Psychopharmacology

, Volume 119, Issue 3, pp 282–290 | Cite as

Systemic or intrahippocampal cannabinoid administration impairs spatial memory in rats

  • A. H. Lichtman
  • K. R. Dimen
  • B. R. Martin
Original Investigation

Abstract

The purpose of the present study was to investigate the disruptive effects of cannabinoids on working memory as assessed in the eight-arm radial-maze. Systemic administration of Δ9-THC, WIN-55,212-2, and CP-55,940 increased the number of errors committed in the radial-maze. CP-55,940 was the most potent cannabinoid in impairing memory (ED50=0.13 mg/kg). Δ9-THC and WIN-55,212-2 disrupted mazechoice accuracy at equipotent doses (ED50 values =2.1 and 2.2 mg/kg, respectively). In addition, systemic administration of each of these agents retarded completion time. Whereas the doses of Δ9-THC and CP-55,940 required to retard maze performance were higher than those needed to increase error numbers, WIN-55,212-2 was equipotent in both of these measures. On the other hand, neither anandamide, the putative endogenous cannabinoid ligand, nor cannabidiol, an inactive naturally occurring cannabinoid, had any apparent effects on memory. A second aim of this study was to elucidate the neuroanatomical substrates mediating the disruptive effects of cannabinoids on memory. Intrahippocampal injections of CP-55,940 impaired maze performance in a dose-dependent manner (ED50=8 µg/rat), but did not retard the amount of time required to complete the maze. The effects of intrahippocampal CP-55,940 were apparently specific to cognition because no other cannabinoid pharmacological effects (e.g., antinociception, hypothermia, and catalepsy) were detected. This dissociation between choice accuracy in the radial-maze and other cannabinoid pharmacological effects suggests that the working memory deficits produced by cannabinoids may be mediated by cannabinoid receptors in the hippocampus.

