Neuropharmacology Poster Session


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Retrieval of Memory Traces: Pharmacological Regulation of Separate Steps.

Contact Person: Vladimir I Arkhipov (arkhipov@arkhipov.iteb.serpukhov.su)

Long-term memory is represented in widely distributed brain cells. From this, the retrieval of memory traces is the principal process for understanding of memory functioning. Findings from behavioral pharmacology pointed out the existence of definite steps for the retrieval processes:
i.) The selection of appropriate cluster of engrams;
ii.) The inhibition of unessential components and strengthening of substantial ones;
iii.) The estimation of selected engrams on suitableness to available circumstances.
There are objective difficulties for the study of these steps in animals because of few possible approaches. Some mechanisms of the retrieval step for memory processing can be revealed, when two phenomena are compared: drug discrimination and pharmacologically induced state-dependent retrieval of responses.
Drug discrimination is the training of animals to perform two tasks in dependence on internal cues created by drugs. Animals are training to discriminate between two states, with and without a drug, by the manipulation with reinforcement.

The specific feature of state-dependent phenomenon (memory dissociation) is specific amnesia when the dissociated learning and task performance are possible in dependence on functional state of the brain. Pharmacologically induced dissociated states of the brain emerge when the retrieval of responses learned before treatment is temporarily blocked by drug influence, but the ability of animals to learn new tasks is kept. Furthermore, memory traces that were formed in drugged state are not accessible for retrieval in normal state and only the same drug influence allows retrieving them. The states are dissociated because the transfer of memories from one brain state to another is difficult or impossible at all. Thus, drug discrimination and memory dissociation are phenomena with different mechanisms /Colpaert, Koek, 1995/.

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The emergency of "dissociated state" under the drug influence is quite specific failure of memory retrieval without essential changing of perception, consolidation and storage a new information. Indeed, in spite of the salient disturbances of task performance in drugged state, memory storage processes and task executive processes are nearly intact. It may be concluded that the emergency of dissociated state is specific disturbance of retrieval process. Therefore, state-dependent learning and retrieval of dissociated responses is helpful behavioral model for the study of memory retrieval mechanisms.

Among drugs resulted in memory dissociation are glutamate-, cholin-, anticholin-, GABA-ergic / Arkhipov, 1992; Arkhipov, Azarashvili, 1988; Nacagawa, Iwasaki,1995; Overton, 1984/. Memory dissociation that appeared from these drugs demonstrates that the blockade of task performance after drug treatment is specific reorganization of the retrieval process. The retrieval of long-term memory traces is possible in spite of amnesic influence of the drugs, but retrieval process is state-dependent. Memory traces are accessible for retrieval in the brain state, if they was encoded in this brain state. Here we emphasize one side of memory dissociation phenomenon: to demonstrate practically separate retrieval of long-term memory traces in dissociated states.

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Thus, dissociated responses in animals can be obtained by training in pharmacologically induced dissociated states. It was shown that more than two dissociated responses may de obtained. For example, learning and retrieval of one response from three previously learned in experimental chamber may be seen when animal placed in this chamber after treatment by saline, pentobarbital (15 mg/kg, i.p.) or sodium oxybutirate (250 mg/kg, i.p.) /Arkhipov, Azarashvili, 1981/. This experimental situation gives opportunity for separate retrieval of several responses. The study of the retrieval of dissociated tasks is possible if another drugs are administrated before the retrieval test. For example, if animals have learned two tasks (R1 in the normal state and R2 in the drugged state), during test for performance the animals can retrieve after pharmacological treatment: i.) R1; ii.) R2; iii.) R1 and R2 during test session, this situation may be considered as the disruption of memory dissociation, because of the animals remembered two tasks simultaneously; iiii.) R1 or R2 does not retrieve but animals are capable for new learning, this situation may be considered as the emergence of new dissociated state. Besides, we does not consider the case when retrieval is not possible from toxic effect of administrated drug.

