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Cannabinoid Interaction with Brain Reward Systems

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Marihuana and Medicine

Abstract

With few exceptions, addicting drugs enhance electrical brain-stimulation reward and act as direct or indirect dopamine agonists in the reward-relevant dopaminergic projections of the medial forebrain bundle. These dopaminergic projections constitute a crucial drug-sensitive link in the brain’s reward circuitry, and addictive drugs derive significant abuse liability from enhancing these circuits. Furthermore, basal aberrations in dopaminergic function within these circuits appear to constitute a major neurobiological vulnerability factor for drug addiction. Marihuana was long considered an “anomalous” addictive drug, lacking pharmacological interaction with these brain reward substrates. However, it is now clear—from more than 10 years of consistent research findings—that ∆9-tetrahydrocannabinol (THC), marihuana’s principal psychoactive constituent, acts on these brain reward substrates in strikingly similar fashion to noncannabinoid addictive drugs. Specifically, THC enhances MFB electrical brain-stimulation reward, and enhances both basal and stimulated dopamine release in reward-relevant MFB projection loci. THC’s actions on these mechanisms is tetrodotoxin-sensitive, calcium-dependent, and naloxone-blockable. Furthermore, THC modulates brain t and S opioid receptors. Also, withdrawal from THC produces neurophysiological and neurochemical sequelae that are strikingly similar to those seen in withdrawal from other addictive drugs. Mechanistically, THC appears to act on brain reward substrates by inhibiting the reuptake of dopamine from the synaptic cleft in reward-relevant synapses of the nucleus accumbens. Behaviorally, THC enhances reward-related behaviors and incentive motivation. This paper reviews these data, and suggests that marihuana’s interaction with brain reward systems is fundamentally similar to that of other addictive drugs. This paper concludes that persistent claims that cannabinoids do not interact with brain reward mechanisms must be dismissed—on the basis of more than 10 years of consistent published findings—as either uninformed or biased pleadings.

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References

  1. Gardner, E. L. (1997) Brain reward mechanisms. In Substance Abuse: A Comprehensive Textbook, 3rd ed. ( Lowinson, J. H., Ruiz, P., Millman, R. B. and Langrod, J. G., eds.), Williams and Wilkins, Baltimore, MD, pp. 51–85.

    Google Scholar 

  2. Gardner, E. L. and Lowinson, J. H. (1993) Drug craving and positive/negative hedonic brain substrates activated by addicting drugs. Sem. Neurosci. 5, 359–368.

    CAS  Google Scholar 

  3. Di Chiara, G. (1995) The role of dopamine in drug abuse viewed from the perspective of its role in motivation. Drug Alc. Depend. 38, 95–137.

    Google Scholar 

  4. Schultz, W., Dayan, P. and Montague, P. R. (1997) A neural substrate of prediction and reward. Science 275, 1593–1599.

    PubMed  CAS  Google Scholar 

  5. Wickelgren, I. (1997) Getting the brain’s attention. Science 278, 35–37.

    PubMed  CAS  Google Scholar 

  6. Kornetsky, C. and Bain, G. (1992) Brain-stimulation reward: a model for the study of the rewarding effects of abused drugs. Natl. Inst. Drug Abuse Res. Monogr. Ser. 124, 73–93.

    CAS  Google Scholar 

  7. Kornetsky, C. and Duvauchelle, C. (1994) Dopamine, a common substrate for the rewarding effects of brain stimulation reward, cocaine, and morphine. Natl. Inst. Drug Abuse Res. Monogr. Ser. 145, 19–39.

    CAS  Google Scholar 

  8. Shizgal, P. (1997) Neural basis of utility estimation. Curr. Opinion Neurobiol. 7, 198–208.

    CAS  Google Scholar 

  9. Wise, R. A. (1996) Addictive drugs and brain stimulation reward. Annu. Rev. Neurosci. 19 319–340.

    Google Scholar 

  10. Goldstein, A. (1994) Addiction: From Biology to Drug Policy. W. H. Freeman, New York.

    Google Scholar 

  11. Nestler, E. J. (1993) Molecular mechanisms of drug addiction in the mesolimbic dopamine pathway. Sem. Neurosci. 5, 369–376.

    CAS  Google Scholar 

  12. Self, D. W. and Nestler, E. J. (1995) Molecular mechanisms of drug reinforcement and addiction. Annu. Rev. Neurosci. 18, 463–495.

    PubMed  CAS  Google Scholar 

  13. Blum, K., Cull, J. G., Braverman, E. R. and Comings, D. E. (1996) Reward deficiency syndrome. Amer. Scientist 84, 132–145.