Key words

Radial-arm maze Δ9-tetrahydrocannabinol (Δ9-THC) CP-55,940 WIN-55,212-2 Anandamide Cannabidiol Hippocampus Antinociception Catalepsy Rectal temperature 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abel EL (1971) Retrieval of information after use of marihuana. Nature 231:58CrossRefPubMedGoogle Scholar
  2. Bloom FE, Young WG, Kim YM (1989) Brain Browser™. Academic Press, San DiegoGoogle Scholar
  3. Carlini EA, Hamaoui A, Bieniek D, Korte F (1970) Effects of (−)Δ9-trans-tetrahydrocannabinol and a synthetic derivative on maze performance of rats. Pharmacology 4:359–368PubMedGoogle Scholar
  4. Compton DR, Little PJ, Martin BR, Gilman JW, Saha JK, Jorapur VS, Sard HP, Razdan RK (1990) Synthesis and pharmacological evaluation of amino, azido, and nitrogen mustard analogues of 10-substituted cannabidiol and 11- or 12-substituted Δ8-tetrahydrocannabinol. J Med Chem 33:1437–1443CrossRefPubMedGoogle Scholar
  5. Compton DR, Gold LH, Ward SJ, Balster RL, Martin BR (1992a) Aminoalkylindole analogs:cannabimimetic activity of a class of compounds structurally distinct from Δ9-tetrahydrocannabinol. J Pharmacol Exp Ther 263:1118–1126PubMedGoogle Scholar
  6. Compton DR, Johnson MR, Melvin LS, Martin BR (1992b) Pharmacological profile of a series of bicyclic cannabinoid analogs—classification as cannabimimetic agents. J Pharmacol Exp Ther 260:201–209PubMedGoogle Scholar
  7. Compton DR, Rice KC, Costa BRD, Razdan RK, Melvin LS, Johnson MR, Martin BR (1993) Cannabinoid structure-activity relationships: correlation of receptor binding and in vivo activities. J Pharmacol Exp Ther 265:218–226PubMedGoogle Scholar
  8. Crawley JN, Corwin RL, Robinson JK, Felder CC, Devane WA, Axelrod J (1993) Anandamide, an endogenous ligand of the cannabinoid receptor, induces hypomotility and hypothermia in vivo in rodents. Pharmacol Biochem Behav 46:967–972CrossRefPubMedGoogle Scholar
  9. D'Amour FE, Smith DL (1941) A method for determining loss of pain sensation. J Pharmacol Exp Ther 72:74–79Google Scholar
  10. Deutsch DG, Chin SA (1993) Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. Biochem Pharmacol 46:791–796CrossRefPubMedGoogle Scholar
  11. Devane WA, Dysarz IFA, Johnson MR, Melvin LS, Howlett AC (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34:605–613PubMedGoogle Scholar
  12. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949PubMedGoogle Scholar
  13. Dewey WL (1986) Cannabinoid pharmacology. Pharmacol Rev 38:151–178PubMedGoogle Scholar
  14. Dewey WL, Harris LS, Howes JF, Nuite JA (1970) The effect of various neurohumoral modulators on the activity of morphine and the narcotic antagonists in the tail-flick and phenylquinone tests. J Pharmacol Exp Ther 175:435–442PubMedGoogle Scholar
  15. Evans (1992) Effects of drugs of abuse on acquisition of behavioral chains in squirrel monkeys. Psychopharmacology 107:55–60CrossRefPubMedGoogle Scholar
  16. Ferraro DP, Grilly DM (1973) Lack of toleance to Δ9-tetrahydrocannabinol in chimpanzees. Science 179:490–492PubMedGoogle Scholar
  17. Fride E, Mechoulam R (1993) Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. Eur J Pharmacol 231:313–314CrossRefPubMedGoogle Scholar
  18. Gold LH, Balster RL, Barrett RL, Britt DT, Martin BR (1992) A comparison of the discriminative stimululs properties of Δ9-THC and CP-55,940 in rats and rhesus monkeys. J Pharmacol Exp Ther 262:479–486PubMedGoogle Scholar
  19. Gralla RJ, Tyson LB, Bordin LA, Clark RA, Kelsen DP, Kris MG, Kalman LB, Groshen S (1984) Antiemetic therapy:a review of recent studies and a report of a random assignment trial comparing metoclopramide with Δ9-tetrahydrocannabinol. Cancer Res Rep 68:163–172Google Scholar
  20. Hanus L, Gopher A, Almog S, Mechoulam R (1993) Two new unsaturated fatty acid ethanolamides in brain that bind to the cannabinoid receptor. J Med Chem 36:3032–3034CrossRefPubMedGoogle Scholar
  21. Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC (1991) Characterization and localization of cannabinoid receptors in rat brain: A quantative in vitro autoradiographic study. J Neurosci 11:563–583PubMedGoogle Scholar
  22. Heyser CJ, Hampson RE, Deadwyler SA (1993) Effects of delta-9-tetrahydrocannabinol on delayed match to sample performance in rats:alterations in short-term memory associated with changes in task specific firing of hippocampal cells. J Pharmacol Exp Ther 264:294–307PubMedGoogle Scholar
  23. Howlett AC, Fleming RM (1984) Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. Mol Pharmacol 26:532–538PubMedGoogle Scholar
  24. Jansen EM, Haycock DA, Ward SJ, Seybold VS (1992) Distribution of cannabinoid receptors in rat brain determined with aminoalkylindoles. Brain Res 575:93–102CrossRefPubMedGoogle Scholar
  25. Jarbe TU, Hiltunen AJ, Lander N, Mechoulam R (1986) Cannabimimetic activity (delta 1-THC cue) of cannabidiol monomethyl ether and two stereoisomeric hexahydrocannabinols in rats and pigeons. Pharmacol Biochem Behav 25:393–399CrossRefPubMedGoogle Scholar
