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Urocortin I (UCN I) is a structural analogue of corticotropin-releasing factor (CRF), which, together with arginine-vasopressin (AVP), are the principle adrenocorticotropic hormone (ACTH) secretagogues in mammals. The aim of the present study was to investigate the effects of UCN I on the hypothalamic CRF and AVP concentration and its impact on the hypothalamic-pituitary-adrenal (HPA) axis. First, male Wistar rats were injected intracerebroventricularly (ICV) with 0.5, 1, 2 and 5 μg of UCN I. After 30 min hypothalamic CRF and AVP concentrations were determined by immunoassays. In parallel, the trunk blood was collected and plasma ACTH and corticosterone concentration was determined by ELISA and chemofluorescent assay, respectively. Second, rats were pretreated ICV with selective antagonists of receptors being implicated in the regulation of the HPA axis (0.1 μg antalarmin for CRFR1, 1 μg astressin 2B for CRFR2 or 0.1 μg deamino-Pen1,Tyr2,Arg8-vasopressin for AVPR3) and treated ICV with the most effective dose of UCN I (5 μg). After 30 min plasma corticosterone concentration was determined by chemofluorescent assay. UCN I induced dose-dependent augmentation of the hypothalamic CRF and AVP concentration, associated with dose-dependent elevation of the plasma ACTH and corticosterone concentration. The most significant effect of UCN I on the plasma corticosterone concentration was inhibited by antalarmin, but was not influenced by astressin 2B or deamino-Pen1,Tyr2,Arg8-vasopressin. The present study demonstrates that UCN I modulates the concentration of the hypothalamic ACTH secretagogues in parallel with the concentration of the plasma ACTH and corticosterone. Our results suggest that UCN I may activate the HPA axis by stimulation of the hypothalamic CRF production, and this process is mediated by CRFR1, and not by CRFR2. UCN I may stimulate the AVP production, as well, but, based on the results with AVPR3 antagonist, this effect is not involved in the regulation of the HPA axis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Urocortin II (Ucn II) and Urocortin III (Ucn III) are selective agonists of the CRF receptor type 2 (CRFR2). The aim of the present experiments was to investigate the effects of Ucn II and Ucn III on the central CRF and peripheral glucocorticoids in rats. Increasing doses (0.5-1-2-5 μg/2 μl) of Ucn II or Ucn III were administered intracerebroventricularly, then CRF concentration was determined by immunoassays in two different brain regions, the amygdala and the hypothalamus, and in two different time paradigms, 5 and 30 min after the administration of peptides. In parallel with the second determination, plasma corticosterone concentration was measured by chemofluorescent assay. The amygdalar CRF amount was increased significantly by 0.5 and 5 μg of UCN II and 2 and 5 μg of UCN III in the 5 min experiments and by 5 μg of UCN II and 0.5 and 5 μg of UCN III in the 30 min experiments. The hypothalamic CRF content was not affected considerably in the 5 min paradigm, but it was influenced significantly in the 30 min paradigm, with 0.5 and 1 μg of UCN II and 0.5-2 μg of UCN III decreasing, and 2 and 5 μg of UCN II and 5 μg of UCN III increasing the hormone concentration, respectively. The plasma corticosterone concentration was decreased by 1 and 2 μg of UCN II and UCN III and increased by 0.5 and 5 μg of UCN III. The present results demonstrate that central administration of Ucn II and Ucn III modulate time-dependently and dose-dependently the amygdalar and the hypothalamic CRF concentration, and, directly or indirectly, the plasma corticosterone concentration. The present experiments suggest that the role of CRFR2 in the regulation of the HPA axis can be inhibitory or stimulatory, depending on the actual concentration of their agonists., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The decapeptide Cetrorelix, an LHRH antagonist, inhibits gonadotropin and sex steroid secretion. Cetrorelix is used for IVF-ET procedures and for the treatment of patients with prostate carcinoma, benign prostatic hyperplasia, endometriosis, leiomyomas and, ovarian cancer. However little is known about the effects of Cetrorelix on the brain function. In the present work the influence of Cetrorelix on different aspects of the brain function was studied following its administration into the lateral brain ventricle in mice. The effects tested included the impairment of the consolidation of a passive avoidance reflex caused by beta-amyloid 25-35, anxiolytic action in the plus-maze, antidepressive action in a forced swimming test and a tail suspension test and open-field behavior. In the passive avoidance test, beta-amyloid 25-35 administered immediately after the learning trial impaired the consolidation of passive avoidance learning. Cetrorelix fully blocked the impairment of the consolidation of passive avoidance learning when given icv 30 min following beta-amyloid 25-35 administration. If beta-amyloid 25-35 and Cetrorelix icv were given simultaneously, the Cetrorelix attenuated, but did not block the action of the beta-amyloid 25-35. Cetrorelix elicited anxiolytic action in the plus-maze, depending on the dose used. In the forced swimming and tail suspension tests, Cetrorelix demonstrated antidepressive-like action. Concerning open-field behavior, Cetrorelix displayed no action on locomotion, rearing or grooming. The results demonstrate that Cetrorelix affects brain function: and is able to correct the impairment of the memory consolidation caused by beta-amyloid 25-35. Cetrorelix also elicits anxiolytic and antidepressive action, but it does not influence the open-field activity. Further experimental work with Cetrorelix is necessary, but the results imply the possible merit of a clinical trial with Cetrorelix in patients with anxiety, depression and Alzheimer's disease.