    Google Scholar 

  14. Koob, G. F. and Le Moal, M. (1997) Drug abuse: hedonic homeostatic dysregulation. Science 278, 52–58.

    PubMed  CAS  Google Scholar 

  15. Kozel, N. J. and Adams, E. H. (1986) Epidemiology of drug abuse: an overview. Science 234, 970–974.

    PubMed  CAS  Google Scholar 

  16. Goldstein, A. and Kalant, H. (1990) Drug policy: striking the right balance. Science 249, 1513–152.

    PubMed  CAS  Google Scholar 

  17. MacCoun, R. and Reuter, P. (1997) Interpreting Dutch cannabis policy: reasoning by analogy in the legalization debate. Science 278, 47–52.

    PubMed  CAS  Google Scholar 

  18. Kleber, H. D. (1988) Introduction—cocaine abuse: historical, epidemiological, and psychological perspectives. J. Clin. Psychiat. 49 (suppl), 3–6.

    Google Scholar 

  19. Crowley, T. J., Macdonald, M. J., Whitmore, E. A. and Mikulich, S. K. (1998) Cannabis dependence, withdrawal, and reinforcing effects among adolescents with conduct symptoms and substance use disorders. Drug Alc. Depend. 50, 27–37.

    CAS  Google Scholar 

  20. Anthony, J. C., Warner, L. A. and Kessler, R. C. (1994) Comparative epidemiology of dependence on tobacco, alcohol, controlled substances and inhalants: basic findings from National Comorbidity Study. Exp. Clin. Psychopharmacol. 2, 244–268.

    Google Scholar 

  21. Hall, W., Solowij, N. and Lemon, J. (1994) The Health and Psychological Consequences of Cannabis Use (National Drug Strategy Monograph Series No. 25 ). Australian Government Publishing Service, Canberra.

    Google Scholar 

  22. Felder, C. C. and Glass, M. (1998) Cannabinoid receptors and their endogenous agonists. Annu. Rev. Pharmacol Toxicol. 38, 179–200.

    PubMed  CAS  Google Scholar 

  23. Gardner, E. L., Paredes, W., Smith, D., Donner, A., Milling, C., Cohen, D. and Morrison, D. (1988) Facilitation of brain stimulation reward by 49-tetrahydrocannabinol. Psychopharmacology 96, 142–144.

    PubMed  CAS  Google Scholar 

  24. Gardner, E. L. and Lowinson, J. H. (1991) Marijuana’s interaction with brain reward systems: update 1991. Pharmacol. Biochem. Behay. 40, 571–580.

    CAS  Google Scholar 

  25. Gardner, E. L. (1992) Cannabinoid interaction with brain reward systems-the neurobiological basis of cannabinoid abuse. In: Marijuana/Cannabinoids: Neurobiology and Neurophysiology ( Murphy, L. L., Bartke, A., eds), CRC Press, New York, pp. 275–335.

    Google Scholar 

  26. Gardner, E. L., Liu, X., Paredes, W., Savage, V., Lowinson, J. and Lepore, M. (1995) Strain-specific differences in A9-tetrahydrocannabinol (THC)-induced facilitation of electrical brain stimulation reward (BSR). Soc. Neurosci. Abstr. 21, 177.

    Google Scholar 

  27. Lepore, M., Liu, X., Savage, V., Matalon, D. and Gardner, E. L. (1996) Genetic differences in A9-tetrahydrocannabinol-induced facilitation of brain stimulation reward as measured by a rate-frequency curve-shift electrical brain stimulation paradigm in three different rat strains. Life Sci. (Pharmacol. Lett.) 58, PL365–PL372.

    Google Scholar 

  28. Ng Cheong Ton, J. M. and Gardner, E. L. (1986) Effects of delta-9-tetrahydrocannabinol on dopamine release in the brain: intracranial dialysis experiments. Soc. Neurosci. Abstr. 12, 135.

    Google Scholar 

  29. Ng Cheong Ton, J. M., Gerhardt, G. A., Friedemann, M., Etgen, A. M., Rose, G. M., Sharpless, N. S. and Gardner, E. L. (1988) The effects of A9-tetrahydrocannabinol on potassium-evoked release of dopamine in the rat caudate nucleus: an in vivo electrochemical and in vivo microdialysis study. Brain Res. 451, 59–68.

    PubMed  CAS  Google Scholar 

  30. Chen, J., Paredes, W., Li, J., Smith, D. and Gardner, E. L. (1989) In vivo brain microdialysis studies of A9tetrahydrocannabinol on presynaptic dopamine efflux in nucleus accumbens of the Lewis rat. Soc. Neurosci. Abstr. 15, 10–96.

    Google Scholar 

  31. Chen, J., Paredes, W., Lowinson, J. H. and Gardner, E. L. (1990) 49-Tetrahydrocannabinol enhances presynaptic dopamine efflux in medial prefrontal cortex. Eur. J. Pharmacol. 190, 259–262.

    Google Scholar 

  32. Chen, J., Paredes, W., Li, J., Smith, D., Lowinson, J. and Gardner, E. L. (1990) 6,9- Tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis. Psychopharmacology 102, 156–162.

