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Systemic or intrahippocampal cannabinoid administration impairs spatial memory in rats

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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.

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References

  • Abel EL (1971) Retrieval of information after use of marihuana. Nature 231:58

    Article  PubMed  Google Scholar 

  • Bloom FE, Young WG, Kim YM (1989) Brain Browser™. Academic Press, San Diego

    Google Scholar 

  • Carlini EA, Hamaoui A, Bieniek D, Korte F (1970) Effects of (−)Δ9-trans-tetrahydrocannabinol and a synthetic derivative on maze performance of rats. Pharmacology 4:359–368

    PubMed  Google Scholar 

  • 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 33:1437–1443

    Article  PubMed  Google Scholar 

  • 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 263:1118–1126

    PubMed  Google Scholar 

  • 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 260:201–209

    PubMed  Google Scholar 

  • 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 265:218–226

    PubMed  Google Scholar 

  • 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 46:967–972

    Article  PubMed  Google Scholar 

  • D'Amour FE, Smith DL (1941) A method for determining loss of pain sensation. J Pharmacol Exp Ther 72:74–79

    Google Scholar 

  • Deutsch DG, Chin SA (1993) Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. Biochem Pharmacol 46:791–796

    Article  PubMed  Google Scholar 

  • Devane WA, Dysarz IFA, Johnson MR, Melvin LS, Howlett AC (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34:605–613

    PubMed  Google Scholar 

  • 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 258:1946–1949

    PubMed  Google Scholar 

  • Dewey WL (1986) Cannabinoid pharmacology. Pharmacol Rev 38:151–178

    PubMed  Google Scholar 

  • 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 175:435–442

    PubMed  Google Scholar 

  • Evans (1992) Effects of drugs of abuse on acquisition of behavioral chains in squirrel monkeys. Psychopharmacology 107:55–60

    Article  PubMed  Google Scholar 

  • Ferraro DP, Grilly DM (1973) Lack of toleance to Δ9-tetrahydrocannabinol in chimpanzees. Science 179:490–492

    PubMed  Google Scholar 

  • Fride E, Mechoulam R (1993) Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. Eur J Pharmacol 231:313–314

    Article  PubMed  Google Scholar 

  • 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 262:479–486

    PubMed  Google Scholar 

  • 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 68:163–172

    Google Scholar 

  • 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 36:3032–3034

    Article  PubMed  Google Scholar 

  • 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 11:563–583

    PubMed  Google Scholar 

  • 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 264:294–307

    PubMed  Google Scholar 

  • Howlett AC, Fleming RM (1984) Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. Mol Pharmacol 26:532–538

    PubMed  Google Scholar 

  • Jansen EM, Haycock DA, Ward SJ, Seybold VS (1992) Distribution of cannabinoid receptors in rat brain determined with aminoalkylindoles. Brain Res 575:93–102

    Article  PubMed  Google Scholar 

  • 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 25:393–399

    Article  PubMed  Google Scholar 

  • Levin ED (1988) Psychopharmacological effects in the radial-arm maze. Neurosci Biobehav Rev 12:168–175

    Article  Google Scholar 

  • Litchfield JT, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments J Pharmacol Exp Ther 96:99–113

    Google Scholar 

  • 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 139:7–9

    Article  PubMed  Google Scholar 

  • Margulies JE, Hammer RP (1991) Δ9-tetrahydrocannabinol alters cerebral metabolism in a biphasic, dose-dependent manner in rat brain. Eur J Pharmacol 202:373–378

    Article  PubMed  Google Scholar 

  • 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 48–58

  • Martin BR (1986) Cellular effects of cannabinoids. Pharmacol Rev 38:45–74

    PubMed  Google Scholar 

  • Martin BR, Prescott WR, Zhu M (1992) Quantitation of rodent catalepsy by a computer-imaging technique. Pharmacol Biochem Behav 43:381–386

    Article  PubMed  Google Scholar 

  • 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 44:137–147

    Article  PubMed  Google Scholar 

  • 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 9:521–528

    PubMed  Google Scholar 

  • McLaughlin MA, Chiou GC (1985) A synopsis of recent developments in antiglaucoma drugs. J Ocul Pharmacol 1:101–121

    PubMed  Google Scholar 

  • Murray CL, Fibiger BC (1985) Learning and memory defecits after lesions of the nucleus basalis magnocellularis:reversal by physostigmine. Neuroscience 14:1025–1032

    Article  PubMed  Google Scholar 

  • 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 28:167–175

    Article  PubMed  Google Scholar 

  • Norwicky AV, Teyler TJ (1987) The modulation of long-term potentiation by delta-9-tetrahydrocannabinol in the rat hippocampus, in vitro. Brain Res Bull 19:663–672

    Article  PubMed  Google Scholar 

  • Noyes JR, Brunk SF, Avery DH, Canter A (1975) The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther 18:84–89

    PubMed  Google Scholar 

  • Olton DS (1987) The radial arm maze as a tool in behavioral pharmacology. Physiol Behav 40:793–797

    Article  PubMed  Google Scholar 

  • Olton DS, Werz MA (1978) Hippocampal function and behavior:spatial discrimination and response inhibition. Physiol Behav 20:597–605

    Article  PubMed  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates

  • Pertwee RG (1972) The ring test:a quantitative method for assessing the “cataleptic” effect of cannabis in mice. Br J Pharmacol 46:753–763

    PubMed  Google Scholar 

  • 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 436:193–198

    Article  PubMed  Google Scholar 

  • Siegel S (1956) Nonparametric statistics for the behavioral sciences 159–166

  • Tallarida RJ, Murray RB (1987) Graded dose-response. Manual of Pharmacologic Calculations 26–31

  • Thomas BF, Compton DR, Martin BR, Semus SF (1991) Modeling the cannabinoid receptor:a three-dimensional quantitative structure-activity analysis. Mol Pharmacol 40:656–665

    PubMed  Google Scholar 

  • 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 263:1383–1390

    PubMed  Google Scholar 

  • 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 438:83–94

    Google Scholar 

  • 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 61:352–355

    PubMed  Google Scholar 

  • Winer BJ (1971) Choice of scale and transformations. In:(eds.) Statistical principles in experimental design. McGraw-Hill, NY, pp 397–402

    Google Scholar 

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  1. Department of Pharmacology and Toxicology MCV Station, Medical College of Virginia/Virginia Commonwealth University, Box 613, 23298, Richmond, VA, USA

    A. H. Lichtman, K. R. Dimen & B. R. Martin

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  1. A. H. Lichtman
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  2. K. R. Dimen
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  3. B. R. Martin
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Lichtman, A.H., Dimen, K.R. & Martin, B.R. Systemic or intrahippocampal cannabinoid administration impairs spatial memory in rats. Psychopharmacology 119, 282–290 (1995). https://doi.org/10.1007/BF02246292

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  • DOI: https://doi.org/10.1007/BF02246292

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