Potentiation by thiorphan and bestatin of the naloxone-insensitive analgesic effects of neurotensin and neuromedin n

Neurotensin induced significant antinociceptive activity as measured in a variety of nociceptive tests 10 and 30 min following intracerebroventricular (i.c.v.) injection in mice. The lowest effective peptide doses were 25 ng in the writhing test, 25–50 ng in the tail-flick test, 50–100 ng in the hot-plate test and 2000 ng in the tail electrical stimulation test. The neurotensin related hexapeptide neuromedin N also displayed antinociceptive properties but only in the writhing and tail-flick tests. Furthermore, as compared to neurotensin, the neuromedin effects required higher doses. ED₅₀'s for neurotensin and neuromedin in the writhing test were 70 ng and 1070 ng, respectively. Separate or combined injections of the endopeptidase 24.11 (enkephalinase) inhibitor thiorphan (l0μg) and the aminopeptidase inhibitor bestatin (50μg) did not affect tail-flick latencies. In contrast, i.c.v. injection of thiorphan together with an ineffective dose of neurotensin (25 ng) resulted in a significant antinociceptive effect. Bestatin did not modify tail-flick latencies in neurotensin-treated mice whether in the absence or presence of thiorphan. On the contrary, each of these peptidase inhibitors promoted antinociceptive effects of subthreshold doses of neuromedin (lμg) in the tail-flick test. Maximal antinociception was obtained by combining both inhibitors, thus conferring antinociceptive effects to neuromedin doses that were as low as 10 ng. Naloxone (0.5–2 mg/kg, s.c.) did not significantly reduced the antinociceptive effects of combinations of neurotensin and thiorphan and of neuromedin, thiorphan and bestatin. The data show that both neurotensin and neuromedin elicit analgesia in mice through an opiate independent mechanism. Furthermore, like enkephalin, neuromedin is readily degraded by brain endopeptidase 24.11 and bestatin sensitive aminopeptidase(s), whereas the resistance of neurotensin to aminopeptidase attack confers to this peptide a broader spectrum and longer duration of action than its congener neuromedin.     

Behavioral effects of thyrotropin releasing hormone in frontal decorticated rats

A low dose intracerebroventricular injection of thyrotropin releasing hormone (TRH, 100 ng) changed many behavioral responses in the rat. TRH increased locomotion, scratching, body shaking, piloerection, and rearing, but decreased sniffing, and resting. Ablation of frontal neocortex further enhanced the TRH effects on locomotion and resting. A dose effect of TRH (0, 5, 10, 50, 100 ng) to increase general activity was established and the effect was further enhanced by decortication. In our test situations decortication had no effect by itself. Since the TRH effects became much more pronounced without the frontal neocortex it appears that the cortex exerts a powerful inhibitory effect to moderate the TRH effects. The TRH effect does not depend upon the frontal cortex, actually a cortical function is to dampen the TRH effects on various behavioral responses.     

The ethanol-induced open-field activity in rodents treated with isethionic acid, a central metabolite of taurine.

The effect of isethionic acid, a central metabolite of taurine, on ethanol-induced locomotor activity was investigated in rodents. Ten minutes following an (i.p.) simultaneous administration of ethanol (0.0, 1.5, 2.0, 2.5, 3.0, 3.5 g/kg) and isethionic acid (0.0, 22.5, 45.0, 90.0, 180.0 mg/kg), mice were placed in the open-field chambers and locomotor activity was measured during a ten-minute testing period. A significant interaction was found between isethionic acid and ethanol. Isethionic acid pre-treated mice (45.0, 90.0 and 180.0 mg/kg) showed a higher locomotor activity than the saline group at 2.5 and 3 g/kg of ethanol. In a second study, isethionic acid (45 mg/kg) and ethanol (1 g/kg) were simultaneously injected to rats. Ten minutes after the two treatments, rats were placed in the open-field chamber for a 30-minute period. The depressant effects that ethanol produced on rat locomotion were amplified by the same dose of isethionic acid as it affected ethanol-induced locomotion in mice (45 mg/kg). However, isethionic acid did not change the spontaneous locomotion at any of the doses tested in mice or rats. Since no differences in blood ethanol levels were detected in both mice and rats, the interaction between isethionic acid's action and ethanol-related locomotion does not seem to be due to different rates of absorption of ethanol or any other pharmacokinetic process related to ethanol levels. The current study displayed that isethionic acid, administered intraperitoneally, behaves in a similar way to its immediate precursor, taurine, by amplifying ethanol-induction of the locomotor activity.     

