Psychopharmacology

, Volume 99, Issue 4, pp 431–438

An hypothesis on the role of glucose in the mechanism of action of cognitive enhancers

  • Gary L. Wenk
Review

Abstract

This review presents evidence that some cognition enhancing drugs produce their beneficial effects on learning and memory by increasing the availability of glucose for uptake and utilization into the brain. The hypothesis further suggests that many cognition enhancing drugs act through a peripheral mechanism rather than directly on the brain. The general hypothesis is supported by four independent and converging pieces of evidence: 1) Some cognition enhancing drugs may not cross the blood-brain barrier, but can still facilitate memory; 2) Some cognition enhancing drugs are effective only when injected peripherally, but not when injected directly into the brain; 3) Many cognition enhancing drugs are not effective after adrenalectomy; 4) Cognitive function is correlated with glucose regulation in aged animals and humans. These four lines of research have implications for the role of glucose in the action of specific cognitive enhancers.

Key words

Cognition enhancers Glucose Nootropics Learning and memory 

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References

  1. Arnsten AFT, Segal DS, Nevile HJ, Hillyard SA, Janowsky DS, Judd LL, Bloom FE (1983) Naloxone augments electrophysiological signs of attention in man. Nature 304:725–727Google Scholar
  2. Bartus RT, Dean RL, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–417Google Scholar
  3. Beani LC, Bianchi C, Giacomelli A, Tamberi F (1978) Noradrenaline inhibition of acetylcholine release from guinea-pig brain. Eur J Pharmacol 48:179–193Google Scholar
  4. Blass JP, Gibson GE (1979) Carbohydrates and acetylcholine synthesis: implications for cognitive discorders. In: Davis KL, Berger PA (eds) Brain acetylcholine and neuropsychiatric disease. Plenum Press, New York, pp 89–101Google Scholar
  5. Borell J, De Kloet ER, Versteeg DHG, Bohus B (1983) The role of adrenomedullary catecholamines in the modulation of memory by vasopressin. Dev Neurosci 16:85–90Google Scholar
  6. Borson S, Barnes RF, Veith RC, Halter JB, Raskind MA (1989) Impaired sympathetic nervous system response to cognitive effort in early Alzheimer's disease. J Gerontol 44:M8–M12Google Scholar
  7. Brioni JD, McGaugh JL (1989) Post-training administration of gabaergic antagonists enhances retention of aversively motivated tasks. Psychopharmacology (in press)Google Scholar
  8. Caldwell DF (1962) Effects of adrenal demedullation on retention of a conditioned avoidance response in the mouse. J Comp Physiol Psychol 55:1079–1081Google Scholar
  9. Carr GD, White NM (1984) The relationship between stereotypy and memory improvement produced by amphetamine. Psychopharmacology 82:203–209Google Scholar
  10. Castellano C (1974) Cocaine, pemoline and amphetanine effects on learning and retention of a discrimination test in mice. Psychopharmacologia 36:67–76Google Scholar
  11. Conner RL, Levine S (1969) The effects of adrenal hormones on the acquisition of signaled avoidance behavior. Horm Behav 1:73–83Google Scholar
  12. Cooper JR, Bloom FE, Roth RH (1986) The biochemical basis of neuropharmacology. Oxford University Press, New YorkGoogle Scholar
  13. Davies P, Maloney AJR (1976) Selective loss of central cholinergic neurons in Alzheimer's disease (Letter). Lancet II:1403Google Scholar
  14. De Almeida MAMR, Kepczinski FP, Izquierdo I (1983) Memory modulation by post-training intraperitoneal, but not intracerebroventricular, administration of ACTH or epinephrine. Behav Neural Biol 39:277–283Google Scholar
  15. Doty B, Doty L (1966) Facilitating effects of amphetamine on avoidance conditioning in relation to age and problem difficulty. Psychopharmacologia 9:234–241Google Scholar
