Behavioral Pharmacology of Memory

Opportunities for Cellular Explanations
  • Arthur Cherkin
  • James F. Flood


Recent progress in understanding molecular and cellular mechanisms of conditioning make it timely to reevaluate interfaces between well-defined unitary cellular mechanisms and subtle, complex, multifactorial animal behaviors. The purpose of this chapter is to call attention to two robust phenomena observed during studies of the behavioral pharmacology of memory. We consider these phenomena to provide interesting possibilities for exploration at the cellular level. The first phenomenon is that pharmacological probes of memory in living organisms can have opposite effects. That is to say, a given drug in a given experimental paradigm can either enhance or impair memory, depending on dose. The second phenomenon is that several two-drug combinations exhibit powerful supraadditivity (as much as 20-fold) of memory-enhancing potency. The question is, can molecular and cellular approaches help to explain these two phenomena? The interfaces involve multiple interactions and functional linkages (Schmitt and Schneider, 1975). Atkinson (1975) has pointed out:

Any discussion of biological processes must always involve oversimplification, because bio-molecular reactions are always part of a larger whole. Biomolecular processes may be of some interest in their own right, but their biological significance relates to their effects on a larger system.

The black box approach, in which the intermediate mechanisms between a stimulus and its induced response are not considered, can lead, and has led, to much useful information in physiology and biophysics. It poses questions that a mechanistically oriented approach can then be used to resolve. However, this approach is limited and in a sense outmoded.

In contrast, biochemists deal with small portions of large systems and frequently become so intrigued with the properties of these parts that they forget that they are, in situ, functioning elements within a complex interacting system....

These two basic approaches must be combined in order to obtain information that is biologically meaningful. Every aspect of an organism is designed by mutation and selection, but we must remember that while it is molecular detail that mutates, it is overall organismic function that is selected. Both the molecular and the black-box approaches must be used, but the area of real interest is in the linkage between them, the ways in which molecular detail is responsible for the overall response or for the living functioning organism.