The effect of inhibitors of endogenous opioid degradation, bacitracin, bestatin, captopril, and D-phenylalanine, on digoxin-induced arrhythmias in guinea pigs

The purpose of this study was to investigate the effect of inhibition of endogenous opioid degradation on digitalis-induced arrhythmias, utilizing the inhibitors bacitracin, bestatin, captopril, and D-phenylalanine. Guinea pigs, anesthetized with pentobarbital, 50 mg/kg i.p., and breathing spontaneously received intracerebroventricular (i.c.v.) injection of bacitracin (6.8 mg/kg), bestatin (1 mg/kg), captopril (2 mg/kg), D-phenylalanine (1.2 mg/kg) or the diluent, saline. Digitalis arrhythmias were induced by a 50 micrograms/kg i.v. bolus of digoxin followed by 500 micrograms.kg-1.h-1 i.v. Bacitracin and bestatin, but not captopril or D-phenylalanine, significantly (p less than 0.05) altered the relationship between the digoxin dose and the first occurrence of arrhythmias, i.e., digoxin-induced ventricular arrhythmias became manifest at lower digoxin doses. The mean digoxin dose and ED50s, at which arrhythmias first occurred, were significantly (p less than 0.05) reduced by bacitracin and bestatin. The findings were similar for fatal arrhythmias, although D-phenylalanine appeared to decrease the digoxin dose at the development of fatal arrhythmias. The opioid antagonist naloxone, in a 50 micrograms/kg bolus and 50 micrograms.kg-1.h-1 i.c.v., completely prevented these effects of bacitracin and reduced the effect of bestatin. The relationship to arrhythmias could not be ascribed to an effect on blood pressure, as the blood pressure response to digoxin was the same in bestatin, D-phenylalanine, and control groups. To examine whether systemic administration of an inhibitor of opioid degradation had similar effects, a second protocol was selected with systemic administration of bacitracin because it altered the dose effect relationship after i.c.v. administration and systemic concentrations could be readily attained. Bacitracin, in a 13.5 mg/kg i.v. bolus and 135 mg.kg-1.h-1 i.v., was followed by 100 micrograms/kg digoxin i.v. every 15 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modification of Morphine-induced Hyperlocomotion and Antinociception in Mice by Clorgyline,a Monoamine Oxidase-A Inhibitor

We evaluated the effects of pretreatment with clorgyline, an irreversible monoamine oxidase (MAO)-A inhibitor, on morphine-induced hyperlocomotion and antinociception. A single administration of morphine (30 mg/kg, i.p.) to male ICR mice induced a hyperlocomotion. ANOVA analysis revealed the statistical significance of the morphine effect on horizontal locomotion and of the clorgyline pretreatment × morphine interaction effect, but not of the effect of clorgyline pretreatment. The initial (5 min after challenge) phase of morphine actions vs. saline challenge appeared as if morphine had a strong inhibitory effect on locomotor activity in combination with different doses of clorgyline. The mice administered with morphine in combination of clorgyline (1 and 10 mg/kg) did not show any stereotypic behaviors. Clorgyline at a dose of 0.1 mg/kg but not other doses tested significantly potentiated morphine-induced antinociception evaluated by tail flick but not hot plate test. During the measurements of locomotor activity and antinociception, clorgyline at doses of 1 and 10 mg/kg significantly inhibited monoamine metabolism through MAO. These results suggest that clorgyline showed an inhibitory effect on morphine-induced hyperlocomotion, but not antinociception, through MAO inhibition. There is not a possibility that clorgyline pretreatment enhanced morphine action on motor activity, resulting in the abnormal behavior from hyperlocomotion to stereotypic movements.     

Effects of unilateral intracerebroventricular microinjections of cholecystokinin (CCK) on circling behavior of rats