  26. Levin ED (1988) Psychopharmacological effects in the radial-arm maze. Neurosci Biobehav Rev 12:168–175CrossRefGoogle Scholar
  27. Litchfield JT, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments J Pharmacol Exp Ther 96:99–113Google Scholar
  28. Mailleux P, Verslijpe M, Vanderhaeghen JJ (1992) Initial observations on the distribution of cannabinoid receptor binding sites in the human adult basal ganglia using autoradiography. Neurosci Lett 139:7–9CrossRefPubMedGoogle Scholar
  29. Margulies JE, Hammer RP (1991) Δ9-tetrahydrocannabinol alters cerebral metabolism in a biphasic, dose-dependent manner in rat brain. Eur J Pharmacol 202:373–378CrossRefPubMedGoogle Scholar
  30. Martin AR, Consroe P, Kane VV, Shah V, Singh V, Lander N, Mechoulam R, Srebnik M (1987) Structure-anticonvulsant activity relationships of cannabidiol analogs. In:Rapaka RA, Makriyannis A (eds) Structure-activity relationships of the cannabinoids. NIDA Res Monogr pp 48–58Google Scholar
  31. Martin BR (1986) Cellular effects of cannabinoids. Pharmacol Rev 38:45–74PubMedGoogle Scholar
  32. Martin BR, Prescott WR, Zhu M (1992) Quantitation of rodent catalepsy by a computer-imaging technique. Pharmacol Biochem Behav 43:381–386CrossRefPubMedGoogle Scholar
  33. McGurk SR, Levin ED, Butcher LL (1991) Impairment of radialarm maze performance in rats following lesions involving the cholinergic medial pathway:reversal by arecoline and differential effecs of muscarinic and nicotinic antagonists. Neuroscience 44:137–147CrossRefPubMedGoogle Scholar
  34. McLamb RL, Mundy WR, Tilson HA (1988) Intradentate colchicine disrupts the acquisition and performance of a working memory task in the radial-arm maze. Neurotoxicology 9:521–528PubMedGoogle Scholar
  35. McLaughlin MA, Chiou GC (1985) A synopsis of recent developments in antiglaucoma drugs. J Ocul Pharmacol 1:101–121PubMedGoogle Scholar
  36. Murray CL, Fibiger BC (1985) Learning and memory defecits after lesions of the nucleus basalis magnocellularis:reversal by physostigmine. Neuroscience 14:1025–1032CrossRefPubMedGoogle Scholar
  37. Nakamura EM, da Silva EA, Concilio GV, Wilkinson DA, Masur J (1991) Reversible effects of acute and long-term administration of Δ9-tetrahydrocannabinol (THC) on memory in the rat. Drug Alcohol Depend 28:167–175CrossRefPubMedGoogle Scholar
  38. Norwicky AV, Teyler TJ (1987) The modulation of long-term potentiation by delta-9-tetrahydrocannabinol in the rat hippocampus, in vitro. Brain Res Bull 19:663–672CrossRefPubMedGoogle Scholar
  39. Noyes JR, Brunk SF, Avery DH, Canter A (1975) The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther 18:84–89PubMedGoogle Scholar
  40. Olton DS (1987) The radial arm maze as a tool in behavioral pharmacology. Physiol Behav 40:793–797CrossRefPubMedGoogle Scholar
  41. Olton DS, Werz MA (1978) Hippocampal function and behavior:spatial discrimination and response inhibition. Physiol Behav 20:597–605CrossRefPubMedGoogle Scholar
  42. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinatesGoogle Scholar
  43. Pertwee RG (1972) The ring test:a quantitative method for assessing the “cataleptic” effect of cannabis in mice. Br J Pharmacol 46:753–763PubMedGoogle Scholar
  44. Scallet AC, Uemura E, Andrews A, Ali SF, McMillan DE, Paule MG, Brown RM, Slikker W (1987) Morphometric studies of the rat hippocampus following chronic delta-9-tetrahydrocannabinol (THC). Brain Res 436:193–198CrossRefPubMedGoogle Scholar
  45. Siegel S (1956) Nonparametric statistics for the behavioral sciences 159–166Google Scholar
  46. Tallarida RJ, Murray RB (1987) Graded dose-response. Manual of Pharmacologic Calculations 26–31Google Scholar
  47. Thomas BF, Compton DR, Martin BR, Semus SF (1991) Modeling the cannabinoid receptor:a three-dimensional quantitative structure-activity analysis. Mol Pharmacol 40:656–665PubMedGoogle Scholar
  48. Thomas BF, Wei X, Martin BR (1992) Characterization and autoradiographic localization of the cannabinoid binding site in rat brain using [3H]11-OH-Δ9-THC-DMH. J Pharmacol Exp Ther 263:1383–1390PubMedGoogle Scholar
  49. Tilson HA, McLamb RL, Shaw S, Rogers BC, Pediatitakis P, Cook L (1988) Radial-arm maze defecitis produced by colchisine administered into the area of the nucleus basalis are ameliorated by cholinergic agents. Brain Res 438:83–94Google Scholar
  50. Vogel Z, Berg J, Levy R, Saya D, Heldman E, Mechoulam R (1993) Anandamide, a brain endogenous compound, interacts specifically with cannabinoid receptors and inhibits adenylate cyclase. J Neurochem 61:352–355PubMedGoogle Scholar
  51. Winer BJ (1971) Choice of scale and transformations. In:(eds.) Statistical principles in experimental design. McGraw-Hill, NY, pp 397–402Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • A. H. Lichtman
    • 1
  • K. R. Dimen
    • 1
  • B. R. Martin
    • 1
  1. 1.Department of Pharmacology and Toxicology MCV StationMedical College of Virginia/Virginia Commonwealth UniversityRichmondUSA

Personalised recommendations