Memory Modulator Memory Retention Recall Score Equipotent Dose Memory Enhancement 
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  1. Aigner, T. G., and Mishkin, M., 1986, The effects of physostigmine and scopolamine on recognition memory in monkeys, Behay. Neural Biol. 45: 81–87.CrossRefGoogle Scholar
  2. Alkon, D. L., Sakakibara, M., Forman, R., Harrigan, J., Lederhendler, I., and Farley, J., 1985, Reduction of two voltage-dependent K+ currents mediates retention of a learned association, Behay. Neural Biol. 44: 278–300.CrossRefGoogle Scholar
  3. Altman, J., 1985, Tuning in to neurotransmitters, Nature 315: 537.PubMedCrossRefGoogle Scholar
  4. Atkinson, D. E., 1975, Allosteric interactions in enzyme systems, in: Functional Linkage in Biomolecular Systems ( F. O. Schmitt and D. M. Schneider, eds.), Raven Press, New York, pp. 43–56.Google Scholar
  5. Bartus, R. T., 1979, Physostigmine and recent memory: Effects in young and aged nonhuman primates, Science 206: 1087–1089.PubMedCrossRefGoogle Scholar
  6. Bartus, R. T., Dean, R. L., Sherman, K. A., Friedman, E., and Beer, B., 1981, Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats, Neurobiol. Aging 2: 105–111.PubMedCrossRefGoogle Scholar
  7. Bechara, A., and van der Kooy, D., 1985, Opposite motivational effects of endogenous opioids in brain and periphery, Nature 314: 533–534.PubMedCrossRefGoogle Scholar
  8. Bovet, D., Bovet-Nitti, F., and Oliverio, A., 1966, Effects of nicotine on avoidance conditioning of inbred strains of mice, Psychopharmacologia (Berl.) 10: 1–5.CrossRefGoogle Scholar
  9. Butler, D. E., Poschel, B. P. H., and Marriott, J. G., 1981, Cognition-activating properties of 3-(aryloxy) pyridines, J. Med. Chem. 24: 346–350.PubMedCrossRefGoogle Scholar
  10. Butler, D. E., Nordin, I. C., L’Italien. Y. J., Zweisler, L., Poschel, P. H., and Marriott, J. G., 1984, Amnesia-reversal activity of a series of N-[(disubstituted-amino) alkyl]-2-oxo-l-pyrrolidineacetamides, including pramiracetam, J. Med. Chem. 27: 684–691.PubMedCrossRefGoogle Scholar
  11. Cherkin, A., Meinecke, R. O., and Garman, M. W., 1975, Retrograde enhancement of memory by mild flurothyl treatment in the chick, Physiol. Behay. 14: 151–158.CrossRefGoogle Scholar
  12. Davies, P., 1985, Is it possible to design rational treatments for the symptoms of Alzheimer’s disease? Drug Dev. Res. 5: 69–76.CrossRefGoogle Scholar
  13. Davis, K. L., Mohs, R. C., Tinklenberg, J.R., Pfefferbaum, J. R., Hollister, L. E., and Kapell, B. S., 1978, Physostigmine: Improvement of long-term memory processes in normal humans, Science 210: 272–274.CrossRefGoogle Scholar
  14. Fekete, M., and De Wied, D., 1982, Dose-related facilitation and inhibition of passive avoidance behavior by the ACTH 4–9 analog (ORG 2766), Pharmacol. Biochem. Behay. 17: 177–182.CrossRefGoogle Scholar
  15. Flood, J. F., and Cherkin, A., 1986, Scopolamine effects on memory retention in mice: A model of dementia? Behay. Neural Biol. 45: 169–184.CrossRefGoogle Scholar
  16. Flood, J. F., Landry, D. W., and Jarvik, M. E., 1981, Cholinergic receptor interactions and their effects on long-term memory processing, Brain Res. 215: 177–185.PubMedCrossRefGoogle Scholar
  17. Hood, J. F., Smith, G. E., and Cherkin, A., 1983, Memory retention: Potentiation of cholinergic drug combinations in mice, Neurobiol. Aging 4: 37–43.CrossRefGoogle Scholar
  18. Flood, J. F., Smith, G. E., and Cherkin, A., 1985, Memory enhancement: Supraadditive effect of subcutaneous cholinergic drug combinations in mice, Psychopharmacology 86: 61–67.PubMedCrossRefGoogle Scholar
  19. Gold, P. E., 1986, Glucose modulation of memory storage, Behay. Neural Biol. 45: 342–349.CrossRefGoogle Scholar
  20. Izquierdo, I., 1984, Endogenous state dependency: Memory depends on the relation between the neurohumoral and hormonal states present after training and at the time of testing, in: Neurobiology of Learning and Memory ( G. Lynch, J. L. McGaugh, and N. M. Weinberger, eds.), Guilford Press, New York, pp. 333–350.Google Scholar