  16. Doty RL, Ferguson-Segall M (1987) Odor detection performance of rats followingd-amphetamine treatment: a signal detection analysis. Psychopharmacology 93:87–93Google Scholar
  17. Ettenberg A, Van Der Kooy D, Le Moal M, Koob GF, Bloom FE (1983) Can aversive properties of (peripherally-injected) vasopressin account for its putative role in memory? Behav Brain Res 7:331–350Google Scholar
  18. Evangelista AM, Izquierdo L (1971) The effect of pre-and post-trial amphetamine injections on avoidance responses in rats. Psychopharmacologia 20:42–47Google Scholar
  19. Fisman M, Gordon B, Feleki V, Helmes E, McDonald T, Dupre J (1988) Metabolic changes in Alzheimer's disease. J Am Geriatr Soc 36:298–300Google Scholar
  20. Fulginitti S, Cancela LM (1983) Effect of naloxone and amphetamine on acquisition and memory consolidation of active avoidance responses in rats. Psychopharmacology, 79:45–48Google Scholar
  21. Gallagher M (1982) Naloxone enhancement of memory processes: effects of other opiate antagonists. Behav Neural Biol 35:375–382Google Scholar
  22. Giurgea C (1976) Piracetam: nootropic pharmacology of neurointegrative activity. Curr Dev Psychopharmacol 3:221–276Google Scholar
  23. Giurgea C, Salama M (1977) Nootropic drugs. Neuropsychopharmacology 1:235–247Google Scholar
  24. Glick SD, Jarvik ME (1969) Impairment byd-amphetamine of delayed matching performance in monkeys. J Pharmacol Exp Ther 169:1–6Google Scholar
  25. Gold PE (1986) Glucose modulation of memory storage processing. Behav Neural Biol 45:342–349Google Scholar
  26. Gold PE, van Buskirk RB (1976) Enhancement and impairment of memory processes with post-trial injections of adrenocorticotrophic hormone. Behav Biol 16:387–400Google Scholar
  27. Gold PE, McGaugh JL (1977) Hormones and memory. In: Miller LH, Sandman CA, Kastin AJ (eds) Neuropeptide influences on the brain and behavior. Raven Press, New York, pp 127–143Google Scholar
  28. Gold PE, Stone WS (1988) Neuroendocrine effects on memory in aged rodents and humans. Neurobiol Aging 9:709–717Google Scholar
  29. Gold PE, Vogt J, Hall JL (1986) Glucose effects on memory behavioral and pharmacological characteristics. Behav Neural Biol 46:145–155Google Scholar
  30. Hall JL, Gold PE (1986) The effects of training, epinephrine, and glucose injection on plasma glucose levels in rats. Behav Neural Biol 46:156–167Google Scholar
  31. Hall JL, Gonder-Frederick L, Vogt J, Chewning WW, Silveira JA, Gold PE (1989) Memory enhancement in aged humans: effects of glucose ingestion. Neuropsychologia (in press)Google Scholar
  32. Heise GA (1987) Facilitation of memory and cognition by drugs. TIPS 8:65–68Google Scholar
  33. Hertz MM, Paulson OB, Barry DI, Christiansen JS, Svendsen PA (1981) Insulin increases glucose transfer across the blood-brain barrier. J Clin Invest 67:597–604Google Scholar
  34. Hoyer S, Oesterreich K, Wager O (1988) Glucose metabolism as the site of the primary abnormality in early onset dementia of Alzheimer's type? J Neurol 235:143–148Google Scholar
  35. Introini-Collison IB, McGaugh JL (1988) Modulation of memory by post-training epinephrine: involvement of cholinergic mechanisms. Psychopharmacology, 94:379–385Google Scholar
  36. Introini I, McGaugh JL, Baratti CM (1985) Pharmacological evidence of a central effect of naltrexone, morphine, and betaendorphin and a peripheral effect of Met-and Leu-enkephalin on retention of an inhibitory response in mice. Behav Neural Biol 44:434–446Google Scholar
  37. Izquierdo I (1979) Effect of naloxone and morphine on various forms of memory in the rat: possible role of endogenous opiate mechanisms in memory consolidation. Psychopharmacology 66:199–203Google Scholar