Unilateral intracerebroventricular (ICV) injections of a high dose of CCK₇ have been reported to elicit barrel rotations accompanied by contralateral postural asymmetry; there was no spontaneous locomotor activity other than barrel rolling. The aim of the present study was to investigate the effects of lower doses of CCK-peptides on circling behavior; it was reasoned that if ambulation was present following unilateral ICV administrations of lower doses of CCK, then the contralateral postural asymmetry previously reported might be expressed as contraversive circling. In the present study, spontaneous locomotor activity was observed following ICV injections of lower doses of CCK sulfated octapeptide (CCK₈), desulfated CCK octapeptide (dCCK₈) and CCK tetrapeptide (CCK₄). As postulated, contraversive circling was induced by CCK₈ (0.5–5000 ng, ICV); the two other CCK fragments, dCCK₈ and CCK₄, were inactive in this respect. In addition, the contraversive circling bias induced by CCK₈ (5.0 ng, ICV) was attenuated by co-injections of the CCK antagonist proglumide (10 and 100 ng) and by intraperitoneal injections of the dopamine (DA) antagonist haloperidol (0.05 and 0.1 mg/kg, 45 min prior to ICV CCK₈). These data suggest that the effect is mediated by CCK receptors and through a facilitatory influence on central DA function.     

Catatonic or hypotonic immobility induced in mice by intracerebroventricular injection of mu or kappa opioid receptor agonists as well as enkephalins or inhibitors of their degradation

The intracerebroventricular injections in mice of the mu receptor agonists morphine and fentanyl induced an immobility state (the animals staying motionless with the head down on a 45° inclined plane) which was apparently hypertonic (catatonia ?) or at least enabled them to remain hanging on a horizontal wire with their forepaws. In similar conditions, injections of the kappa receptor agonists ketocyclazocine and bremazocine induced an immobility state which was hypotonic, in contrast with the preceding one. In a similar way to the mu agonists, Met-enkephalin or Leu-enkephalin injected i.c.v. in association with the inhibitor of enkephalinase thiorphan induced an apparently hypertonic immobility which was easily antagonized by naloxone. The association of thiorphan with bestatin ( an inhibitor of aminopeptidases involved in enkephalins inactivation ) produced similar results. In contrast, the hypotonic immobility induced by the kappa receptor agonists required relatively high doses of naloxone to be antagonized. The opiate antagonist MR 2266 antagonized equipotent doses of all the above mentioned agents with a similar efficacy. From these data it is suggested that enkephalins could induce an apparently tonic immobility by stimulating mu receptors and that endogenous enkephalins could be involved in a tonic mediation modulating the locomotor activity or regulating the muscular tone.     

The effect of MSH/ACTH 4-10 on delayed response performance and post-test locomotor activity in rats

Delayed response performance was measured in male, Long-Evans rats 1 hr after IP administration of various doses of MSH/ACTH 4-10 or control in a Hunter delayed reaction apparatus. Additional treatments consisting of naloxone 500 micrograms/kg (IP) and naloxone 500 micrograms/kg in conjunction with MSH/ACTH 4-10 95 micrograms/kg were also administered. Directly after delayed response performance was assessed, gross locomotor activity was determined. MSH/ACTH 4-10, at a dose of 95 micrograms/kg, significantly enhanced retention of a visual stimulus, while MSH/ACTH 4-10, at doses of 195 and 285 micrograms/kg, significantly impaired delayed response performance. Naloxone treatment resulted in significantly impaired delayed response performance when compared to control. However, naloxone plus MSH/ACTH 4-10 treatment failed to produce a significant difference from control in the delayed response performance paradigm. In post-test locomotor activity determination, an apparent dose-response existed for MSH/ACTH 4-10 with the two highest doses (190 and 285 micrograms/kg) resulting in significantly increased locomotor activity. The observed delayed response performance data support theories implicating MSH/ACTH peptides in attentional processes involving visual stimuli. The fact that large doses of MSH/ACTH 4-10 disrupt delayed response performance while increasing post-test activity suggest that an optimum level of effect caused by the MSH/ACTH peptide exists in this paradigm.     

Influence of enkephalinase inhibitors on gastric emptying in mice depends on the nature of the meal

