Effect of a spirocyclic cyclodipeptide derivate of MIF on passive avoidance behavior and amnesia in rats

Cyclo (1-amino-1-cyclopentane-carbonyl-L-alanyl)-c(Acp-Ala), a derivative of MIF (prolyl-leucyl-glycinamide) affected passive avoidance behavior of rats when administered at different phases of the step-through type of experimental paradigm. c(Acp-Ala) given s.c. or orally in a 1 mg/kg dose increased avoidance latencies not only when administered before, or immediately after the shock trial but also when given before the pretraining trial, i.e. at the first exposure of animals to the experimental situation without shock treatment. The notion is discussed, that it is the influence of c(Acp-Ala) on processing of information received during the pretraining trial that manifests itself in the facilitation of avoidance response. The drug appears to have a long-term action since it was active when given 20 h before the pretraining trial or the shock trial or the test of retention. c(Acp-Ala) when administered immediately after the shock trial, attenuated amnesia in rats induced by electroconvulsive shock (ECS).     

The long-term effect of acute hypoxic hypoxia on shuttlebox avoidance learning in rats

Long-term influence was studied of the acute hypoxic hypoxia seance on rats behaviour in situation of elaboration of the conditioned reaction of active avoidance of electric shocks in shuttle chamber. It was found that in 2.5-3 months after the hypoxia seance, the experimental animals significantly differed from the intact controls by dynamics of CR elaboration (rats which had hypoxia were ahead of the control ones) and by distribution of the conditioned reactions latencies (for experimental animals this distribution was shifted to minor values). The character of these behavioural shifts coincided with that observed in the group of rats with local unilateral hippocampus lesion. The obtained results and numerous data presented in literature on the influence of the hippocampus lesion on animals shuttle avoidance learning, allow to conclude that the seance of hypoxic hypoxia leads to the disturbance of the hippocampus function. This conclusion conforms to the data on diffusive death of the hippocampal and neocortical neurones as a result of hypoxia action.     

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.     

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.     

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.     

Analysis of the facilitatory effect of the ACTH-(4-9) analog ORG 2766 on active social contact in rats

Pairs of male rats were tested for active social interaction, either in a familiar test arena under low illumination or in an unfamiliar test arena under high illumination conditions. Rats tested in an unfamiliar environment and under high light, spent less time in active social contact than rats tested under familiar, low light conditions. This effect was most pronounced during the first half of the 10 minute test period. Intraperitoneal injections of ACTH-(1-24) and ACTH-(4-10) (50 micrograms/kg) administered 5 minutes before the test decreased, whereas the same dose of the synthetic ACTH-(4-9) analog ORG 2766 increased the time spent in active social contact, when rats were tested under unfamiliar, high light conditions. The effects of ACTH-(4-10) and ORG 2766 were present in the second and first half of the test period respectively. Dose response relationship studies with ORG 2766 showed that 0.5 micrograms/kg of this peptide facilitated social contact under both test conditions and the dose response relation followed an inverted U-shaped curve under the familiar low light condition, but not under the unfamiliar, high light condition. ACTH-(4-10) and ORG 2766 failed to influence active social contact, when administered 30 minutes before the test. The change in social contact by ACTH-(4-10) and ORG 2766 was not accompanied by an alteration in ambulation of the rats. It is concluded that ACTH-(4-10) and ORG 2766 decrease and increase respectively social interaction of pairs of rats. The expression of these effects however, depends on the test and treatment conditions and may be related to the action of brain-born ACTH-like peptides.     

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.     

Biochemistry and molecular biology of exocellular fungal beta-(1,3)- and beta-(1,6)-glucanases

Many fungi produce exocellular beta-glucan-degrading enzymes, the beta-glucanases including the noncellulolytic beta-(1,3)- and beta-(1,6)-glucanases, degrading beta-(1,3)- and beta-(1,6)-glucans. An ability to purify several exocellular beta-glucanases attacking the same linkage type from a single fungus is common, although unlike the beta-1,3-glucanases, production of multiple beta-1,6-glucanases is quite rare in fungi. Reasons for this multiplicity remain unclear and the multiple forms may not be genetically different but arise by posttranslational glycosylation or proteolytic degradation of the single enzyme. How their synthesis is regulated, and whether each form is regulated differentially also needs clarifying. Their industrial potential will only be realized when the genes encoding them are cloned and expressed in large quantities. This review considers what is known in molecular terms about their multiplicity of occurrence, regulation of synthesis and phylogenetic diversity. It discusses how this information assists in understanding their functions in the fungi producing them. It deals largely with exocellular beta-glucanases which here refers to those recoverable after the cells are removed, since those associated with fungal cell walls have been reviewed recently by Adams (2004). It also updates the earlier review by Pitson et al. (1993).     