    Google Scholar 

  33. Taylor, D. A., Sitaram, B. R. and Elliot-Baker, S. (1988) Effect of A-9-tetrahydrocannabinol on release of dopamine in the corpus striatum of the rat. In: Marijuana: An International Research Report ( Chesher, G., Consroe, R. and Musty, R., eds.), Australian Government Publishing Service, Canberra, pp. 405–408.

    Google Scholar 

  34. Tanda, G., Pontieri, F. E. and Di Chiara, G. (1997) Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common µl opioid receptor mechanism. Science 276, 2048–2050.

    PubMed  CAS  Google Scholar 

  35. Pontieri, F. E., Tanda, G. and Di Chiara, G. (1995) Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the “shell” as compared with the “core” of the rat nucleus accumbens. Proc. Natl. Acad. Sci. USA 92, 12304–12308.

    PubMed  CAS  Google Scholar 

  36. Johnson, R. I., Goodman, J. B., Condon, R. and Stellar, J. R. (1995) Reward shifts and motor responses following microinjections of opiate-specific agonists into either the core or shell of the nucleus accumbens. Psychopharmacology 120, 195–202.

    PubMed  CAS  Google Scholar 

  37. Carlezon, W. A. Jr. and Wise, R. A. (1996) Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex. J. Neurosci. 16, 3112–3122.

    PubMed  CAS  Google Scholar 

  38. Carlezon, W. A. Jr. and Wise, R. A. (1996) Microinjections of phencyclidine (PCP) and related drugs into nucleus accumbens shell potentiate medial forebrain bundle brain stimulation reward. Psychopharmacology 128, 413–420.

    PubMed  CAS  Google Scholar 

  39. Castaneda, E., Moss, D. E., Oddie, S. D. and Whishaw, I. Q. (1991) THC does not affect striatal dopamine release: microdialysis in freely moving rats. Pharmacol. Biochem. Behay. 40, 587–591.

    CAS  Google Scholar 

  40. Gysling, K. and Wang, R. Y. (1983) Morphine-induced activation of A10 dopamine neurons in the rat. Brain Res. 277, 119–127.

    PubMed  CAS  Google Scholar 

  41. Grenhoff, J., Aston-Jones, G., Svensson, T. H. (1986) Nicotinic effects on the firing pattern of midbrain dopamine neurons. Acta Physiol. Scand. 128, 351–358.

    PubMed  CAS  Google Scholar 

  42. Gifford, A. N., Gardner, E. L. and Ashby, C. R. Jr. (1997) The effect of intravenous administration of delta9-tetrahydrocannabinol on the activity of A10 dopamine neurons recorded in vivo in anesthetized rats. Neuropsychobiology 36, 96–99.

    PubMed  CAS  Google Scholar 

  43. French, E. D. (1997) A9-Tetrahydrocannabinol excites rat VTA dopamine neurons through activation of cannabinoid CB 1 but not opioid receptors. Neurosci. Lett. 226, 159–162.

    PubMed  CAS  Google Scholar 

  44. Rosenkrantz, H., Sprague, R. A., Fleischman, R. W. and Braude, M. C. (1975) Oral A9-tetrahydrocannabinol toxicity in rats treated for periods up to six months. Toxicol. Appl. Pharmacol. 32, 399–417.

    CAS  Google Scholar 

  45. Cannon, D. S. and Carrell, L. E. (1987) Rat strain differences in ethanol self-administration and taste aversion. Pharmacol. Biochem. Behay. 28, 57–63.

    CAS  Google Scholar 

  46. George, F. R. (1987) Genetic and environmental factors in ethanol self-administration. Pharmacol. Biochem. Behay. 27, 379–384.

    CAS  Google Scholar 

  47. Suzuki, T., George, F. R. and Meisch, R. A. (1988) Differential establishment and maintenance of oral ethanol reinforced behavior in Lewis and Fischer 344 inbred rat strains. J. Pharmacol. Exp. Ther. 245, 164–170.

    PubMed  CAS  Google Scholar 

  48. George, F. R. and Goldberg, S. R. (1989) Genetic approaches to the analysis of addiction processes. Trends Pharmacol. Sci. 10, 78–83.

    PubMed  CAS  Google Scholar 

  49. Guitart, X., Beitner-Johnson, D., Marby, D. W., Kosten, T. A. and Nestler, E. J. (1992) Fischer and Lewis rat strains differ in basal levels of neurofilament proteins and their regulation by chronic morphine in the mesolimbic dopamine system. Synapse 12, 242–253.

    PubMed  CAS  Google Scholar 

  50. Kosten, T. A., Miserendino, M. J., Chi, S. and Nestler, E. J. (1994) Fischer and Lewis rat strains show differential cocaine effects in conditioned place preference and behavioral sensitization but not in locomotor activity or conditioned taste aversion. J. Phannacol. Exp. Ther. 269, 137–144.

    CAS  Google Scholar 

  51. George, F. R. and Meisch, R. A. (1984) Oral narcotic intake as a reinforcer: genotype x environment interaction. Behan Genetics 14, 603.