The effects of two enkephalinase inhibitors (thiorphan and acétorphan) and DALAMIDE on gastric emptying of fat or non-fat meals were evaluated in mice. When administered intraperitonally at low doses (0.1 and 0.2 mg/kg) 30 min prior to a fatty (milk) meal, both thiorphan and acetorphan increased significantly (P less than 0.01) gastric emptying; these effects were maximal for 0.2 and 0.1 mg/kg respectively and decreased progressively to be not significant for doses higher than 5 mg/kg for thiorphan and 0.5 mg/kg for acetorphan. Similarly DALAMIDE given IP increased significantly (P less than 0.05) gastric emptying at doses of 0.5 and 1 mg/kg while a slowing of gastric emptying was obtained for 10 times higher doses. The effects of thiorphan (0.2 mg/kg) and DALAMIDE (0.5 mg/kg) were blocked by previous administration of naloxone (0.3 mg/kg) and methyl-naloxone (0.5 mg/kg) while only naloxone (0.3 mg/kg) blocked the slowing effect of high dose of DALAMIDE. Administered prior to a non-fat meal, thiorphan (1 mg/kg) stimulated gastric emptying and inhibited it at higher dosage (10 mg/kg). Neither acetorphan nor DALAMIDE at similar dosages affected the gastric emptying of a non-fat meal and the effects of thiorphan (1 and 0.1 mg/kg) were not blocked by naloxone (0.3 mg/kg). It is concluded that enkephalinase inhibitors (thiorphan and acetorphan) administered systemically stimulate the gastric emptying of a fat meal by increasing enkephalin levels in peripheral tissues, while thiorphan exhibits non-opiate effects on gastric emptying of a non-fat meal.     

Corticotropin-releasing factor has an anxiogenic action in the social interaction test

The effects of intracerebroventricular (icv) injections of corticotropin-releasing factor (CRF, 100 and 300 ng) were investigated in the social interaction test of anxiety in rats. Both doses of CRF significantly decreased active social interaction without a concomitant decrease in locomotor activity. CRF also significantly increased self-grooming, an effect that was independent of the decrease in social interaction. These results indicate an anxiogenic action for CRF. Chlordiazepoxide (CDP, 5 mg/kg ip) pretreatment reversed the anxiogenic effects of icv CRF (100 ng), but CRF did not prevent the sedative effects of CDP. There were no statistically significant changes due to CRF in locomotor activity or rears or head dipping in the holeboard test. Both doses of CRF significantly increased plasma concentrations of corticosterone. The possible mechanisms of the behavioral effects of CRF are discussed.     

Potency of L-364,718 as an antagonist of the behavioral effects of peripherally administered cholecystokinin

A new antagonist of the peripheral cholecystokinin receptor, L-364,718, was found to block the reductions in food intake and exploratory activity induced by intraperitoneal administration of cholecystokinin octapeptide sulfate. L-364,718 significantly reversed the cholecystokinin-induced reduction in feeding at doses of 10 micrograms/kg - 10 mg/kg i.p. L-364,718 significantly reversed the cholecystokinin-induced reduction in exploratory activity at doses of 500 ng/kg - 10 mg/kg i.p. The time course of antagonist activity of L-364,718 was immediate to 90 minutes after intraperitoneal administration. L-364,718 had no significant effect on food intake or exploratory activity when administered alone, over the dose range of 100 ng/kg-10 mg/kg i.p. This compound appears to be at least one hundred times more potent than proglumide or benzotript as an antagonist of the behavioral effects of peripherally administered cholecystokinin.     

Bimodal effect of neuropeptide Y on feeding, and its antagonism by receptor blocking agents in rats.

Satiated rats received intracerebroventricular (icv.) injections of several doses of neuropeptide Y (NPY) and the food intake was measured in the following 4 h. The peptide exerted a dose-dependent biphasic effect; the 100 dose significantly suppressed the food intake, but doses of 1 microgram and 5 micrograms stimulated feeding. After the injection of 2 microliters NPY-antiserum (icv., 1:50 dilution), the cumulative food intake decreased significantly in the first 24 h. From the drugs tested the alpha-1-antagonist prazosine (4 micrograms icv.) and the opiate antagonist naloxone (NX, 0.5 micrograms, icv.) selectively inhibited the feeding-stimulatory effect a high icv. dose of NPY. The alpha-2-antagonist yohimbine (4 micrograms icv.) and the non-selective beta-antagonist propranolol (5 micrograms icv.) did not influence either effect of NPY on feeding. The results suggest the involvement of alpha-1-adrenergic and opiate receptors in the food intake-stimulatory effect of a large icv. dose of NPY. The food intake-inhibitory effect of a low icv. peptide dose was not selectively antagonized by the receptor blocking agents used.     