Effect of different doses of centrally administered brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were examined in rats with respect to anxiolytic properties in an elevated plus-maze model. BNP in doses of 100, 200 and 400 ng, and CNP in doses of 100 and 200 ng abolished the normal preference for the closed arms of the maze, and increased the percentage time spent in the open arms; this is consistent with an 'anxiolytic-like' effect. Doses of 50 and 1000 ng BNP, and of 25, 50, 400 and 1000 ng CNP produced no behavioural effects in the elevated plus-maze model. Pretreatment with an alpha-adrenoreceptor antagonist or a muscarinergic cholinergic blocker, antagonized the effect of 200 ng BNP in the elevated plus-maze test. The 'anxiolytic-like' effects of a BNP were not modulated by a dopaminergic blocker, an alpha-adrenoreceptor antagonist, a GABA receptor antagonist, a 5-HT receptor antagonist or an opiate antagonist. The 'anxiolytic-like' effect of CNP was prevented by a dopamine receptor antagonist, or an alpha- or beta-adrenoreceptor blocker but not by a muscarinergic cholinergic blocker, a GABA receptor, a 5-HT receptor antagonist or an opiate receptor antagonist. These results suggest that multiple neurotransmitter system activation might be responsible for the BNP and CNP-induced 'anxiolytic-like' activity.

beta-/Tyr9/melanotropin-/9-18/ significantly increased apomorphine-induced cage-climbing, while only a tendency towards an increase was observed after supersensitization with haloperidol. Amphetamine also enhanced apomorphine-induced climbing behavior. The peptide showed only a tendency to increase dopamine release from striatal slices, while amphetamine elevated this significantly. The results suggest that the striatal dopamine system is involved in the behavioral action of beta-/Tyr9/melanotropin-/9-18/.

The effects of cholecystokinin octapeptide sulfate ester (CCK-8-SE), its N-terminal tripeptide (CCK-2-4-SE) and its C-terminal tetrapeptide (CCK-5-8) were investigated on hypothalamic self-stimulation in rats. CCK-8-SE and CCK-5-8 in 400 pmole doses inhibited self-stimulation behaviour, while CCK-2-4-SE was ineffective. In 80 pmole doses the peptides showed no effect. It is suggested that CCK-5-8 itself influences self-stimulation behaviour.

