Effects of cholecystokinin octapeptide sulphate ester and unsulphated cholecystokinin octapeptide on active avoidance behaviour in rats

The effects of peripherally administered cholecystokinin octapeptide sulphate ester and its unsulphated form on the active avoidance behaviour of rats were studied. The acquisition of avoidance behaviour was impaired, while extinction was facilitated, following cholecystokinin octapeptide sulphate ester or unsulphated cholecystokinin octapeptide treatment. These peptides had no action on open-field activity. It is concluded that peripherally administered cholecystokinin octapeptide influences acquisition and extinction of active avoidance behaviour and this effect is unrelated to general motor activity of the animals.     

Effects of intraventricular administration of cholecystokinin octapeptide sulfate ester and unsulfated cholecystokinin octapeptide on active avoidance and conditioned feeding behaviour of rats

The effects of cholecystokinin octapeptide sulfate ester (CCK-8-SE) and unsulfated cholecystokinin (CCK-8-NS) were studied following intraventricular administration on active avoidance and conditioned feeding behaviour of rats. In the CCK-8-NS and CCK-8-SE treated animals the acquisition of active avoidance and conditioned feeding behaviour were considerably impaired compared to the control; furthermore, these peptides caused a facilitated extinction of active avoidance and conditioned feeding behaviour. The data suggest that cholecystokinin octapeptide is capable of modifying the fear and hunger motivated behaviours of rats.     

The effect of linear somatostatin on the active avoidance behaviour and open-field activity on haloperidol, phenoxybenzamine and atropine pretreated rats

Somatostatin administered intracerebroventricularly inhibited the extinction of active avoidance behaviour. The dopamine receptor blocking agent haloperidol, the alpha 1-receptor blocker phenoxybenzamine and the muscarinic anticholinergic agent atropine inhibited the behavioural effect of the peptide. Furthermore, somatostatin increased the locomotor activity of the animals. Neither of these drugs influenced the effect of the peptide exerted on locomotor activity. The peptide was ineffective on other parameters of the open-field test while phenoxybenzamine decreased the defecation rate of the animals and this effect was not influenced by somatostatin. The results suggest that the catecholaminergic and the cholinergic system play an important role in the inhibition of extinction produced by somatostatin but these mechanisms to not have a role in the locomotor activity induced by the peptide.     

The effects of dogfish MSH''s and of corticotrophin-like intermediate lobe peptides (CLIP''s) on avoidance behavior in rats

Recently purified melanocyte-stimulating hormones (MSH's) from dogfish pituitary tissue were tested on extinction of a conditioned avoidance response (CAR). Corticotrophin like intermediate lobe peptides (CLIP's) from dogfish and porcine origin were tested for an effect on avoidance extinction as well. All peptides appeared to delay extinction of the CAR.The results suggest that the pituitary contains various peptides which influence adaptive behavior. The observation that MSH is more potent in delaying extinction of the CAR then CLIP leads to the conclusion that the behavioral active sequence of the ACTH molecules is located in the N terminal part rather than in the C terminal part of the polypetide.     

The effects of different receptor blockers on the H-Phe-Ile-Tyr-His-Ser-Tyr-Lys-OH induced inhibition of extinction of active avoidance behaviour

H-Phe-Ile-Tyr-His-Ser-Tyr-Lys-OH after intracerebroventricular (icv.) administration inhibited the extinction of active avoidance behaviour for a short period. The dopamine receptor blocker haloperidol completely blocked this effect of the heptapeptide, while the muscarinic anticholinergic agent atropine only partly inhibited it. The alpha 1-receptor blocker phenoxybenzamine and the beta-receptor blocker propranolol did not significantly influence the extinction inhibition induced by the peptide. These results suggest that the dopaminergic and, in part the cholinergic system, play important roles in this behavioural action of H-Phe-Ile-Tyr-Ser-Tyr-Lys-OH.     