  38. James DTD (1975) Post-triald-amphetamine sulfate and one-trial learning in mice. J Comp Physiol Psychol 89:626–635Google Scholar
  39. Johnson FN, Waite K (1971) Apparent delayed enhancement of memory following post-trial methylamphetamine HCl. Experientia 27:1316–1317Google Scholar
  40. Koob GF, Dantzer R, Rodriguez F, Bloom FE, Le Moal M (1985) Osmotic stress mimics effects of vasopressin on learned behavior. Nature 315:750–752Google Scholar
  41. Koob GF, Dantzer R, Bluthe R-M, Le Brun C, Bloom FE, Le Moal M (1986) Central injections of arginine vasopressin prolong extinction of active avoidance. Peptides 7:213–218Google Scholar
  42. Kovacs GL, Bohus B, Versteeg DHG (1979) Facilitation of memory consolidation by vasopressin: mediation by terminals of the dorsal noradrenergic bundle? Brain Res 172:73–85Google Scholar
  43. Kyriakis JM, Hausman RE, Peterson SW (1987) Insulin stimulates choline acetyltransferase activity in cultured embryonic chicken retina neurons. Proc Natl Acad Sci USA 84:7463–7467Google Scholar
  44. Le Brun CJ, Rigter H, Martinez JL, Koob GF, Le Moal M, Bloom FE (1984) Antagonism of effects of vasopressin (AVP) on inhibitory avoidance by a vasopressin antagonist peptide [dPtyr-(Me)AVP]. Life Sci 35:1505–1512Google Scholar
  45. Lee MK, Graham SN, Gold PE (1988) Memory enhancement with posttraining intraventricular glucose injections in rats. Behav Neurosci 102:591–595Google Scholar
  46. Le Moal M, Koob GF, Koda LY, Bloom FE, Manning M, Sawyer WH, Rivier J (1981) Vasopressor receptor antagonist prevents behavioral effects of vasopressin. Nature 291:491–493Google Scholar
  47. Levine S, Holiday S (1962) An effect of adrenal demedullation on the acquisition of a conditioned avoidance response. J Comp Physiol Psychol 55:214–216Google Scholar
  48. Liang KC, McGaugh JL (1983) Lesions of the stria terminalis attenuate the enhancing effect of post-training epinephrine on retention of an inhibitory avoidance response. Behav Brain Res 9:49–58Google Scholar
  49. Ljungberg T, Enquist M (1987) Disruptive effects of low doses ofd-amphetamine on the ability of rats to organize behavior into functional sequences. Psychopharmacology 93:146–151Google Scholar
  50. Martinez JL (1986) Memory: drugs and hormones. In: Martinez JL, Kesner RP (eds) Learning and memory: a biological view. Academic Press, Orlando, pp 127–163Google Scholar
  51. Martinez JL, de Graaf JS (1985) Quaternary naloxone enhances acquisition of a discriminated Y-maze escape and a one-way active avoidance task in mice. Psychopharmacology 87:410–413Google Scholar
  52. Martinez JL, Rigter H (1982) Enkephalin actions on avoidance conditioning may be related to adrenal medullary function. Behav Brain Res 6:289–299Google Scholar
  53. Martinez JL, Jensen RA, Messing RB, Vasquez BJ, Soumireu-Mourat B, Geddes D, Liang KC, McGaugh JL (1980a) Central and peripheral actions of amphetamine on memory storage. Brain Res 182:157–166Google Scholar
  54. Martinez JL, Vasquez BJ, Rigter H, Messing RB, Jensen RA, Liang KC, McGaugh JL (1980b) Attenuation of amphetamine-induced enhancement of learning. Brain Res 195:433–443Google Scholar
  55. Martinez JL, Jensen RA, McGaugh JL (1981) Attenuation of experimentally-induced amnesia. Prog Neurobiol 16:155–186Google Scholar
  56. Martinez JL, Ishikawa K, Liang KC, Jensen RA, Bennett C, Sternberg DB, McGaugh JL (1983) 4-OH Amphetamine enhances retention of an active avoidance response in rats and decreases regional brain concentrations of norepinephrine and dopamine. Behav Neurosci 97:969Google Scholar
  57. Martinez JL, Schulteis G, Janak PH, Weinberger SB (1988) Behavioral assessment of forgetting in aged rodents and its relationship to peripheral sympathetic function. Neurobiol Aging 9:697–708Google Scholar
