLean (1957) would be one example as would the signs of sexual excitation observed. Bertolini, et al. (1975) report similar signs of sexual arousal after injection of ACTH1–24 into the lateral ventricle of the rabbit. However, the presumed sexual arousal reflects an activation of the mechanisms related to sexual behavior without an enhanced motivation to copulate. During the peptide-induced stimulation the animals do not seek copulation. For example, the injection of the peptide into the ventricles of male rats does not increase the percentage of males copulating with females. It is as if the animal is 'tuned in' to its own pleasurable bodily reactions that may include those of a sexual nature. Bertolini et al. also provided evidence that the sexual activation in male rats or rabbits instituted by ACTH1–24 depends on the integrity of the testes. However, the excessive grooming observed in rats after the intraventricular injection of ACTH1–24 or β-endorphin, in the amounts used in our laboratories, as well as the grooming induced by novelty does not concentrate on the genital area. Few signs of sexual arousal can be observed. However, it is possible that a 'pleasurable', positive affective state is induced by these treatments and that at greater magnitudes the pleasurable state could facilitate signs of sexual arousal. This would suggest that in the rat the central state induced by i.c.v. administration of ACTH1–24 is closely limited to the grooming response but is may be tied to other, many more varied responses in other species.