ACTH-induced Excessive Grooming Research Articles

Nitric oxide is involved in the ACTH-induced behavioral syndrome.

In many animal species, the ICV injection of ACTH and of several shorter sequences of the ACTH molecule (melanocortin peptides) induces a peculiar behavioral syndrome mainly characterized by excessive grooming and by repeated acts of stretching and yawning. In adult males, spontaneous penile erections with ejaculation are also induced. We have studied the effect of NO synthase inhibition on this behavioral syndrome. The IP injection of the NO synthase inhibitor L-NG-nitroarginine methyl ester (NAME) significantly prevented--at the doses of 50 and 100 mg/kg--all the behavioral symptoms induced by the ICV administration of ACTH(1-24) (4 micrograms/rat). On the other hand, the ICV injection of NAME (up to 300 micrograms/rat) had no influence on the ACTH-induced excessive grooming and stretching, while significantly inhibited the display of yawnings and penile erections. These data indicate that brain NO synthase is involved in the mechanism of ACTH-induced yawning and penile erections, whereas peripheral NO synthase is involved in the induction of stretching and grooming.

Molecular transduction mechanisms in ACTH-induced grooming.

Intraventricular administration of ACTH1-24 induces excessive grooming in the rat. Ethogram analysis shows that the peptide does not alter grooming behavior seen in a novel box, but that it prolongs the duration of the grooming bout. Extensive structure-activity studies have been performed which suggest that the active site lies in a region (5-13) of the ACTH molecule. Interestingly, the (1-24) sequence is fully active, whereas (1-10) and (11-24) alone or in combination are inactive, pointing to a specific stereoconformation necessary to induce grooming. However, despite the fact that there are ACTH-and/or alpha-MSH-containing peptidergic neurons, no conclusive evidence is available demonstrating stereospecific, saturable binding sites for these peptides in brain. The analysis of the neural substrate underlying ACTH-induced excessive grooming has been performed by means of electrolytic lesions of specific brain regions and by neuropharmacological manipulations. The data suggest that the periaqueductal gray is the primary target for ACTH and that the activity of neostriatum and accumbens, via a nigro-colliculus-periaqueductal gray pathway, modulates the display of excessive grooming. An important feature of the neural substrate is that it displays single-dose tolerance to the peptide during the first hours after the first peptide injection. It is suggested that the tolerance is a feature of an opioid receptor-containing component of the neural substrate. The molecular mechanism of action of ACTH is complex and may involve different transmembrane signal transduction systems. The peptide decreases the degree of phosphorylation of a neuron-specific, synaptic phosphoprotein B-50 by inhibition of protein kinase C. It is concluded that changes in the degree of phosphorylation of B-50 regulate the activity of the lipid kinase phosphatidylinositol 4-phosphate kinase. Therefore, the B-50 protein seems to be part of a negative feedback loop in the receptor-activated hydrolysis of phosphatidylinositol 4,5-bis-phosphate (PIP2). There is increasing evidence that the molecular mechanism by which ACTH brings about the grooming response involves a change in phosphorylation of B-50. Firstly, the structure-activity relationship of ACTH-induced excessive grooming is nearly identical to that obtained for ACTH-induced inhibition of protein kinase C.(ABSTRACT TRUNCATED AT 400 WORDS)

The influence of neurotensin, naloxone, and haloperidol on elements of excessive grooming behavior induced by ACTH

Naloxone, haloperidol, and neurotensin suppress ACTH-induced grooming. The suppressive effects of naloxone and of haloperidol on ACTH-induced grooming are observed following subcutaneous as well as intracerebroventricular administration. The suppression of ACTH-induced grooming by these drugs is not accompanied by a change in the relative distribution of grooming elements. From previous data and from the results of the present study it is suggested that the underlying substrate involved in ACTH-induced excessive grooming may differ from that of bombesin-induced grooming.

The collicus superior modulates ACTH-induced excessive grooming

In previous studies the involvement of nigrostriatal dopaminergic activity in ACTH(1–24)-induced grooming has been established. It was suggested that the dopaminergic modulation of ACTH(1–24)-induced excessive grooming is exerted through the striato-nigro-collicular pathway. To obtain further evidence it was investigated, whether local application of GABAergic agents into the colliculus superior modulates excessive grooming occurring after an intraventricular injection with ACTH(1–24). It appeared that intra-collicular picrotoxin (a GABAergic antagonist ssuppressed ACTH-induced grooming, whereas muscimol (a GABAergic agonist) enhanced the grooming response. The picrotoxin-induced R(unning) F(it) B(ehavior), elicited from the colliculus superior was also seen after intraventricular administration of picrotoxin. A detailed comparison of this behavioral response seen after both routes of administration of picrotoxin suggests that intraventricularly injected picrotoxin may well induce the RFB via a direct effect on the colliculus superior. Lesions placed in the colliculus superior completely abolished picrotoxin-induced RFB, exploration and orientation behavior. Yet, these lesions did not reduce excessive grooming suggesting that although this region may be involved in the modulation of ACTH-induced grooming it is not the primary site of peptide action.