    Google Scholar 

  52. Khodzhagel’diev, T. (1986) Formirovanie vlecheniia k nikotinu u myshei linii C57B1/6 i CBA [Development of nicotine preference in C57B 1/6 and CBA mice]. Biull. Eksp. Biol. Med. 101, 48–50.

    PubMed  Google Scholar 

  53. Miserendino, M. J. D., Kosten, T. A., Guitart, X., Chi, S. and Nestler, E. J. (1992) Individual differences in vulnerability to drug addiction: behavioral and biochemical correlates. Soc. Neurosci. Abstr. 18, 1078.

    Google Scholar 

  54. Gardner, E. L., Paredes, W., Smith, D., Seeger, T., Donner, A., Milling, C., Cohen, D. and Morrison, D. (1988) Strain-specific sensitization of brain stimulation reward by A9-tetrahydrocannabinol in laboratory rats. Psychopharmacology 96 (suppl), 365.

    Google Scholar 

  55. Gardner, E. L., Chen, J., Paredes, W., Li, J. and Smith, D. (1989) Strain-specific facilitation of brain stimulation reward by A9-tetrahydrocannabinol in laboratory rats is mirrored by strain-specific facilitation of presynaptic dopamine efflux in nucleus accumbens. Soc. Neurosci. Abstr. 15, 638.

    Google Scholar 

  56. Chen, J., Paredes, W., Lowinson, J. H. and Gardner, E. L. (1991) Strain-specific facilitation of dopamine efflux by A9-tetrahydrocannabinol in the nucleus accumbens of rat: an in vivo microdialysis study. Neurosci. Lett. 129, 136–140.

    PubMed  CAS  Google Scholar 

  57. Gardner, E. L., Paredes, W., Smith, D. and Zukin, R. S. (1989) Facilitation of brain stimulation reward by A9-tetrahydrocannabinol is mediated by an endogenous opioid mechanism. Adv. Biosci. 75, 671–674.

    CAS  Google Scholar 

  58. Gardner, E. L., Chen, J., Paredes, W., Smith, D., Li, J. and Lowinson, J. (1990) Enhancement of presynaptic dopamine efflux in brain by A9-tetrahydrocannabinol is mediated by an endogenous opioid mechanism. In: New Leads in Opioid Research ( van Ree, J. M., Mulder, A. H., Wiegant, V. M. and van Wimersma Greidanus, T. B., eds.), Elsevier Science Publishers, Amsterdam, pp. 243–245.

    Google Scholar 

  59. Bloom, A. S. and Dewey, W. L. (1978) A comparison of some pharmacological actions of morphine and 49tetrahydrocannabinol in the mouse. Psychopharmacology 57, 243–248.

    PubMed  CAS  Google Scholar 

  60. Chen, J., Marmur, R., Pulles, A., Paredes, W. and Gardner, E. L. (1993) Ventral tegmental microinjection of A9-tetrahydrocannabinol enhances ventral tegmental somatodendritic dopamine levels but not forebrain dopamine levels: evidence for local neural action by marijuana’s psychoactive ingredient. Brain Res. 621, 65–70.

    PubMed  CAS  Google Scholar 

  61. Gardner, E. L., Paredes, W. and Chen, J. (1990) Further evidence for A9-tetrahydrocannabinol as a dopamine reuptake blocker: brain microdialysis studies. Soc. Neurosci. Abstr. 16, 1100.

    Google Scholar 

  62. Westerink B. H., Tuntler, J., Damsma, G., Rollema, H. and de Vries, J. B. (1987) The use of tetrodotoxin for the characterization of drug-enhanced dopamine release in conscious rats studied by brain dialysis. Naunyn Schmiedeberg’s Arch. Pharmacol. 336, 502–507.

    PubMed  CAS  Google Scholar 

  63. Shore, P. A., McMillen, B. A., Miller, H. H., Sanghera, M. K., Kiserand, R. S. and German, D. C. (1979) The dopamine neuronal storage system and non-amphetamine psychotogenic stimulants: a model for psychosis. In: Catecholamines: Basic and Clinical Frontiers ( Usdin, E., Kopin, I. J. and Barchas, J., eds.), Pergamon, New York, pp. 722–735.

    Google Scholar 

  64. Chen, J., Paredes, W. and Gardner, E. L. (1994) A9-Tetrahydrocannabinol’s enhancement of nucleus accumbens dopamine resembles that of reuptake blockers rather than releasers-evidence from in vivo microdialysis experiments with 3-methoxytyramine. Natl. Inst. Drug Abuse Res. Monogr. Ser. 141, 312.

    Google Scholar 

  65. Wood, P. L. and Altar, C. A. (1988) Dopamine release in vivo from nigrostriatal, mesolimbic, and mesocortical neurons: utility of 3-methoxytyramine measurements. Pharmacol. Rev. 40, 163–187.

    PubMed  CAS  Google Scholar 

  66. Heal, D. J., Frankland, A. T. J. and Buckett, W. R. (1990) A new and highly sensitive method for measuring 3-methoxytyramine using HPLC with electrochemical detection: studies with drugs which alter dopamine metabolism in the brain. Neuropharmacology 29, 1141–1150.