  58. McGaugh JL (1973) Drug facilitation of learning and memory. Ann Rev Pharmacol Toxicol 13:229–241Google Scholar
  59. Meck WH, Church RM, Olton DS (1984) Hippocampus, time, and memory. Behav Neurosci 98:3–12Google Scholar
  60. Meck WH, Church RM, Wenk GL (1986) Arginine vasopressin innoculates against age-related increases in sodium-dependent high affinity choline uptake and discrepancies in the content of temporal memory. Eur J Pharmacol 130:327–331Google Scholar
  61. Messing RB, Jensen RA, Martinez JL Jr, Speihler VR, Vasquez BJ, Soumireu-Mourat B, Liang KC, McGaugh JL (1979) Naloxone enhancement of memory. Behav Neural Biol 27:266–275Google Scholar
  62. Mohs RC, Davis BM, Johns CA, Mathe AA, Greenwald BS, Horvath TB, Davis KL (1985) Oral physostigmine treatment of patients with Alzheimer's disease. Am J Psychiatry 142:28–33Google Scholar
  63. Mondadori C, Petschke F (1987) Do piracetam-like compounds act centrally via peripheral mechanisms? Brain Res 435:310–314Google Scholar
  64. Mondadori C, Classen W, Borkowski J, Ducret T, Buerki H, Schade A (1986) The effects of oxiracetam on learning and memory in animals. Comparison to piracetam. Neuropharmacology 7:27–38Google Scholar
  65. Morilak DC, Fornal C, Jacobs B (1987) Effects of physiological manipulations on locus coeruleus neuronal activity in freely moving cats. III. Gluco-regulating challenge. Brain Res 422:32–39Google Scholar
  66. Moyer KE, Bunnell BN (1959) Effect of adrenal demedullation on an avoidance response in the rat. J Comp Physiol Psychol 62:215–216Google Scholar
  67. Murray CL, Fibiger HC (1986) The effect of pramiracetam (CI-879) on the acquisition of a radial arm maze task. Psychopharmacology 89:378–381Google Scholar
  68. Orsingher OA, Fulginitti S (1971) Effects of alpha-methyl-tyrosine and adrenergic blocking agents on the facilitating action of amphetamine and nicotine on learning in rats. Psychopharmacology 19:213–240Google Scholar
  69. Orsingher OA, Fulginitti S (1973) Influence of peripheral mechanisms on the facilitatory learning action of amphetamine and nicotine. Pharmacology 9:138–144Google Scholar
  70. Piercey MF, Vogelsang GD, Franklin SR, Tang AH (1987) Reversal of scopolamine-induced amnesia and alterations in energy metabolism by the nootropic piracetam: implications regarding identification of brain structures involved in consolidation of memory traces. Brain Res 424:1–9Google Scholar
  71. Pugsley TA, Shih YH, Coughenour L, Stewart SF (1983) Some neurochemical properties of pramiracetam (Cl-879), a new cognition-enhancing agent. Drug Dev Res 3:407–420Google Scholar
  72. Reisberg B, Ferris SH, Anand R, Pervez Mir MA, Geibel V, de Leon MJ, Roberts E (1983) Effects of naloxone in senile dementia: a double-blind trial. N Engl J Med 308:721–722Google Scholar
  73. Riekkinen P, Legros J-J, Senner C, Jolkkonen J, Smitz S, Soininen H (1987) Penetration of DGAVP (Org 5667) across the blood-brain barrier in human subjects. Peptides 8:261–265Google Scholar
  74. Sahgal A (1987) Contrasting effects of vasopressin, desglycinamide-vasopressin and amphetamine on a delayed matching to position in rats. Psychopharmacology 93:243–249Google Scholar
  75. Sansone M, Castellan C, Ammassari-Teule M (1985) Improvement of avoidance acquisition by the nootropic drug oxiracetam in mice. Arch Int Pharmacodyn 275:86–92Google Scholar
  76. Sara SJ (1988) Glucose effects on firing rate of neurons of the locus coeruleus: another attempt to put memory back in the brain. Neurobiol Aging 9:31–33Google Scholar
  77. Sara SJ, Deweer B (1982) Memory retrieval enhanced by amphetamine after a long retention interval. Behav Neural Biol 36:146–160Google Scholar