The periaqueductal gray: A prerequisite for ACTH-induced excessive grooming

The periaqueductal gray is known to be involved in the expression of a variety of behaviours such as aggression, beta-endorphin-induced immobility and peptide-induced excessive grooming. In order to establish whether the periaqueductal gray (PAG) is indispensible for peptide-induced excessive grooming, lesions were placed in the dorsal part of this structure. Subsequently, the grooming-inducing abilities of adrenocorticotropin (ACTH), beta-endorphin and bombesin were tested. The lesioned animals did not display excessive grooming after intracerebroventricular injection of ACTH. beta-Endorphin administration into the lesioned animals resulted in an extreme display of immobility. Local injection of bombesin into the PAG resulted in reduced scratching behaviour followed by immobility. It was hypothesized that excessive grooming (elicited by ACTH) may be mediated through a non-opioid primary target site-situated in the lesioned region of the PAG-while excessive scratching and immobility (elicited by bombesin or beta-endorphin, respectively) may be mediated through an opioid primary target site (situated in the remaining part of the PAG). Furthermore, the analysis of social behaviour of lesioned animals revealed that these animals reacted towards an unfamiliar partner predominantly with freezing behaviour. The increase of beta-endorphin-induced immobility and socially induced freezing (which is morphologically very similar to beta-endorphin-induced immobility) in lesioned animals supports the hypothesis that the release of opioid peptides such as beta-endorphin in the PAG plays a role in the regulation of social behaviour.

Dopaminergic modulation of ACTH-induced grooming

ACTH-(1-24)-induced grooming was studied after administration of the peptide into the substantia nigra or intracerebroventricularly (i.c.v.). The modulation of dopamine receptors in neostriatum (with haloperidol and apomorphine) and nucleus accumbens (with 3,4-dihydroxyphenylamino-2-imidazoline hydrochloride; DPI and ergometrine) was investigated. In the nucleus accumbens, the modulatory effects of ergometrine and DPI on ACTH-(1-24)-induced grooming were based on their affinity for dopamine receptors and not on their affinity for adrenoceptors. Intrastriatal application of dopaminergic agents inhibited i.c.v. ACTH-(1-24)-induced excessive grooming, whereas the grooming score was enhanced if ACTH-(1-24) was administered into the substantia nigra. The finding of differential effects of dopaminergic agents on ACTH-induced excessive grooming depending on the route of administration indicate that i.c.v. ACTH-induced excessive grooming is not mediated solely through the substantia nigra. The increase in grooming behavior seen after the intrastriatal administration of dopaminergic agents - when ACTH was injected into the substantia nigra - suggests the involvement of the striato-nigral GABAergic pathway. Local injections of ACTH-(1-24) into the periaqueductal gray also induced excessive grooming. Since a second injection of ACTH-(1-24) into the periaqueductal gray did not lead to a grooming response, irrespective of where the first injection of ACTH-(1-24) was given (i.c.v. into the nigra or via the periaqueductal gray) it is suggested that this structure seems to play a primary role in the induction of excessive grooming. Therefore the modulatory effects of the dopaminergic influence on ACTH-(1-24)-induced grooming may be exerted via the striato-nigro-collicular pathway.