    PubMed  CAS  Google Scholar 

  67. Banerjee, S. P., Snyder, S. H. and Mechoulam, R. (1975) Cannabinoids: influence on neurotransmitter uptake in rat brain synaptosomes. J. Pharmacol. Exp. Ther. 194, 74–81.

    PubMed  CAS  Google Scholar 

  68. Hershkowitz, M., Szechtman, H. (1979) Pretreatment with Al-tetrahydrocannabinol and psychoactive drugs: effects on uptake of biogenic amines and on behavior. Eur. J. Pharmacol. 59, 267–276.

    PubMed  CAS  Google Scholar 

  69. Poddar, M. K. and Dewey, W. L. (1980) Effects of cannabinoids on catecholamine uptake and release in hypothalamic and striatal synaptosomes. J. Pharmacol. Exp. Ther. 214, 63–67.

    PubMed  CAS  Google Scholar 

  70. Tulunay, F. C., Ayman, I. H., Portoghese, P. S. and Takemori, A. E. (1981) Antagonism by chlornaltrexamine of some effects of 49-tetrahydrocannabinol in rats. Eur. J. Pharmacol. 70, 219–224.

    PubMed  CAS  Google Scholar 

  71. Wilson, R. S. and May, E. L. (1975) Analgesic properties of the tetrahydrocannabinols, their metabolites, and analogs. J. Med. Chem. 18, 700–703.

    PubMed  CAS  Google Scholar 

  72. Bhargava, N. M. (1976) Inhibition of naloxone-induced withdrawal in morphine dependent mice by 1-trans49-tetrahydrocannabinol. Eur. J. Pharmacol. 36, 259–262.

    PubMed  CAS  Google Scholar 

  73. Hine, B., Friedman, E., Torrelio, M. and Gershon, S. (1975) Morphine-dependent rats: blockage of precipitated abstinence by tetrahydrocannabinol. Science 187, 443–445.

    PubMed  CAS  Google Scholar 

  74. Kumar, M. S. and Chen, C. L. (1983) Effect of an acute dose of delta-9-THC on hypothalamic luteinizing hormone releasing hormone and met-enkephalin content and serum levels of testosterone and corticosterone in rats. Subst. Alcohol Actions Misuse 4, 37–43.

    PubMed  CAS  Google Scholar 

  75. Vaysse, P. J. -J., Gardner, E. L. and Zukin, R. S. (1987) Modulation of rat brain opioid receptors by cannabinoids. J. Pharmacol. Exp. Ther. 241, 534–539.

    PubMed  CAS  Google Scholar 

  76. Ali, S. E, Newport, G. D., Scallet, A. C., Gee, K. W., Paule, M. G., Brown, R. M. and Slikker, W. Jr. (1989) Effects of chronic delta-9-tetrahydrocannabinol (THC) administration on neurotransmitter concentrations and receptor binding in the rat brain. Neurotoxicology 10, 491–500.

    PubMed  CAS  Google Scholar 

  77. Kumar, M. S., Patel, V. and Millard, W. J. (1984) Effect of chronic administration of 49-tetra-hydrocannabinol on the endogenous opioid peptide and catecholamine levels in the diencephalon and plasma of the rat. Subst. Alcohol Actions Misuse 5, 201–210.

    PubMed  CAS  Google Scholar 

  78. Kumar, A. M., Solomon, J., Patel, V., Kream, R. M., Drieze, J. M. and Millard, W. J. (1986) Early exposure to 49-tetrahydrocannabinol influences neuroendocrine and reproductive functions in female rats. Neuroendocrinology 44, 260–264.

    PubMed  CAS  Google Scholar 

  79. Kumar, A. M., Haney, M., Becker, T., Thompson, M. L., Kream, R. M., Miczek, K. (1990) Effect of early exposure to 49-tetrahydrocannabinol on the levels of opioid peptides, gonadotropin-releasing hormone and substance P in the adult male rat brain. Brain Res. 525, 78–83.

    PubMed  CAS  Google Scholar 

  80. Schaefer, G. J. and Michael, R. P. (1986) Changes in response rates and reinforcement thresholds for intracranial self-stimulation during morphine withdrawal. Pharmacol. Biochem. Behay. 25, 1263–1269.

    CAS  Google Scholar 

  81. Frank, R. A., Martz, S. and Pommering, T. (1988) The effect of chronic cocaine on self-stimulation train-duration thresholds. Pharmacol. Biochem. Behay. 29, 755–758.

    CAS  Google Scholar 

  82. Schulteis, G., Markou, A., Gold, L. H., Stinus, L. and Koob, G. F. (1994) Relative sensitivity of multiple indices of opiate withdrawal: a quantitative dose-response analysis. J. Pharmacol. Exp. Ther. 271, 1391–1398.