Effects of pituitary adenylate cyclase polypeptide (PACAP) on extinction of active avoidance learning in rats: involvement of neurotransmitters

The effects of PACAP-38 on the extinction of active avoidance learning were studied in rats. The action of transmitter mediation was followed by pretreating the animals with appropriate receptor antagonists. PACAP-38 administered into the lateral brain ventricle caused a transitory facilitation of the extinction of a learned active avoidance response at 3 and 6 h following extinction, which had returned to or even above the control level at the 24-h testing. PACAP 6-38, which is an antagonist of PACAP-38, and an antibody against PACAP-38, prevented this action. When the animals were retested during a further 10 days, the control animals demonstrated response extinction on day 7, while the PACAP-38-treated animals still showed a high proportion (70%) of positive responses. The following receptor blockers diminished the action of PACAP-38 on the facilitation of extinction: propranolol, haloperidol, naloxone, bicuculline and nitro-L-arginine, the latter by blocking nitric oxide formation. Phenoxybenzamine and atropine were ineffective. The data reveal that the transitory action of PACAP-38 within 24 h on the facilitation of extinction is mediated by beta-adrenergic, dopaminergic, GABA-ergic and opiate receptors and nitric oxide. This transitory facilitated extinction is caused partly by depressed locomotion and presumably also an increased body temperature. Following a transitory facilitation of extinction from 24 h on, PACAP-38 demonstrated a greatly delayed extinction, which lasted for more than 7 days, while the control animals displayed complete extinction. The data suggest that PACAP-38 facilitates memory retrieval processes in the extinction of the active avoidance reflex.     

Effect of sexual steroids and androgen sterilization on avoidance and exploratory behaviour in the rat

The effect on avoidance and exploratory behavior of large doses of sexual steroids or of changes in ovarian steroid secretion induced by gonadotropin treatment or androgen sterilization was studied in female R-Amsterdam rats. Estrogen, progesterone, testosterone, androgen sterilization, and human chorionic gonadotropin (HCG) effects were tested and evaluated. Estrogen in castrated female rats delayed extinction of the conditioned avoidance response from Day 8 of extinction and increased intertrial activity during extinction. Estrogen treatment applied from extinction was ineffective. Progesterone treatment of castrated female rats applied from the first days of conditioning delayed extinction from Day 12. If the treatment was begun at extinction, this was delayed after Day 8. Intertrial activity was also higher between Day 8 and Day 15 of extinction. Testosterone treatment of castrated male rats increased intertrial activity during acquisition. In the animals treated from extinction, a delay was observed from Day 9, and intertrial activity was increased simultaneously. In androgen-sterilized female rats, extinction was facilitated. HCG treatment of intact female rats delayed the extinction. The steroids used failed to affect the exploratory activity of castrated rats, indicating that, under the conditions tested, general activity and exploratory activity are not motivated by the same mechanism.     

The effects of cholecystokinin-octapeptide and pentagastrin on electrical and motor activities of canine colonic circular muscle

The effects of cholecystokinin-octapeptide (CCK-OP) and pentagastrin on electrical and motor activities of circular muscle of the canine colon were studied with the sucrose gap technique. Additional organ bath experiments were performed to further characterize the motor response to the peptides and to elucidate their site of action. The electrical activity consisted of slow waves having an initial potential followed by a plateau potential, at a regular frequency of 4.5 cycles/min. Both peptides prolonged the duration and increased the amplitude of the plateau phase of the slow waves. Concomitantly, the slow wave frequency was reduced. In addition, CCK-OP increased spiking activity. Both spiking activity and the prolonged plateau potential generated contractile activity, prolonged phasic contraction occurring with slow waves with a prolonged plateau. In organ bath experiments, both CCK-OP and pentagastrin increased the basal tone of the muscle strips and prolonged the duration of the phasic contractions. The prolongation of the duration of the contractions was not antagonized by tetrodotoxin (TTX) and atropine. CCK-OP but not pentagastrin increased the force of contractions, this action was not affected by atropine but was reduced in the presence of TTX, suggesting that the increase in force may be partially mediated by noncholinergic excitatory nerves. The increase in basal tension by the peptides was enhanced in the presence of TTX indicating that myenteric inhibitory neurones were tonically active under our experimental conditions. The results provide the electrophysiological basis for CCK-OP and pentagastrin induced changes in colonic motility.     