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It is possible to summarize some results from the study of memory dissociation. The phenomenon demonstrates:
1) The possibility of separate memory retrieval in dependence on functional state. The choice of the R1 or R2 for the retrieval can be regulated by pharmacological influences.
2) The clasterization of engrams. Some engrams are accessible for the retrieval, while others are repressed.
3) Regulation of retrieval processes by cholinergic and GABA-ergic systems.
4) The key role of hippocampus in memory dissociation processes. Some evidence of this assertion is the possibility for long-lasting dissociated state after cholinergic stimulation of hippocampus /Arkhipov, Azarashvili, 1985/ and relation of memory dissociation to declarative form of memory.
From the necessity to inhibit some part of memory traces for state dependent retrieval of responses it may be supposed that declarative (attention-dependent) form of memory /Squire, Zola, 1996/ is capable to dissociate. Therefore experimental expressiveness of memory dissociation is critically determined by the involvement of attention-dependent memory in used task. It was suggested the key role of hippocampus in the emergence of dissociated states /Arkhipov, Azarashvili, 1985; Arkhipov, Shchipakina, 1992; Zharikova, Arkhipov, 1994/. Possible role of hippocampus in the retrieval of declarative memory traces is to estimate the suitability of activated memory traces for the current situation. It is known that exploratory activity and attention critically depend on cholinergic processes and hippocampal activity. Hippocampus may estimate the stimulus novelty and filter external and internal informational signals /Vinogradova, 1995/. Thus, attention-dependent memory is the foundation of memory dissociation processes. It may be suggested that the retrieval of not only dissociated responses occurs with participation of cholinergic and GABA-ergic systems of hippocampus. Such processes are controlling the attention-dependent retrieval of memory traces in widespread circumstances.

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  1. Arkhipov, V.I., Learning of rats under amnesia caused by pentobarbital, Behav. Neural Biol., 57 (1992) 244-247.
  2. Arkhipov, V.I. and Azarashvili A.A. Dissociated learning with sodium oxybutirate, Pharmacol.Toxicolog., 44 (1981), 667-669 (in Russian).
  3. Arkhipov, V.I. and Azarashvili, A.A., The dissociated state in rats after injection of carbacholine into hippocampus, Zhurn.vyssh.nervn.dejat., 35 (1985) 920-925 [in Russian].
  4. Arkhipov, V.I. and Azarashvili, A.A., Role of cholinergic and monoaminergic brain systems in dissociated learning, Neurosci. Behav. Physiol., 11 (1988) 226-229.
  5. Arkhipov, V.I. and Shchipakina, T.G., Phosphorylation of the proteins of synaptic membranes during the emergence of prolonged dissociated states induced by carbacholine, Neurosci. Behav. Physiol. 22 (1992) 51-56.
  6. Bremner, J.D. and Brett, E., Trauma-related dissociative states and long-term psychopathology in posttraumatic stress disorder, J. Traum. Stress, 10 (1997) 37-49.
  7. Colpaert, F.C. and Koek, W., Empirical evidence that the state dependence and drug discrimination paradigms can generate different outcomes, Psychopharmacol., 120 (1995) 272-279.
  8. Kenealy, P.M., Mood-state-dependent retrieval: the effects of induced mood on memory reconsidered, Q. J. Exp. Psychol., A, 50 (1997) 290-317.
  9. Nakagawa, Y. and Iwasaki, T., Involvement of benzodiazepine/GABA-A receptor complex in ethanol-induced state-dependent learning in rats, Brain Res., 686 (1995) 70-76.
  10. Overton, D.A., State dependent learning and drug discriminations. In L.L Iversen et al., (Eds.), Handbook of Psychopharmacology, Vol. 18, Plenum Publishing Corp., New York, 1984, pp. 59-127.
  11. Overton, D.A., Historical context of state dependent learning and discriminative drug effects, Behav. Pharmacol., 2 (1991) 253-264.
  12. Stokes, K.A. and McIntyre, D.C., Lateralized state-dependent learning produced by hippocampal kindled convulsions effect on split-brain, Physiol. Behav., 34 (1985) 217-224.
  13. Squire, L., R. and Zola, S. M., Structure and function of declarative and nondeclarative memory systems, Proc. Natl. Acad. Sci. USA, 93 (1996) 13515-13522.
  14. Vinogradova, O.S., Expression, control, and probable functional significance of the neuronal theta-rhythm, Progress in Neurobiol., 45 (1995) 523-583.
  15. Zharikova, A.D. and Arkhipov, V.I., Reversible activation of GABA and l-glutamate uptake into synaptosomes isolated from the rat brain in response to a single carbacholine injection into hippocampus, Behav. Neural Biol., 61 (1994)

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Arkhipov, V.; (1998). Retrieval of Memory Traces: Pharmacological Regulation of Separate Steps.. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Available at URL http://www.mcmaster.ca/inabis98/neuropharm/arkhipov0328/index.html
© 1998 Author(s) Hold Copyright