    PubMed  CAS  Google Scholar 

  83. Wise, R. A. and Munn, E. (1995) Withdrawal from chronic amphetamine elevates baseline intracranial self-stimulation thresholds. Psychopharmacology 117, 130–136.

    PubMed  CAS  Google Scholar 

  84. Parsons, L. H., Smith, A. D. and Justice, J. B. Jr. (1991) Basal extracellular dopamine is decreased in the rat nucleus accumbens during abstinence from chronic cocaine. Synapse 9, 60–65.

    PubMed  CAS  Google Scholar 

  85. Pothos, E., Rada, P., Mark, G. P. and Hoebel, B. G. (1991) Dopamine microdialysis in the nucleus accumbens during acute and chronic morphine, naloxone-precipitated withdrawal and clonidine treatment. Brain Res. 566, 348–350.

    PubMed  CAS  Google Scholar 

  86. Rossetti, Z. L., Hmaidan, Y. and Gessa, G. L. (1992) Marked inhibition of mesolimbic dopamine release: a common feature of ethanol, morphine, cocaine and amphetamine abstinence in rats. Eur. J. Pharmacol. 221, 227–234.

    PubMed  CAS  Google Scholar 

  87. Koob, G. F., Markou, A., Weiss, F. and Schulteis, G. (1993) Opponent process and drug dependence: neuro-biological mechanisms. Sem. Neurosci. 5, 351–358.

    Google Scholar 

  88. Merlo Pich, E., Lorang, M., Yeganeh, M., Rodriguez de Fonseca, F., Raber, J., Koob, G. F. and Weiss, F. (1995) Increase in extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. J. Neurosci. 15, 5439–5447.

    PubMed  CAS  Google Scholar 

  89. Koob, G. F. (1996) Drug addiction: the yin and yang of hedonic homeostasis. Neuron 16, 893–896.

    PubMed  CAS  Google Scholar 

  90. Cador, M., Robbins, T. W. and Everitt, B. J. (1989) Involvement of the amygdala in stimulus-reward associations: interaction with the ventral striatum. Neuroscience 30, 77–86.

    PubMed  CAS  Google Scholar 

  91. Everitt, B. J., Cador, M. and Robbins, T. W. (1989) Interactions between the amygdala and ventral striatum in stimulus-reward associations: studies using a second-order schedule of sexual reinforcement. Neuroscience 30, 63–75.

    PubMed  CAS  Google Scholar 

  92. Gaffan, D. (1992) Amygdala and the memory of reward. In: The Amygdala: Neurobiological Aspects of Emotion ( Aggleton, J. P., ed.), Wiley, New York, pp. 471–483.

    Google Scholar 

  93. Hiroi, N. and White, N. M. (1991) The lateral nucleus of the amygdala mediates expression of the amphetamine conditioned place preference. J. Neurosci. 11, 2107–2116.

    PubMed  CAS  Google Scholar 

  94. White, N. M. and Hiroi, N. (1993) Amphetamine conditioned cue preference and the neurobiology of drug-seeking. Sem. Neurosci. 5, 329–336.

    CAS  Google Scholar 

  95. Gardner, E. L. and Lepore, M. (1996) Withdrawal from a single dose of marijuana elevates baseline brain-stimulation reward thresholds in rats. Paper presented at meetings of the Winter Conference on Brain Research, Aspen, CO, January 1996.

    Google Scholar 

  96. Rodriguez de Fonseca, Carrera, M. R. A., Navarro, M., Koob, G. F., Weiss, F. (1997) Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal. Science 276, 2050–2054.

    Google Scholar 

  97. Elsmore, R. F. and Fletcher, G. V. (1972) A9-Tetrahydrocannabinol: aversive effects in rats at high dosages. Science 175, 911–912.

    PubMed  CAS  Google Scholar 

  98. Kay, J. (1975) Aversive effects of repeated injections of THC in rats. Psychol. Rep. 14, 89–92.

    Google Scholar 

  99. Fischer, G. J. and Vail, B. J. (1980) Preexposure to delta-9-THC blocks THC-induced conditioned taste aversion in rats. Behay. Neural Biol. 30, 191–196.

    CAS  Google Scholar 

  100. Switzman, L., Fishman, B. and Amit, Z. (1981) Pre-exposure effects of morphine, diazepam and 6.9-THC on the formation of conditioned taste aversions. Psychopharmacology 74, 149–157.

    PubMed  CAS  Google Scholar 

  101. Parker, L. A. and Gillies, T. (1995) THC-induced place and taste aversions in Lewis and Sprague-Dawley rats. Behay. Neurosci. 109, 71–78.

    CAS  Google Scholar 

  102. McGregor, I. S., Issakidis, C. N. and Prior, G. (1996) Aversive effects of the synthetic cannabinoid CP 55,940 in rats. Pharmacol. Biochem. Behay. 53, 657–664.

    CAS  Google Scholar 

  103. Reicher, M. and Holman, E. (1977) Location preference and flavor aversion reinforced by amphetamine in rats. Animal Learning Behay. 5, 343–346.