Endorphins and extinction: differential actions on appetitive and adversive tasks.

Alpha and gamma endorphin both inhibited the extinction of a runway task for water reward in water-deprived rats after subcutaneous injections of microgram dosages. At similar doses, these same peptides produced opposing actions on the extinction of a pole-jumping avoidance task: alpha endorphin inhibited and gamma endorphin facilitated extinction. The effects of these peptides on motivated behavior may thus be situation-dependent.     

Effect of hormones of the neurohypophysis on different types of behavioral responses in the rat

In experiments on male rats arginyl-vasopressin (AVP), lysyl-vasopressin (LVP) and vasotocin (VT) in doses of 0.005-0.010 mg/kg decreased motor activity and emotional behaviour in the open field test. In a dose of 0.001 mg/kg AVP significantly accelerated the elaboration of active avoidance; oxytocin delayed it, but LVP and VT had no significant influence. AVP also somewhat attenuated the elaboration of passive avoidance. None of the four studied peptides significantly affected the rate of elaboration of conditioned food-rewarded reaction to place.     

Dissociation of exteroceptive and idiothetic orientation cues: effect on hippocampal place cells and place navigation.

Navigation by means of cognitive maps appears to require the hippocampus; hippocampal place cells (PCs) appear to store spatial memories because their discharge is confined to cell-specific places called firing fields (FFs). Experiments with rats manipulated idiothetic and landmark-related information to understand the relationship between PC activity and spatial cognition. Rotating a circular arena in the light caused a discrepancy between these cues. This discrepancy caused most FFs to disappear in both the arena and room reference frames. However, FFs persisted in the rotating arena frame when the discrepancy was reduced by darkness or by a card in the arena. The discrepancy was increased by ''field clamping'' the rat in a room-defined FF location by rotations that countered its locomotion. Most FFs dissipated and reappeared an hour or more after the clamp. Place-avoidance experiments showed that navigation uses independent idiothetic and exteroceptive memories. Rats learned to avoid the unmarked footshock region within a circular arena. When acquired on the stable arena in the light, the location of the punishment was learned by using both room and idiothetic cues; extinction in the dark transferred to the following session in the light. If, however, extinction occurred during rotation, only the arena-frame avoidance was extinguished in darkness; the room-defined location was avoided when the lights were turned back on. Idiothetic memory of room-defined avoidance was not formed during rotation in light; regardless of rotation, there was no avoidance when the lights were turned off, but room-frame avoidance reappeared when the lights were turned back on. The place-preference task rewarded visits to an allocentric target location with a randomly dispersed pellet. The resulting behaviour alternated between random pellet searching and target-directed navigation, making it possible to examine PC correlates of these two classes of spatial behaviour. The independence of idiothetic and exteroceptive spatial memories and the disruption of PC firing during rotation suggest that PCs may not be necessary for spatial cognition; this idea can be tested by recordings during the place-avoidance and preference tasks.     

The action of tropic adenohypophyseal hormones when administered intraventricularly on rat behavioral reactions

In experiments on rats the influence was studied of tropic hormones of adenohypophysis--somatotropin, thyrotropin and adrenocorticotropin (STH, ThTN and ACTH respectively) on the elaboration and extinction of conditioned reaction of active avoidance (CRAA) in Y-maze and behaviour in the open field under microinjections of hormones into the brain lateral ventricle (0.001-0.002 ME). It has been shown that all studied hormones improve animals learning at negative pain reinforcement; ThTH and ACTH retard it in contrast to STH, which accelerates the extinction of the elaborated CRAA; tropic hormones exert differentiated influence on rats behaviour in the open field. No distinct correlation was found between behavioural manifestation and the level of catecholamines in the rats hypothalamus.     