The influence of intracysternal insulin administration on the rat temporal behaviour dynamics

Rat behaviour in the open field and elevated plus-maze was analyzed in rats after intracysternal administration of 2.5, 25, 50 and 200 ng of insulin in 45 min, 24 hrs and on the 9th day after single injection. Dose-dependent changes in 45 min occurred in both behavioural tests: insulin in low doses (2.5 and 25 ng) increased probability of locomotion and investigative activity in open field, while insulin in high doses (50 and 200 ng) did not alter locomotor activity and showed tendency to weakening of the investigative behavior (especially in the dose of 50 ng). Tendency was found in 24 hrs to increase probability of investigative behavior in open field after injection of 25 ng of insulin, although on the 9th day after insulin administration this behaviour increased in all experimental groups for all used doses. Insulin in the doses 2.5 and 200 ng decreased anxiety in elevated plus-maze in 45 min during the first five min; the doses 2.5 and 25 ng at the second five min exerted the same effect. In 24 hrs, the anxiety level increased for the doses 50 and 200 ng, and there was a tendency for an increase in the doses 2.5 and 25 ng; anxiety was decreased on the 9th day for all used doses of insulin. Thus, single insulin administration induced weakness of non-associative memory in open field on the day 2 and day 9 as well as increase of anxiety level on the day 2 and decrease of anxiety level on the day 9 in elevated plus-maze.     

Supraspinal FMRFamide antagonizes morphine-induced horizontal, but not vertical, locomotor activity

Morphine and the molluscan neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFamide) were administered to mice alone or in combination intracerebroventricularly (ICV) and the effect on locomotor activity was measured. Morphine given alone (0.5 micrograms) significantly increased horizontal locomotor activity compared to vehicle-treated controls. FMRFamide at low doses (0.01-10 micrograms) had no effect of its own, but blocked the morphine-induced increase in horizontal locomotor activity. Unlike the opiate antagonist naloxone (1.0 micrograms), FMRFamide (up to 10 micrograms) had no effect on morphine-induced decrease in vertical activity. These data further support a role for FMRFamide as a modulator of opiate action, but comparison to naloxone suggests that FMRFamide might not act as a pure competitive antagonist of this opiate effect.     

Modulation of locomotor activity by substance P in rats

The effects of intraperitoneally or intracerebrally (DA A-10 area) administered substance P (SP) on locomotor activity of rats were studied in an exact 12-h light/12-h dark cycle changing from dark to light at 6 a.m. SP was administered either at 11 a.m. (light phase, minimal locomotor activity) or at 7 p.m. (dark phase, maximal locomotor activity). The effects of 12.5 micrograms/kg SP intracerebral and 125 micrograms/kg SP intraperitoneal were very similar. In the light phase SP produces excitation but inhibition of locomotion in darkness. Hence, the effect of SP depends on the internal mechanisms controlling motor activity and tends to level off the spontaneous circadian oscillation. We found a long lasting SP effect during both the light and dark period. The present experiments led us to the conclusion that SP has a levelling effect on locomotor activity. Probably this effect might be explained as SP's action on the dopaminergic pathway or dopamine metabolism, because the dopamine content in neurons also has a circadian rhythm.     

Preventive effect of cholecystokinin octapeptide on experimental amnesia in rats

The effect of intracerebroventricular (ICV) administration of cholecystokinin octapeptide (CCK-8) on electroconvulsive shock (ECS)-induced amnesia in passive avoidance response was studied in rats. In normal rats, CCK-8 in doses from 1 ng to 1 microgram had no effect on the response when injected before the training trials, immediately after foot shock or before the first retention test. However, proglumide, a CCK-8 receptor blocker, induced marked amnesia when injected in doses from 0.1 to 10 micrograms before the training trials and in doses of 1 and 10 micrograms before the first retention test, though not subsequent to foot shock. ECS given immediately after the foot shock caused amnesia in the 24 hr and 48 hr retention tests, which could have been prevented by CCK-8 injected in doses of 10 ng to 1 microgram prior to the training trials, of 10 ng to 1 microgram following ECS and of 0.1 and 1 microgram before the first retention test. In addition, the effects of CCK-8 and proglumide became pronounced following chronic ICV infusion, using an osmotic minipump, for 7 days at a dose of 1 ng/day and 10 ng/day, respectively. The amnesia induced by proglumide was not affected by arginine vasopressin (AVP), while AVP in doses of 10 ng and 100 ng given 30 min before the training trials prevented ECS-induced amnesia. The antiamnesic effect of AVP was abolished by simultaneous administration of proglumide. On the other hand, AVP-antiserum produced marked amnesia which could be antagonized by CCK-8. However, the antiamnesic effect of CCK-8 was not suppressed by AVP-antiserum.(ABSTRACT TRUNCATED AT 250 WORDS)     

Central injections of arginine vasopressin prolong extinction of active avoidance

