Advertisement

Cannabinoid Interaction with Brain Reward Systems

  • Eliot L. Gardner

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.

Keywords

Nucleus Accumbens Conditioned Place Preference Conditioned Taste Aversion Medial Forebrain Bundle Brain Reward 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 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. 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.Google Scholar
  3. 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. 4.
    Schultz, W., Dayan, P. and Montague, P. R. (1997) A neural substrate of prediction and reward. Science 275, 1593–1599.PubMedGoogle Scholar
  5. 5.
    Wickelgren, I. (1997) Getting the brain’s attention. Science 278, 35–37.PubMedGoogle Scholar
  6. 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.Google Scholar
  7. 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.Google Scholar
  8. 8.
    Shizgal, P. (1997) Neural basis of utility estimation. Curr. Opinion Neurobiol. 7, 198–208.Google Scholar
  9. 9.
    Wise, R. A. (1996) Addictive drugs and brain stimulation reward. Annu. Rev. Neurosci. 19 319–340.Google Scholar
  10. 10.
    Goldstein, A. (1994) Addiction: From Biology to Drug Policy. W. H. Freeman, New York.Google Scholar
  11. 11.
    Nestler, E. J. (1993) Molecular mechanisms of drug addiction in the mesolimbic dopamine pathway. Sem. Neurosci. 5, 369–376.Google Scholar
  12. 12.
    Self, D. W. and Nestler, E. J. (1995) Molecular mechanisms of drug reinforcement and addiction. Annu. Rev. Neurosci. 18, 463–495.PubMedGoogle Scholar
  13. 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. 14.
    Koob, G. F. and Le Moal, M. (1997) Drug abuse: hedonic homeostatic dysregulation. Science 278, 52–58.PubMedGoogle Scholar
  15. 15.
    Kozel, N. J. and Adams, E. H. (1986) Epidemiology of drug abuse: an overview. Science 234, 970–974.PubMedGoogle Scholar
  16. 16.
    Goldstein, A. and Kalant, H. (1990) Drug policy: striking the right balance. Science 249, 1513–152.PubMedGoogle Scholar
  17. 17.
    MacCoun, R. and Reuter, P. (1997) Interpreting Dutch cannabis policy: reasoning by analogy in the legalization debate. Science 278, 47–52.PubMedGoogle Scholar
  18. 18.
    Kleber, H. D. (1988) Introduction—cocaine abuse: historical, epidemiological, and psychological perspectives. J. Clin. Psychiat. 49 (suppl), 3–6.Google Scholar
  19. 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.Google Scholar
  20. 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. 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. 22.
    Felder, C. C. and Glass, M. (1998) Cannabinoid receptors and their endogenous agonists. Annu. Rev. Pharmacol Toxicol. 38, 179–200.PubMedGoogle Scholar
  23. 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.PubMedGoogle Scholar
  24. 24.
    Gardner, E. L. and Lowinson, J. H. (1991) Marijuana’s interaction with brain reward systems: update 1991. Pharmacol. Biochem. Behay. 40, 571–580.Google Scholar
  25. 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. 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. 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. 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. 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.PubMedGoogle Scholar
  30. 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. 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. 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. 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. 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.PubMedGoogle Scholar
  35. 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.PubMedGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. 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.PubMedGoogle Scholar
  38. 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.PubMedGoogle Scholar
  39. 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.Google Scholar
  40. 40.
    Gysling, K. and Wang, R. Y. (1983) Morphine-induced activation of A10 dopamine neurons in the rat. Brain Res. 277, 119–127.PubMedGoogle Scholar
  41. 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.PubMedGoogle Scholar
  42. 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.PubMedGoogle Scholar
  43. 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.PubMedGoogle Scholar
  44. 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.Google Scholar
  45. 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.Google Scholar
  46. 46.
    George, F. R. (1987) Genetic and environmental factors in ethanol self-administration. Pharmacol. Biochem. Behay. 27, 379–384.Google Scholar
  47. 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.PubMedGoogle Scholar
  48. 48.
    George, F. R. and Goldberg, S. R. (1989) Genetic approaches to the analysis of addiction processes. Trends Pharmacol. Sci. 10, 78–83.PubMedGoogle Scholar
  49. 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.PubMedGoogle Scholar
  50. 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.Google Scholar
  51. 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. 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.PubMedGoogle Scholar
  53. 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. 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. 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. 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.PubMedGoogle Scholar
  57. 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.Google Scholar
  58. 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. 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.PubMedGoogle Scholar
  60. 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.PubMedGoogle Scholar
  61. 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. 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.PubMedGoogle Scholar
  63. 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. 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. 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.PubMedGoogle Scholar
  66. 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.PubMedGoogle Scholar
  67. 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.PubMedGoogle Scholar
  68. 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.PubMedGoogle Scholar
  69. 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.PubMedGoogle Scholar