    Google Scholar 

  104. Wise, R. A., Yokel, R. A. and DeWit, H. (1976) Both positive reinforcement and conditioned aversion from amphetamine and from apomorphine in rats. Science 191, 1273–1275.

    PubMed  CAS  Google Scholar 

  105. White, N., Sklar, L. and Amit, Z. (1977) The reinforcing action of morphine and its paradoxical side effect. Psychopharmacology 52, 63–66.

    PubMed  CAS  Google Scholar 

  106. van der Kooy, D. (1987) Place conditioning: a simple and effective method for assessing the motivational properties of drugs. In Methods for Assessing the Reinforcing Properties of Abused Drugs ( Bozarth, M. A., ed), Springer-Verlag, New York, pp. 229–240.

    Google Scholar 

  107. Goett, J. M. and Kay, E. J. (1981) Lithium chloride and delta-9-THC lead to conditioned aversions in the pigeon. Psychopharmacology 72, 215–216.

    PubMed  CAS  Google Scholar 

  108. Sanudo-Pena, M. C., Tsou, K., Delay, E. R., Hohman, A. G., Force, M. and Walker, J. M. (1997) Endogenous cannabinoids as an aversive or counter-rewarding system in the rat. Neurosci. Lett. 223, 125–128.

    PubMed  CAS  Google Scholar 

  109. Lepore, M., Lowinson, J. and Gardner, E. L. (1994) A9-Tetrahydrocannabinol produces conditioned place-preference in laboratory rats. Paper presented at meetings of the International Cannabis Research Society, Esterel, Quebec, July 1994.

    Google Scholar 

  110. Lepore, M., Vorel, S. R., Lowinson, J. and Gardner, E. L. (1995) Conditioned place preference induced by A9-tetrahydrocannabinol: comparison with cocaine, morphine, and food reward. Life Sci. 56, 2073–2080.

    PubMed  CAS  Google Scholar 

  111. Fudala, P. J., Teoh, K. W. and Iwamoto, E. T. (1985) Pharmacologic characterization of nicotine-induced conditioned place preference. Pharmacol. Biochem. Behay. 22, 237–241.

    CAS  Google Scholar 

  112. Jorenby, D. E., Steinpreis, R. E., Sherman, J. E. and Baker, T. B. (1990) Aversion instead of preference learning indicated by nicotine place conditioning in rats. Psychopharmacology 101, 533–538.

    PubMed  CAS  Google Scholar 

  113. Fudala, P. J. and Iwamoto, E. T. (1990) Conditioned aversion after delay place conditioning with amphetamine. Pharmacol. Biochem. Behay. 35, 89–92.

    CAS  Google Scholar 

  114. Noyes, J. R., Brunk, S. F., Avery, D. H. and Canter, A. (1975) The analgesic properties of delta-9 -tetrahydrocannabinol and codeine. Clin. Pharmacol. Ther. 18, 84–89.

    PubMed  Google Scholar 

  115. Raft, D., Gregg, J., Ghia, J. and Harris, L. (1977) Effects of intravenous tetrahydrocannabinol on experimental and surgical pain. Psychological correlate of the analgesic response. Clin. Pharmacol. Ther. 21, 26–33.

    PubMed  CAS  Google Scholar 

  116. Laszlo, J., Lucas, V. S., Hanson, D. C., Cronin, C. M., Sallan, S. E. (1981) Levonantradol for chemotherapy-induced emesis: phase I-II oral administration. J. Clin. Pharmacol. 21, 51S - 56S.

    PubMed  CAS  Google Scholar 

  117. Rubio, P., Rodriguez de Fonseca, F., Munoz, R. M., Ariznavarreta, C., Martin-Calderón, J. L. and Navarro, M. (1995) Long-term behavioral effects of perinatal exposure to A9-tetrahydrocannabinol in rats: possible role of pituitary-adrenal axis. Life Sci. 56, 2169–2176.

    PubMed  CAS  Google Scholar 

  118. Sofia, R. D. and Knoblock, L. C. (1976) Comparative effects of various naturally occurring cannabinoids on food, sucrose and water consumption by rats. Pharmacol. Biochem. Behay. 4, 591–599.

    Google Scholar 

  119. Brown, J. E., Kassouny, M. and Cross, J. K. (1977) Kinetic studies of food intake and sucrose solution preference by rats treated with low doses of delta-9-tetrahydrocannabinol. Behay. Biol. 20, 104–110.

    CAS  Google Scholar 

  120. Milano, W. C., Wild, K. D., Hui, Y. Z., Hubbell, C. L. and Reid, L. D. (1988) PCP, THC, ethanol, and morphine and consumption of palatable solutions. Pharmacol. Biochem. Behay. 31, 893–897.

    CAS  Google Scholar 

  121. McGregor, I. S., Saharov, T., Dielenberg, R. A., Arnold, J. C., Booker, S. L. and Topple, A. N. (1997) The effects of cannabinoids on beer and sucrose consumption in rats. Paper presented at meetings of the International Cannabinoid Research Society, Stone Mountain, Georgia June 1997.

