Henk Rigter

The effects of ACTH- and vasopressin-analogues on CO2-induced retrograde amnesia in rats

Amnesia for a one-trial step-through passive avoidance response was induced in rats by application of CO2 until respiratory arrest occurred. The ACTH-analogue ACTH4–10 alleviated the amnesia when administered 1 hr prior to the retrieval test but not when given 1 hr prior to the acquisition trial. The behaviourally inert ACTH-analogue ACTH11–24 appeared to have no effect on the amnesia. The vasopressin-analogue desglycinamide lysine vasopressin (DG-LVP) antagonized the amnesia when administered 1 hr prior to the acquisition trial or 1 hr prior to the test trial. The relevance of these date to present theories on amnesia is discussed.

Endorphins alter acquisition and consolidation of an inhibitory avoidance response in rats

Peripheral i.p. administration of 1.0 microgram/kg gamma-endorphin to rats, 30 min prior to training in a 1-trial inhibitory avoidance task, enhanced retention performance measured 72 h later. A much smaller dose of 0.1 microgram/kg beta-endorphin administered immediately following training produced a retention deficit. Both of these endorphin effects were time dependent, since gamma-endorphin given 90 min prior to, and beta-endorphin given 90 min after training produced no effect on retention performance. A wide dose range of either gamma-endorphin (0.1-10 micrograms/kg) administered after training or beta-endorphin (0.1-10 micrograms/kg) administered before training had no effect. These results suggest that the behavioral actions of beta-endorphin and smaller beta-lipotropin sequences such as gamma-endorphin, are distinct. We also found that 0.1-100 micrograms/kg of either alpha-endorphin or Met-enkephalin given before or after training was without effect on retention of the response.

Anti-amnesic effect of ACTH4–10: Its independence of the nature of the amnesic agent and the behavioral test

Abstract It was found previously that ACTH 4–10 is able to alleviate the CO 2 -induced retrograde amnesia for a step-through passive avoidance response when injected into rats 1 hr prior to the retrieval test. The present investigation was undertaken to establish whether ACTH 4–10 has a similar effect if a different amnesia agent and a different behavioral task are used. It appeared that electroconvulsive shock induced amnesia for a one-trial thirst-motivated response. This amnesia could be reduced by administration of ACTH 4–10 1 hr prior to the retrieval test. Administration of ACTH 4–10 1 hr prior to the acquisition was ineffective. It was concluded that ACTH 4–10 exerts a retrieval-promoting effect independent of the nature of the amnesic agent and the behavioral task.

Hormonal influences on the extinction of conditioned taste aversion

Conditioned taste aversion for a 5% glucose solution (sugar water) was induced in rats by an i.p. injection of LiCl 30 min after the first presentation of sugar water. Extinction of conditioned taste aversion was measured either in the forced-drinking test or in the preference-drinking test. In the forced-drinking test sugar water was the only fluid presented to the animals during extinction sessions. In the preference-drinking test the animals had the choice of tap water or sugar water. The rate of extinction was much slower in the preference test.The ACTH-analogues, ACTH4–10 and ACTH4–10 7D Phe, and α-MSH delayed extinction in the preference test but not extinction in the forced-drinking test. ACTH11–24 was without any effect. MSH-release inhibiting factor (MIF) facilitated extinction in the forced-drinking test but did not alter extinction in the preference test. The peptides did not affect intake of tap water or preference of sugar water over tap water by control rats.

Modulation of Memory by Pituitary Hormones and Related Peptides

Publisher Summary This chapter discusses the modulation of memory by pituitary hormones and related peptides. The phenomenon of memory can be differentiated into a number of conceptual classifications according to various schemata. The memory processing involves four steps: (1) selection of some stimuli from the perceptual environment; (2) consolidation or storage into memory by some neurobiological mechanisms; (3) decay, or the eventual forgetting of information; and (4) retrieval of stored information by an equally ill-understood neurobiological mechanism. Adrenocorticotropic hormone (ACTH)-like peptides facilitates retrieval of memory in animals. This effect derives from sites of action within the central nervous system. The facilitated retrieval is transient and does not persist beyond the period of treatment. ACTH-like peptides enhance vigilance in humans. This effect also derives from sites of action within the central nervous system. ACTH-like peptides may facilitate memory storage. The chapter also reviews the evidence for specific modulatory influences, both enhancing and disrupting, of a variety of peptides. The disruptive effects of oxytocin and the facilitatory effects of vasopressin on memory suggest that when endogenous peptides are active in normal memory functioning they interact in a complex fashion.