The anti-conflict effect of cyproheptadine is not mediated by its 5-hydroxytryptamine antagonistic property

Cyproheptadine, a 5HT2 receptor antagonist with prominent antimuscarinic and anti-histaminic properties, was shown to have an anti-conflict effect in rats using a modified Geller-Seifter test and also enhanced extinction of conflict behaviour. The selective 5HT2 receptor antagonist ritanserin, however, had neither an anti-conflict effect nor an effect on extinction of conflict behaviour. The muscarinic receptor antagonist scopolamine, on the other hand, was active in both paradigms. The effect of cyproheptadine on extinction of conflict behaviour was decreased by co-administration of physostigmine, an acetylcholinesterase inhibitor, but not affected by the concomitant administration of the muscarine receptor agonist oxotremorine. The results suggest that the anti-conflict effect of cyproheptadine has to be ascribed to its anti-muscarinic activity and is not due to its 5HT2 antagonism.     

Avoidance reactions to painful stimulation of another individual following destruction of the rat amygdala]

Experiments in male albino rats have shown that bilateral lesion of the amygdala does not prevent avoidance conditioning to pain stimulation of another rat, improvement of the reaction after a painful action of the experimental animal and its extinction after the discontinuation of pain stimulation of the partner. Amygdalectomy performed after elaboration of a conditioned avoidance reaction, improves or worsens it, depending on which of the two rivaling motivations (sensitivity to signals of the other animal or fear of an open field) relatively predominanted in the given animal before the operation. The facts obtained suggest that the amygdala may be classified as belonging to the system of brain structures, where the "interrupting function" of emotions is achieved directing the behaviour to meet the predominant need.     

Effects of part sequences of human growth hormone on in vivo hepatic glycogen metabolism in the rat.

Acute effects of two part sequences of human growth hormone on the in vivo activity levels of hepatic glycogen synthase and glycogen phosphorylase were examined. The peptide corresponding to residues 6 to 13 of the hormone (hGH 6--13) decreased the percentage of phosphorylase in the active form without affecting synthase activity. This action was indirect and dependent upon insulin. The peptide hGH 177--191 decreased the level of the active form of synthase without affecting phosphorylase activity. This effect was also observed with analogous peptides containing the sequence hGH 178--191 (i.e., hGH 172--191 and hGH 178--191), whereas the peptide hGH 179--191 was inert. The onset of these effects was rapid, and maximum changes in activity were produced in 5 min by both peptides. The effect for hGH 177--191 was short-lived, and synthase activity had returned to normal levels by 15 min, whereas the action of hGH 6--13 was of longer duration and was still quite marked at 60 min. Both peptides showed a linear dependence of response to the log dose of peptide injected over the range 0.1--250 microgram hGH 6--13 per kg body weight and 0.05--25 microgram hGH 177--191 per kg body weight. Hepatic 3',5'-cyclicadenylic acid levels were not affected by either peptide. Incorporation of glycerol carbon into liver glycogen was increased by hGH 6--13 and decreased by hGH carbon into liver glycogen was increased by hGH 6--13 and decreased by hGH 177--191. This is discussed in terms of a futile cycle between glycogen and hexose phosphate in the liver, as the basis for a control mechanism for hepatic glycogen metabolism. The present observations are consistent with other in vivo and in vitro actions of these and related peptides.     

The ACTH-(4-9) analog ORG 2766 and desglycinamide9-(Arg8)-vasopressin reverse the retrograde amnesia induced by disrupting circadian rhythms in rats

Disrupting circadian organization by exposing rats to a shifted illumination schedule after training for passive avoidance and shuttle box avoidance behavior resulted in retrograde amnesia as evidenced by impaired performance during retention and extinction testing respectively. A single treatment with either the ACTH-(4-9) analog ORG 2766 or desglycinamide9-(Arg8)-vasopressin (DGAVP) 1 hour prior to the retention of passive avoidance or extinction of shuttle box avoidance behavior restored the behavioral impairment. It is suggested that these peptides may be useful to relieve memory deficits induced by disturbances in circadian organization.     