Behavioral and physiological effects of arginine vasopressin (AVP) were examined following intracerebroventricular (ICV) injection in the rat. ICV injections prolonged extinction of active avoidance at doses of 1.0 and 10.0 ng/rat and this effect was blocked by peripheral injection of the vasopressor antagonist of vasopressin [dPtyr(Me)AVP] at a dose of 30 micrograms/kg (SC). However, 1.0 ng of AVP ICV failed to alter systemic blood pressure and also failed to produce taste aversions in a one or two bottle test. Results suggest that central AVP has a central action independent of systemic changes in blood pressure, but that the receptor mediating this action is functionally similar to the AVP V1 (vasopressor) receptor.     

Centrally and peripherally administered bombesin decreases food intake in turkeys

The effects of intracerebroventricular (ICV) and intravenous injections of bombesin (BBS) on food intake were investigated in turkeys. Adult turkey hens were injected ICV with 50 to 1000 ng of BBS. In addition, the effect of pretreatment with the BBS antagonist [d-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P was investigated. To determine if BBS also had a peripheral site of action, 0.5 to 8 micrograms/kg body weight of BBS was injected IV into turkey poults. The ICV and IV injections of BBS decreased food and water intake in a dose-dependent manner. The most efficacious doses when injected ICV for decreasing food and water intake were 1000 and 500 ng, respectively, whereas 8 micrograms/kg was most efficacious in decreasing food intake when administered IV. The satiating effect of ICV-injected BBS could be attenuated with pretreatment with the BBS antagonist. The results of these studies suggest that BBS acts to decrease food and water intake in both the periphery and the central nervous systems of turkeys.     

Fluoxetine potentiates the effects of corticotropin-releasing factor on locomotor activity and serotonergic systems in the roughskin newt, Taricha granulosa

The anxiety- and stress-related neuropeptide corticotropin-releasing factor (CRF) elicits behavioral changes in vertebrates including increases in behavioral arousal and locomotor activity. Intracerebroventricular injections of CRF in an amphibian, the roughskin newt (Taricha granulosa), induces rapid increases in locomotor activity in both intact and hypophysectomized animals. We hypothesized that this CRF-induced increase in locomotor activity involves a central effect of CRF on serotonergic neurons, based on known stimulatory actions of serotonin (5-hydroxytryptamine, 5-HT) on spinal motor neurons and the central pattern generator for locomotor activity in vertebrates. In Experiment 1, we found that neither intracerebroventricular injections of low doses of CRF (25 ng) nor the selective serotonin reuptake inhibitor fluoxetine (10, 100 ng), by themselves, altered locomotor activity. In contrast, newts treated concurrently with CRF and fluoxetine responded with marked increases in locomotor activity. In Experiment 2, we found that increases in locomotor activity following co-administration of CRF (25 ng) and fluoxetine (100 ng) were associated with decreased 5-HT concentrations in a number of forebrain structures involved in regulation of emotional behavior and emotional states, including the ventral striatum, amygdala pars lateralis, and dorsal hypothalamus, measured 37 min after treatment. These results are consistent with the hypothesis that CRF stimulates locomotor activity through activation of serotonergic systems.     

Effects of urocortin 2 and 3 on motor activity and food intake in rats

Urocortin 2 (Ucn 2) and Ucn 3 are new members of the corticotropin-releasing factor (CRF) family and bind selectively to the CRF type 2 receptor (CRF2). The effects of these peptides on behavioral changes induced by CRF were examined in rats. In a familiar environment, intracerebroventricular injection of Ucn 2 attenuated the stimulatory effect of CRF on motor activity, although it alone produced no effect. Ucn 3 suppressed motor activity and attenuated the stimulatory effect of CRF. In an open field, CRF decreased locomotion and rearing but increased grooming behavior. Ucn 2 attenuated the inhibition of locomotor activity induced by CRF without affecting other activities, such as rearing or grooming behavior. Ucn 3 had no effect on the behavioral changes induced by CRF, although it alone decreased locomotion and rearing in a manner similar to CRF. Ucn 2 was thus found to have an antagonistic effect on bi-directional motor activation induced by CRF, while Ucn 3 had a suppressive effect on motor activity. Both Ucn 2 and Ucn 3 suppressed food intake in freely-fed rats, but not immediately after injection. These results suggest that the CRF2 receptor is involved in motor suppressive effects as well as anxiolytic and anorectic effects of Ucn 2 and Ucn 3.