  21. Johns, C. A., Haroutunian, V., Greenwall, B. S., Mohs, R. G., Davis, B. M., Kanof, P., Horvath, T. B., and Davis, K. L., 1985, Development of cholinergic drugs for the treatment of Alzheimer’s disease, Drug Dev. Res. 5: 77–96.CrossRefGoogle Scholar
  22. Kandel, E. R., 1985, Cellular mechanisms of learning and the biological basis of individuality, in: Principles of Neural Science, 2nd ed. ( E. R. Kandel and J. H. Schwartz, ed.), Elsevier, New York, pp. 816–833.Google Scholar
  23. Krivanek, J. A., and McGaugh, J. L., 1968, Effects of pentylenetetrazol on memory storage in mice, Psychopharmacologia (Berl.) 12: 303–321.CrossRefGoogle Scholar
  24. Krivanek, J. A., and McGaugh, J. L., 1969, Facilitating effects of pre-and posttrial amphetamine and discrimination learning, Agents Actions 1: 36–42.PubMedCrossRefGoogle Scholar
  25. Lee, M., and Gold, P. E., 1987, Memory enhancement and impairment with intracerebroventricular glucose injections (in preparation).Google Scholar
  26. McGaugh, J. L., and Krivanek, J. A., 1970, Strychnine effects on discrimination learning in mice: Effects of dose and time of administration, Physiol. Behay. 5: 1437–1442.CrossRefGoogle Scholar
  27. McGaugh, J. L., Liang, K. C., Bennett, C., and Sternberg, D. B., 1984, Adrenergic influences on memory storage: Interaction of peripheral and central systems, in: Neurobiology of Learning and Memory ( G. Lynch, J. L. McGaugh, and N. M. Weinberger, eds.), Guilford Press, New York, pp. 313–332.Google Scholar
  28. Paalzow, L. K., Paalzow, G. H. M., and Tfelt-Hansen, P., 1985, Variability in bioavailability: Concentration versus effect, in: Variability in Drug Therapy: Description, Estimation, and Control ( M. Rowland, L. B. Sheiner, and J. L. Steimer, eds.), Raven Press, New York, pp. 167–185.Google Scholar
  29. Platel, A., Jalfre, M., Pawelec, C., Roux, S., and Porsolt, R. D., 1984, Habituation of exploratory activity in mice: Effects of combinations of piracetam and choline on memory processes, Pharmacol. Biochem. Behay. 21: 209–212.CrossRefGoogle Scholar
  30. Popot, J. L., and Changeux, J. P., 1984, Nicotinic receptor of acetylcholine: Structure of an oligomeric integral membrane protein, Physiol. Rev. 64: 1162–1239.PubMedGoogle Scholar
  31. Riege, W. H., and Cherkin, A., 1976, Memory performance after flurothyl treatment in rainbow trout, Psychopharmacologia 46: 31–35.PubMedCrossRefGoogle Scholar
  32. Schmitt, F. O., and Schneider, D. M., eds., 1975, Functional Linkage in Biomolecular Systems, Raven Press, New York.Google Scholar
  33. Shih, Y. H., and Pugsley, T. A., 1985, The effects of various cognition-enhancing drugs on in vitro rat hippocampal synaptosomal sodium dependent high affinity choline uptake, Life Sci. 36: 2145–2152.PubMedCrossRefGoogle Scholar
  34. Steinberg, S. F., Chow, Y. K., and Bilezikian, J. P., 1986, Regulation of rat heart membrane adenylate cyclase by magnesium and manganese, J. Pharmacol. Exp. Ther. 237: 764–772.PubMedGoogle Scholar
  35. Stratton, L. O., and Petrinovich, L., 1963, Post-trial injections of an anticholinesterase drug and maze learning in two strains of rats, Psychopharmacologia 5: 47–54.PubMedCrossRefGoogle Scholar
  36. Votava Z., 1967, Pharmacology of the central cholinergic synapses, Annu. Rev. Pharmacol. 7: 233–240.CrossRefGoogle Scholar
  37. Wilson, C. A., 1986, Society for drug reasearch symposium: Senile dementia of the Alzheimer type, Neurobiol. Aging 7: 219–222.CrossRefGoogle Scholar
  38. Wolthuis, O. L., 1981, Behavioral effects of etiracetam in rats, Pharmacol. Biochem. Behay. 15: 247–255.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1988

Authors and Affiliations

  • Arthur Cherkin
    • 1
    • 2
  • James F. Flood
    • 1
    • 2
  1. 1.Geriatric Research, Education and Clinical Center and Psychobiology Research LaboratoryVeterans Administration Medical CenterSepulvedaUSA
  2. 2.Department of Psychiatry and Biobehavioral SciencesUniversity of California at Los Angeles School of MedicineLos AngelesUSA

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