    Google Scholar 

  122. Arnone, M., Maruani, J., Chaperon, F., Thiébot, M.-H., Poncelot, M., Soubrié, P. and Le Fur. G. (1997) Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CBI) receptors. Psychopharmacology 132, 104–106.

    PubMed  CAS  Google Scholar 

  123. Kaymakçalan, S. (1972) Physiology and psychological dependence on THC in Rhesus monkeys. In Cannabis and its Derivatives (Paton, W.D.M. and Crown, J., eds.), Oxford Univ. Press, London, pp. 142–149.

    Google Scholar 

  124. Corcoran, M. E. and Amit, Z. (1974) Reluctance of rats to drink hashish suspensions: free-choice and forced consumption, and the effects of hypothalamic stimulation. Psychopharmacologia 35, 129–147.

    PubMed  CAS  Google Scholar 

  125. Leite, J. R. and Carlini, E. A. (1974) Failure to obtain “cannabis directed behavior” and abstinence syndrome in rats chronically treated with cannabis sativa extracts. Psychopharmacologia 36, 133–145.

    PubMed  CAS  Google Scholar 

  126. Harris, R. T., Waters, W. and McLendon, D. (1974) Evaluation of reinforcing capability of 49-tetrahydrocannabinol in monkeys. Psychopharmacologia 37, 23–29.

    PubMed  CAS  Google Scholar 

  127. Carney, J. M., Uwaydah, I. M. and Balster, R. L. (1977) Evaluation of a suspension system for intravenous self-administration of water insoluble substances in the rhesus monkey. Pharmacol. Biochem. Behay. 7, 357–364.

    CAS  Google Scholar 

  128. Takahashi, R. N. and Singer, G. (1981) Cross self-administration of delta 9-tetrahydrocannabinol and D-amphetamine in rats. Braz. J. Med. Biol. Res. 14, 395–400.

    PubMed  CAS  Google Scholar 

  129. Pickens, R., Thompson, T. and Muchow, D. C. (1973) Cannabis and phencyclidine self-administered by animals In• Psychic Dependence (Bayer-Symposium IV] (Goldfarb, L. and Hoffmeister, F., eds.), Springer-Verlag, Berlin, pp. 78–86.

    Google Scholar 

  130. Deneau, G. A. and Kaymakçalan, S. (1971) Physiological and psychological dependence to synthetic A9tetrahydrocannabinol (THC) in rhesus monkeys. Pharmacologist 13, 246.

    Google Scholar 

  131. Takahashi, R. N., Singer, G. (1979) Self-administration of A9-tetrahydrocannabinol by rats. Pharmacol. Biochem. Behay. 11, 737–740.

    CAS  Google Scholar 

  132. Takahashi, R. N. and Singer, G. (1980) Effects of body weight levels on cannabis self-administration. Pharmacol. Biochem. Behay. 13, 877–881.

    CAS  Google Scholar 

  133. Onaivi, E. S., Green, M. R. and Martin, B. R. (1990) Pharmacological characterization of cannabinoids in the elevated plus-maze. J. Pharmacol. Exp. Ther. 253, 1002–1009.

    PubMed  CAS  Google Scholar 

  134. Rodriguez de Fonseca, F., Rubio, P., Menzaghi, F., Merlo-Pich, E., Rivier, J., Koob, G. F. and Navarro, M. (1996) Corticotropin-releasing factor (CRF) antagonist [D-Phe12, N1e21,38, CaMeLeu371CRF attenuates the acute actions of the highly potent cannabinoid receptor agonist HU-210 on defensive-withdrawal behavior in rats. J. Pharmacol. Exp. Ther. 276, 56–64.

    PubMed  CAS  Google Scholar 

  135. Fratta, W., Martellotta, M. C., Cossu, G. and Fattore, L. (1997) WIN 55, 212–2 induces intravenous self-administration in drug-naive mice. Soc. Neurosci. Abstr. 23, 1869.

    Google Scholar 

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  1. Eliot L. Gardner
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Editors and Affiliations

  1. Department of Anesthesiology, New York University School of Medicine, USA

    Gabriel G. Nahas MD, PhD, DSc  & Kenneth M. Sutin MD, MS  & 

  2. Department of Biochemistry, Oxford University, USA

    David Harvey PhD

  3. Faculty of Pharmacy, University of Uppsala, Sweden

    Stig Agurell PhD, PharmD, DSc

  4. NYU School of Medicine, USA

    Nicholas Pace MD  & Robert Cancro MD  & 

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Gardner, E.L. (1999). Cannabinoid Interaction with Brain Reward Systems. In: Nahas, G.G., Sutin, K.M., Harvey, D., Agurell, S., Pace, N., Cancro, R. (eds) Marihuana and Medicine. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-710-9_19

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  • DOI: https://doi.org/10.1007/978-1-59259-710-9_19

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