Stimulation of protein kinase C reduces ACTH-induced excessive grooming

Stimulation of protein kinase C reduces ACTH-induced excessive grooming

Hippocampal Damage: Effects on Dopaminergic Systems of the Basal Ganglia

Although the research topics discussed in this chapter cover a substantial range of areas, methods, and behaviors, there is a consistent central issue: the alterations of brain and behavior subsequent to hippocampal lesions. The initial hypothesis that important secondary changes occur in the basal ganglia after hippocampal lesions has been sustained, at least in part, but other and unexpected results have been obtained that both clarify and mystify at the same time. The restoration of normal locomotion to animals with hippocampal damage by the application of a DAi agonist, DPI, to n. accumbens certainly supports our general idea, but the fact that membrane and transmitter changes in accumbens are transitory needs to be explained and perhaps related to alterations in DA receptor populations. The fact that intra-accumbens DPI can restore ACTH-induced excessive grooming at 28 days after hippocampal damage supports the idea that progressive changes are occurring in DA receptors in n. accumbens, but we need to know their nature more precisely. To do this, however, will probably require advances in our general knowledge of central DA receptors. One of the more interesting aspects of our observations is that the intra-accumbens administration of DPI restores normal behavioral patterns in several types of behaviors, especially locomotion and the excessive grooming response. These two behaviors are not closely linked in nature because large changes can occur in them independently, given appropriate conditions for testing. On the basis of available evidence both of these behaviors seem linked to activities in forebrain DA systems. This would further support the idea that the hippocampus modulates DA activities in basal ganglia systems. The results that suggest the presence of multiple sites for the central induction of grooming were also unexpected. As evidence mounts in support of this idea, it is likely that the one located in n. accumbens is more influenced by hippocampal destruction than the region(s) affected by icv neuropeptide administration. The interactions that take place in the basal ganglia can be extensive. Afferents from the entirety of the neocortical surface, the limbic system, and the projections from the brainstem DA cell groups meet in the striatum and ventral striatum. The efferents from this region not only reach motor cortical and subcortical sites but also project back onto diffusely projecting monoaminergic cells of the brainstem.(ABSTRACT TRUNCATED AT 400 WORDS)

Actions of antidepressant and neuroleptic drugs on ACTH- and novelty-induced behavior in the rat

The present study deals with the effects of psychoactive drugs (neuroleptics and antidepressants) on ACTH-induced excessive grooming in the rat. The neuroleptics haloperidol and clozapine and the antidepressants amitriptyline, nomifensine and mianserin all suppressed the grooming response in a dose-dependent manner. The neuropleptic sulpiride was ineffective even at high doses. Experimental evidence is presented suggesting that the suppression of peptide-induced grooming was not the result of competing behavioral activity elicited by the drug itself. Instead it is assumed that the psychoactive drugs tested affected directly the activity of the neural substrate underlying the peptide-induced behavior. In view of the complexity of the mechanisms of action of the drugs tested it is argued that this substrate may be a more complex one than the dopamine systems as suggested before.

ACTH-induced excessive grooming in the rat

ACTH-induced excessive grooming in the rat

Modulation of ACTH-induced grooming by [DES-TYR 1]-γ-endorphin and haloperidol

Intraventricular administration of ACTH 1–24 into the rat induced excessive grooming behavior. This response could be blocked by local administration of neuroleptics into either the nucleus accumbens or the neostriatum. Local administration of [Des-Tyr 1]-γ-endorphin (LPH 62–77) but not α-endorphin (LPH 61–76) in either the nucleus accumbens or the neostriatum mimicked the effect of the neuroleptics. A second intraventricular injection of ACTH 1–24 4 h after the first did not cause excessive grooming suggesting the development of acute tolerance. Both haloperidol and DTγE reduced the development of acute tolerance to ACTH-induced grooming. It is suggested that DTγE modulates the dopaminergic activity underlying the display of ACTH-induced excessive grooming.

ACTH-induced excessive grooming in the rat: The influence of environmental and motivational factors

Intraventricularly administered ACTHt 1–24 in rats initiated excessive grooming followed by stretching and yawning syndrome. The present study provides evidence that novelty is not an essential prerequisite for its expression and that a variety of environmental variables is not able to influence the peptide-induced behavior. Only very strong motivational variables as severe hunger/thirst and anxiety are able to modulate the ACTH-initiated excessive grooming: This response is significantly depressed in water-deprived rats bar pressing for water in a Skinner box, as well as in rats receiving unavoidable electric foot shock. The results are indicative of the strength of the ACTH-initiated motivation to groom, and it is suggested that excessive grooming is a secondary response serving to dearouse the organism after activation by ACTH.

Limbic-midbrain lesions and acth-induced excessive grooming

The induction of excessive grooming by intraventricular administration of ACTH 1–24 was studied in rats with lesions in midbrain-limbic 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 hypothalamic/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 hippocampal damage. Amygdala and hippocampal 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.

ACTH-induced excessive grooming in the rat: Latent activity of ACTH 4–10

Intraventricular injection of ACTH or peptides of the N-terminal part of ACTH in rats induces excessive grooming behavior. The present study deals with the grooming-induction potencies of short peptides sharing sequences with ACTH4–10 (H-Met — Glu — His — Phe — Arg — Trp — Gly-OH). Although ACTH4–10 itself is inactive, ACTH4–7 and [d-Phe7]ACTH4–10 are capable of inducing excessive grooming behavior. From the ineffectiveness of a variety of other oligopeptides within the ACTH4–10 sequence, it was concluded that ACTH4–7 is the shortest sequence to induce this behavioral response as was found in studies on the effect of these peptides on the maintenance of a conditioned avoidance response. The present data underscore the need of detailed information on the configuration of peptides at the CNS receptor site.

ACTH-induced excessive grooming involves brain dopamine

ACTH-induced excessive grooming involves brain dopamine