  70. 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.PubMedGoogle Scholar
  71. 71.
    Wilson, R. S. and May, E. L. (1975) Analgesic properties of the tetrahydrocannabinols, their metabolites, and analogs. J. Med. Chem. 18, 700–703.PubMedGoogle Scholar
  72. 72.
    Bhargava, N. M. (1976) Inhibition of naloxone-induced withdrawal in morphine dependent mice by 1-trans49-tetrahydrocannabinol. Eur. J. Pharmacol. 36, 259–262.PubMedGoogle Scholar
  73. 73.
    Hine, B., Friedman, E., Torrelio, M. and Gershon, S. (1975) Morphine-dependent rats: blockage of precipitated abstinence by tetrahydrocannabinol. Science 187, 443–445.PubMedGoogle Scholar
  74. 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.PubMedGoogle Scholar
  75. 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.PubMedGoogle Scholar
  76. 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.PubMedGoogle Scholar
  77. 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.PubMedGoogle Scholar
  78. 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.PubMedGoogle Scholar
  79. 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.PubMedGoogle Scholar
  80. 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.Google Scholar
  81. 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.Google Scholar
  82. 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.PubMedGoogle Scholar
  83. 83.
    Wise, R. A. and Munn, E. (1995) Withdrawal from chronic amphetamine elevates baseline intracranial self-stimulation thresholds. Psychopharmacology 117, 130–136.PubMedGoogle Scholar
  84. 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.PubMedGoogle Scholar
  85. 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.PubMedGoogle Scholar
  86. 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.PubMedGoogle Scholar
  87. 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. 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.PubMedGoogle Scholar
  89. 89.
    Koob, G. F. (1996) Drug addiction: the yin and yang of hedonic homeostasis. Neuron 16, 893–896.PubMedGoogle Scholar
  90. 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.PubMedGoogle Scholar
  91. 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.PubMedGoogle Scholar
  92. 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. 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.PubMedGoogle Scholar
  94. 94.
    White, N. M. and Hiroi, N. (1993) Amphetamine conditioned cue preference and the neurobiology of drug-seeking. Sem. Neurosci. 5, 329–336.Google Scholar
  95. 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. 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. 97.
    Elsmore, R. F. and Fletcher, G. V. (1972) A9-Tetrahydrocannabinol: aversive effects in rats at high dosages. Science 175, 911–912.PubMedGoogle Scholar
  98. 98.
    Kay, J. (1975) Aversive effects of repeated injections of THC in rats. Psychol. Rep. 14, 89–92.Google Scholar
  99. 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.Google Scholar
  100. 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.PubMedGoogle Scholar
  101. 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.Google Scholar
  102. 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.Google Scholar
  103. 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. 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.PubMedGoogle Scholar
  105. 105.
    White, N., Sklar, L. and Amit, Z. (1977) The reinforcing action of morphine and its paradoxical side effect. Psychopharmacology 52, 63–66.PubMedGoogle Scholar
  106. 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. 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.PubMedGoogle Scholar
  108. 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.PubMedGoogle Scholar
  109. 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. 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.PubMedGoogle Scholar
  111. 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.Google Scholar
  112. 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.PubMedGoogle Scholar
  113. 113.
    Fudala, P. J. and Iwamoto, E. T. (1990) Conditioned aversion after delay place conditioning with amphetamine. Pharmacol. Biochem. Behay. 35, 89–92.Google Scholar
  114. 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.PubMedGoogle Scholar
  115. 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.PubMedGoogle Scholar
  116. 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.PubMedGoogle Scholar
  117. 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.PubMedGoogle Scholar
  118. 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. 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.Google Scholar
  120. 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.Google Scholar
  121. 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. 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.PubMedGoogle Scholar
  123. 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. 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.PubMedGoogle Scholar
  125. 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.PubMedGoogle Scholar
  126. 126.
    Harris, R. T., Waters, W. and McLendon, D. (1974) Evaluation of reinforcing capability of 49-tetrahydrocannabinol in monkeys. Psychopharmacologia 37, 23–29.PubMedGoogle Scholar
  127. 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.Google Scholar
  128. 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.PubMedGoogle Scholar
  129. 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. 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. 131.
    Takahashi, R. N., Singer, G. (1979) Self-administration of A9-tetrahydrocannabinol by rats. Pharmacol. Biochem. Behay. 11, 737–740.Google Scholar
  132. 132.
    Takahashi, R. N. and Singer, G. (1980) Effects of body weight levels on cannabis self-administration. Pharmacol. Biochem. Behay. 13, 877–881.Google Scholar
  133. 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.PubMedGoogle Scholar
  134. 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.PubMedGoogle Scholar
  135. 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

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Eliot L. Gardner

There are no affiliations available

Personalised recommendations