In the present study the role of beta-receptors in the behavioral action of somatostatin was investigated. Somatostatin inhibited extinction of the active avoidance behavior. Propranolol alone had no action on this behavior but significantly inhibited the peptide-induced effect. In the open-field test somatostatin induced locomotor activation; propranolol did not influence this effect of the peptide. Somatostatin inhibited electroconvulsive shock-induced amnesia. Propranolol alone had no action in this test, but significantly decreased the antiamnesic effect of the peptide. These results suggest that the central beta-receptors play an important role in the behavioral action of somatostatin.

Several doses of the C-terminal tetrapeptide fragment of cholecystokinin octapeptide (CCK-5-8) were injected intraperitoneally (ip.) and intracerebroventricularly (icv.), and their effects on the feeding of 24-hr food-deprived rats in familiar and novel environments were studied. In the familiar environment, CCK-5-8 ip. or icv. had no effect on the food intake of the rats. In the novel environment (i.e. in an open field), CCK-5-8 showed merely slight effects on the main open-field parameters: only ip. administered CCK-5-8 enhanced the incidence of grooming. Of the feeding parameters tested in the open field, mainly the food intake/approach to food ratio was depressed by CCK-5-8 ip. or icv. The 24 mumole/kg ip. dose of CCK-5-8 decreased the food intake, while the 8 pmole icv. dose increased the number of approaches to food. After the treatments found to be the most effective, the latency to first bite was also enhanced. The results suggest that CCK-5-8 can amplify the arousal enhancement elicited by novelty through a central mechanism.

The effects of several doses of intracerebroventricularly injected cholecystokinin octapeptide sulfate ester (CCK-8-SE) and nonsulfated scholecystokinin octapeptide (CCK-8-NS) were studied on electroconvulsive shock (ECS)-induced retrograde amnesia, as measured in a one-trial step-through passive avoidance paradigm. Both CCK-8-SE and CCK-8-NS were able to attenuate amnesia slightly when they were injected into rats 10 min prior to ECS treatment, possibly by reducing the severity of the ECS-induced seizures. Of the treatments carried out immediately after ECS, only the 0.8 pmole dose of CCK-8-NS could significantly restore retrograde amnesia. After treatment 20 min prior to testing 24-hr retention, no effect of the peptides was observed. The lack of a dose-dependency and of any effect on retrieval raises the possibility that the CCK octapeptides influence memory processes by an indirect mechanism.

The catalepsy induced by subcutaneously (sc.) and intracerebroventricularly (icv.) administered cholecystokinin octapeptide sulfate ester (CCK-8-SE) and desulfated cholecystokinin octapeptide (CCK-8-NS), and the effects of CCK-8-SE and CCK-8-NS on haloperidol-induced catalepsy, were investigated in mice. The results demonstrate the bimodal effect of CCK octapeptides in a catalepsy test. With sc. administration CCK-8-SE in the doses of 0.4 or 0.8 mumole/kg, but not CCK-8-NS at any dose, induced catalepsy. Furthermore, the catalepsy induced by CCK-8-SE was of short duration. With icv. administration only 40 pmole CCK-8-NS induced significant catalepsy. When 0.2, 0.4 and 0.8 mumole/kg sc. doses of CCK-8-NS or 0.4 pmole icv. dose of CCK-8-SE or CCK-8-NS was given in combination with intraperitoneal (ip.) administration of 1.0 mg/kg haloperidol, the total duration of catalepsy was suppressed. Finally, CCK-8-SE sc. when given in combination with haloperidol ip., exerted a biphasic, synergistic-antagonistic effect on the haloperidol-induced catalepsy.