  78. Sara SJ, Farnett J, Toussaint P (1982) Facilitation of appetitive brightness discrimination learning by lysine vasopressin. Behav Proc 7:157–167Google Scholar
  79. Schindler U, Rush DK, Fielding S (1984) Nootropic drugs: animal models for studying effects on cognition. Drug Dev Res 4:567–576Google Scholar
  80. Serota R, Roberts R, Flexner L (1972) Acetoxycycloheximide-induced transient amnesia: protective effects of adrenergic stimulants. Proc Natl Acad Sci USA 69:340–342Google Scholar
  81. Silva MTA (1974) Extinction of a passive avoidance response in adrenalectomized and demedullated rats. Behav Biol 9:553–567Google Scholar
  82. Sloviter RS, Valiquette G, Abrams GM, Ronk EC, Sollas AL, Paul LA, Neubort S (1989) Selective loss of hippocampal granule cells in the mature rat brain after adrenalectomy. Science 243:535–538Google Scholar
  83. Spignoli G, Pepeu G (1987) Interactions between oxiracetam, aniracetam and scopolamine on behavior and brain acetylcholine. Pharmacol Biochem Behav 27:491–495Google Scholar
  84. Stone WS, Cottrill KL, Gold PE (1987) Glucose and epinephrine attenuation of scopolamine induced increases in locomotor activity in mice. Neurosci Res Commun 1:105–111Google Scholar
  85. Stone WS, Croul CE, Gold PE (1989) Attenuation of scopolamide induced amnesia in mice. Psychopharmacology (in press)Google Scholar
  86. Summers WK, Majovski LV, Marsh GM, Tachiki K, Kling A (1986) Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer's type (Letter). N Engl J Med 316:1605–1609Google Scholar
  87. Tyce GM, Wong KL (1983) Glucose and amino acid metabolism in rat brain during sustained hypoglycemia. Neurochem Res 8:401–415Google Scholar
  88. Vincent G, Verderese A, Gamzu A (1985) The effects of aniracetam (RO 13-5057) on the enhancement and protection of memory. Ann NY Acad Sci 444:489–491Google Scholar
  89. Weldon DA, Wool RS, Teicher MH, Shaywitz BA, Cohen DJ, Anderson GM (1982) Effects of apomorphine on appetitive conditioning in 6-hydroxydopamine treated rat pups. Pharmacol Biochem Behav 17:1281–1284Google Scholar
  90. Wenk GL, Grey CM, Ingram DK, Spangler EL, Olton DS (1989) Retention of maze performance inversely correlates with NMDA receptor number in hippocampus and frontal neocortex in rat. Behav Neurosci (in press)Google Scholar
  91. Wenk GL, Olton DS (1989) Cognitive enhancers: potential strategies and experimental results. Prog Neuropsychopharmacol Biol Psychiatry (in press)Google Scholar
  92. White NM, Messier C (1988) Effects of adrenal demedullation on conditioned emotional response and on the memory impoving action of glucose. Behav Neurosci 102:499–503Google Scholar
  93. Wied D de, van Ree JM (1982) Neuropeptides, mental performance and aging. Life Sci 31:709–719Google Scholar
  94. Wimersma Greidanus TB van, van Ree JM, de Weid D (1983) Vasopressin and memory. Pharmacol Ther 20:437–458Google Scholar
  95. Wolthuis OL (1971) Experiments with UCB 6215, a drug which enhances acquisition in rats: its effects compared with those of metamphetamine. Eur J Pharmacol 16:283–297Google Scholar
  96. Wool RS, Weldon DA, Shaywitz BA, Anderson GM, Cohen DJ, Teicher MH (1987) Amphetamine reverses learning deficits in 6-hydroxydopamine-treated rat pups. Dev Psychobiol 20:219–232Google Scholar
  97. Wurtman RJ, Magil SG, Reinstein DK (1981) Piracetam diminishes hippocampal ACh levels in rats. Life Sci 28:1091–1093Google Scholar
  98. Zhang S, McGaugh JL, Juler RG, Introini-Collison IB (1987) Naloxone and [Met5]enkephalin effects on retention: attenuation by adrenal denervation. Eur J Pharmacol 138:37–44Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • Gary L. Wenk
    • 1
  1. 1.Neuromnemonics Laboratory, Department of PsychologyJohns Hopkins UniversityBaltimoreUSA

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