Vasopressin and memory: The influence of prior experience with the training situation

The importance of behavioral variables for the efficacy of arginine vasopressin to facilitate memory consolidation in male Wistar rats using a step-through inhibitory (passive) avoidance test was examined. Prior to the acquisition trial (shock), different amounts of experience with the box without shock were given (pretraining). Pretraining involved two components: allowing the rats to practice the step-through response by entering the box, and familiarizing the rats with the conditioning box by allowing them to explore the box for discrete periods of 3 to 4 min. When the experimental design contained both components of pretraining, sc administration of 0.1 or 1 μg of vasopressin immediately after the acquisition trial enhanced avoidance behavior during retention testing. This effect of the peptide was time dependent: delaying administration of vasopressin for 90 min rendered the peptide ineffective. In the absence of any pretraining or of one of the components of pretraining, the posttrial effect of vasopressin was also lost. The data indicate that vasopressin may facilitate memory consolidation in rats, depending on the nature of prior experience with the training situation.

Failure of naloxone to prevent reduction of amnesia by enkephalins

Abstract The enkephalins attenuate in rats carbon dioxide-induced amnesia for an avoidance response when injected s.c. before the retrieval test in a dose of 3 μg/rat. Naloxone (1 mg/kg) does not prevent the anti-amnesic activity of the enkephalins. This suggests that the effects on these pentapeptides on amnesia is not mediated through opiate receptors.

Reversal of amnesia by an orally active ACTH 4-9 analog (Org 2766).

The ACTH 4-9 analog, H-Met((O2)-Glu-His-Ph-D-Lys-Phe-OH (Or 2766), attenuates in rats CO2-induced amnesia for a one-trial passive avoidance step-through response when administered prior to the retrieval test but not when given prior to acquisition. Even a dose of 0.001 mug/rat Org 2766 yields an anti-amnesic effect. In this respect Org 2766 is more active than the ACTH fragment ACTH 4-10. An anti-amnesic effect was also obtained when Org 2766 was administered orally. ACTH 4-10 (100 mug/rat) has to be given SC within 8 hr of the retrieval test in order to be effective. A similar time span of effectiveness was observed when Org 2766 was SC injected in a dose of 0.1 mug/rat. The anti-amnesic effect of ACTH 4-10 remains when the time interval between acquisition and retrieval is extended beyond the usual 24 hr. The same appeared to be true for SC ADMINISTERED Org 2766. It is suggested that ACTH-like peptides, and particularly the orally active Org 2766, may be helpful in the treatment of deficient mental performance.

Possible significance of ACTH fragments for human mental performance

Evidence that ACTH has an effect on behavior that is independent of its effects on the adrenals is reviewed. Results of experiments with rats indicate that ACTH 4–10 and other fragments or analogs that are devoid of endocrine effects have an effect on acquisition and delay extinction of conditioned behavior. ACTH 4–10 has a facilitating effect on retrieval from memory. This is shown to be independent of the type of test design used to evaluate retrieval. It is suggested that ACTH activates the reticulolimbic circuits, which may result in increased motivation or attention. Safety studies in rats and dogs did not reveal any adverse effects of chronic treatment with very high dosages of ACTH 4–10 . The results of the first studies of ACTH 4–10 (Org OI 63) in man are discussed and interpreted to indicate that ACTH 4–10 probably improves attentional processes, including retrieval functions, and that further evaluation of ACTH-like peptides is justified.

Analysis of behavioural responses to an ACTH analog in CXB/By recombinant inbred mice

Male mice of the C57BL/6By and BALB/cBy inbred strains, their reciprocal F1 hybrids, and 7 recombinant inbred strains, were tested for open-field activity, a shock-motivated successive reversal position discrimination problem in a T-maze, and a toggle box exploration task. The test battery was repeated one month later. Finally, mice were tested for the acquisition and extinction of a taste aversion conditioned by ethanol injection. Mice of each strain were tested after injection with saline or one of 3 doses of an ACTH analogue. Highly significant genotypic differences were found for all measures, an expected result. The strain distribution pattern seen in the toggle box suggested single gene mediation of exploratory activity after habituation. One aspect of avoidance responding and extinction of conditioned taste aversion also yielded strain distribution pattern consistent with single gene control. Peptide treatment reduced internal field crossings in the open field. This effect was not strain dependent. Peptide treatment had no effect on T-maze learning, conditioned taste aversion, or toggle-box exploration.