Differential effects of DGAVP on acquisition and extinction of active avoidance behavior

DGAVP facilitates consolidation and retrieval of active and passive avoidance behavior. In this study it was tested whether the long-term behavioral effects of DGAVP are the consequence of an initial increase in behavioral arousal during the learning phase. Animals that were preestimated in an open field test to be low active showed a lower number of conditioned avoidance responses (CAR's) during acquisition and extinction of a shuttle-box task than high active rats. DGAVP was administered 40 min prior to the 1st acquisition session. The immediate effect of DGAVP was a shift in the bell-shaped curve of the relation between arousal and performance (13); an increase in acquisition performance was observed with a low dose of DGAVP (0.1 microgram), while a decrease was found with a high dose of DGAVP (1 microgram). A dose-dependent inhibition of extinction was found in both low and high active animals. These results suggest an immediate effect of DGAVP on the rate of acquisition behavior, which may be a direct consequence of its arousing properties, and a long-term effect on extinction, indicating the formation of memory traces specific for vasopressin-related neuropeptides.     

Synthesis of 11beta-(4-dimethylaminophenyl)-17beta-hydroxy-17alpha- (3-methyl-1-butynyl)-4, 9-estradien-3-one and 11beta-(4-acetophenyl)- 17beta-hydroxy-17alpha-(3-methyl-1-butynyl)-4, 9-estradien-3-one: two new analogs of mifepristone (RU-486)

From the structure activity relationship, two new analogs, 2 and 3, of the potent progesterone antagonist mifepristone 1 have been designed. The syntheses of these two analogs have been achieved in eleven steps through modified synthetic sequences and improved procedures starting from (+)-estrone. In comparison with mifepristone 1, the relative binding affinities of compound 2 for the progesterone receptor was found to be more, whereas that of compound 3 was less.     

Effect of superlow doses (10(-18)-10-(-14) M) of biologically active substances: general rules, features, and possible mechanisms]

The effects of ultra-low (10(-18)-10(-14) M) doses (ULD) of biologically active substances have been reviewed in terms of common regularities of ULD effects and peculiarities of action of various groups of compounds. The most common and at the same time paradoxical regularities of ULD action are bi- or polymodal patterns of dose dependence, absence or presence of an inverse effect at higher doses, and instability of ULD effect. Possible mechanisms of ULD action including the mechanism based on the adaptation theory are discussed.     

The effect of training conditions on passive avoidance performance in rats

Male outbred rats were trained for step-through avoidance in different experimental conditions: 1) in a two-compartment chamber with a small dark compartment and a chamber with illuminated suspended platform; 2) with or without acquaintance with experimental chamber 24 hours prior to learning; 3) with or without a possibility of the chamber exploration 3 min immediately before training procedure; 4) with inescapable or escapable pain reinforcement (5 electric footshocks, 0.45 mA, 1 s, with 2-s between-shock intervals); 5) with 2 or 5 inescapable footshocks of the same rate, duration, and intensity. The acquired performance was tested 24 h after training. It was shown that the procedure of exploration of the experimental chamber 24 prior to training improved the reproduction and the same procedure conducted immediately before training impaired the reproduction of the acquired behavior. Different training conditions improved the reproduction of the acquired behavior in the chamber with a suspended platform to a greater extent than in the two-compartment chamber. The decrease in the number of pain stimuli from 5 to 2 or the possibility to escape the punishment during training did not significantly change the reproduction.     

125I-d(CH2)5[Tyr(Me)2, Tyr(NH2)9]AVP: iodination and binding characteristics of a vasopressin receptor ligand

A radioiodinated vasopressin antagonist, d(CH2)5[Tyr(NH2)9]AVP has been prepared. Iodination was carried out at the phenyl moiety of the tyrosylamide residue at position 9, followed by HPLC purification. Non-radiolabelled monoiodinated antagonist was used as a reference for identification. 125I-d(CH2)5[Tyr(Me)2, Tyr(NH2)9]AVP binding appeared to take place with a dissociation constant of 0.28 +/- 0.09 nM (Kd +/- SD) to V1 vasopressin receptors on rat liver membranes.