The interrelation between individual behavioral characteristics and the indices of brain energy metabolism in rats]

In rats with active type of behaviour in "open field" and "forced swimming" tests in response to weak stress (handling) both the rate of local blood flow (RLBF) and free oxygen tension level (pO2) in the brain are increased, and in rats with passive type of behaviour RLBF is increased, but the pO2 level is decreased. The character of pO2 level changes in the brain under stress is significantly (r = -0.74, p less than 0.001) connected with the level of depressiveness (time of passive swimming) and is nonsignificantly connected with the level of the motor activity. Indices of the active type of behaviour (the number of crossed squares, rearings, comings out to the center of the field and the time of extinction of the motor activity) positively correlate with succinate dehydrogenase (SDG) activity and negatively with NADH-dehydrogenase (NADH-DG) activity and the index of the passive type of behaviour (time of passive swimming) positively correlates with NADH-DG activity and negatively--with SDG activity.     

Angiotensin II--derived peptides devoid of phenylalanine in position 8 have full psychotropic activity of the parent hormone.

In this work we compared in rats the influence of heptapeptide 1-7-angiotensin II, hexapeptide 2-7-angiotensin II, pentapeptide 3-7-angiotensin II and angiotensin II on motility, stereotypy, learning of conditioned avoidance responses and recall of passive avoidance behaviour allowing to avoid aversive stimulation. The 4 peptides administered 15 min before the experiment, tended to increase the number of crossings, rearings and bar approaches in open field, significantly accelerated acquisition of conditioned avoidance responses and improved recall of the passive avoidance. All the peptides applied immediately before the experiment intensified stereotypy evoked by apomorphine in the dose 1 mg/kg and amphetamine in the dose 6.5 mg/kg given intraperitoneally. These results show full psychotropic activity of the examined fragments of angiotensin II, comparable with the activity of the parent octapeptide. Our previous hypothesis that the Val-Tyr-Ile-His-Pro fragment of angiotensin II is responsible for the psychotropic activity evoked by angiotensins in rats is thus confirmed.     

Arginine vasopressin and a vasopressin antagonist peptide: Opposite effects on extinction of active avoidance in rats

Systemic injection of arginine vasopressin (AVP) (1 μ/rat) significantly prolonged extinction of a pole-jump, active avoidance response in rats; lateral ventricular injection of 1000-fold less AVP (1 ng/rat) produced similar results. A new AVP analogue, [1-deaminopenicillamine-2-(O-methyl)-tyrosine]arginine vasopressin (dPTyr-(Me)AVP), is known to antagonize behavioral and vascular effects of exogenous AVP at molar ratios of 5:1. At a dose of 100 μ/rat (subcutaneously) dPTyr-(Me)AVP produces, by itself, a behavioral effect opposite to that of exogenous AVP, namely a facilitation of extinction. Injections of dPTyr-(Me)AVP into the lateral ventricle were ineffective except at a dose of 10 μg/rat. These results confirm previous reports of the effect of vasopressin on delaying extinction of avoidance behavior, but suggest a site of action distant from the lateral ventricle.     

Interaction of N-methyl-D-aspartate and Dopamine D1 receptors in modulation of passive avoidance extinction at mice with depressive-like state

The effect of activation of N-methyl-D-aspartate (D-cycloserine) and dopamine D1 (SKF 38393) receptors on learning and extinction of the passive avoidance response in mice under normal conditions and after formation of "behavioural despair" is studied. The data on ineffectiveness of D-cycloserine and SKF 38393 on training a conditional reflex were obtained. In mice with the normal state, SKF 38393 did not alter the dynamics of extinction, and D-cycloserine facilitated a more rapid decline in retrieval of memory trace when testing without penalty. On exposure to D-cycloserine + SKF 38393 injection, dynamics of extinction was similar to that under the action of D-cycloserine. In mice with the reaction of "behavioral despair", D-cycloserine and SKF 38393 reduced the deficit of the passive avoidance extinction typical for "depressed" animals without drugs. With simultaneous activation of NMDA and D1 receptors we observed acceleration of the extinction start and development of complete extinction of the memory trace about pain impact as compared with single injections of D-cycloserine and SKF 38393.