The presence of FMRFamide (Phe-Met-Arg-Phe-amide)-like immunoreactivity in neuronal elements in the hypothalamus suggested a role for this in the hypothalamic control of the anterior pituitary function. We report here the action of FMRFamide on growth hormone release following intracerebroventricular administration to rats. The injection of 200 ng (313.8 picomoles) of FMRFamide (in 2 ul) produced a significantly increased plasma GH 15 min after injection. The GH-increasing effect of 400-800 ng (627-1255 picomoles) of FMRFamide was already developed after 5 min and lasted up to 30 min. No change was detected in the plasma FSH, LH and prolactin levels at any time during the experimental period. The intravenous administration of 10, 30 or 100 ug of FMRFamide had no effect on the plasma GH level. We conclude that FMRFamide can act at low doses to increase GH release through the inhibition of somatostatin release or the stimulation of GRF. We could not exclude a direct site of action in the pituitaries.

The effects of graded doses of cholecystokinin octapeptide sulphate (CCK-8-S) and non-sulphated CCK-8 (CCK-8-NS) on the development of tolerance to the hypothermic effect of ethanol were investigated in mice. The animals were pretreated with daily doses of CCK-8-S, CCK-8-NS (0.003-30 nmol/animal s.c.) or vehicle, followed two hours later by the i.p. administration of ethanol (4 g/kg). The same treatments were repeated on three consecutive days. The hypothermic response to ethanol administration gradually diminished, this phenomenon being accepted as indicating the development of tolerance to ethanol. Both CCK-8-S and CCK-8-NS inhibited the development of tolerance. While CCK-8-S resulted in a linear dose-response effect (0.3-30 nmol/animal), CCK-8-NS gave rise to a bell-shaped curve with effective blocking doses of 0.3-3 nmol/animal. There was no difference in colonic temperature between peptide and vehicle-treated, ethanol-naive animals, indicating that the peptide did not change the initial sensitivity to ethanol.

The effects of intracerebroventricular administration of synthetic ovine corticotropin-releasing factor (CRF 1-41) have been investigated on the retention of passive avoidance behaviour, and on the dopamine, norepinephrine and serotonin contents of the hypothalamus, mesencephalon, amygdala, septum and striatum, as well as on the plasma corticosterone levels of hypophysectomized and sham-operated rats. Treatment with CRF 1-41 20 min before the first retention test, 24 hours after the learning trial, significantly facilitated the passive avoidance behaviour of hypophysectomized animals in a dose-dependent manner. No effect was found in sham-operated rats. No significant effects of a wide dose range of intracerebroventricularly injected CRF on the monoamine contents of limbic brain structures were detected. However, the same doses of CRF 1-41 increased the plasma corticosterone level in sham-operated rats. The data suggest that the release of CRF from neurons in the limbic system does not alter the monoamine contents in this system, although this peptide facilitates the retention of the passive avoidance behaviour of hypophysectomized rats.

The effects of graded amounts of centrally injected [intracerebroventricular, i.c.v.] oxytocin [OXT] have been studied on the steady-state level and pargyline-induced accumulation of serotonin [5-HT] in the hypothalamus, mesencephalon and dorsal hippocampus of rats. OXT only weakly affected the steady-state level of 5-HT. The pargyline-induced accumulation, on the other hand, was inhibited by central OXT treatment. Whereas OXT inhibited 5-HT accumulation in a dose-dependent manner in the hypothalamus, only the lowest amount of OXT was effective in the mesencephalon and the dorsal hippocampus. The data raise the possibility that an altered 5-HT metabolism is likely to have functional significance in the endocrine and behavioral effects of OXT.

The effects of FMRFamide on passive avoidance behaviour and electroshock-induced amnesia following intracerebroventricular administration were studied in rats. FMRFamide given immediately after the learning trial, or 20 min before the retention trial, attenuated the avoidance response, thereby impairing the consolidation and retrieval processes. Electroshock induced amnesia when applied immediately after the learning trial. Treatment with FMRFamide facilitated the amnesia of the passive avoidance response. The results indicate that FMRFamide peptide belongs in the class of neuropeptide which are amnesic.