Cocaine pp 37-79 | Cite as

The Neurobiology of Cocaine

  • Mark S. Gold
Part of the Drugs of Abuse book series (DOAC, volume 3)


The abuse and addiction potential of cocaine results, at least partly, from its effects on specific neurotransmitter systems of the brain. Recent laboratory research has established that cocaine and other drugs of abuse act directly on the brain’s reward pathways. Although it may seem obvious that the euphoric effects of cocaine enhance the abuse potential of the drug, many attempts at understanding addiction have instead focused on etiologies other than endogenous reward, such as the self-medication theory. According to this theory, cocaine administration is an attempt to correct a major psychiatric problem such as depression. Although it is true that a psychological state like depression may be associated with the drug taking, cocaine itself is not an antidepressant. Furthermore, controlled studies have found that depressed or anxious people do not drink more than nondepressed or nonanxious individuals.1


Ventral Tegmental Area Locus Coeruleus Conditioned Place Preference Cocaine Abuse Medial Forebrain Bundle 
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  1. 1.
    Miller NS, Mahler JC, Belkin BM, Gold MS. Psychiatric diagnosis in alcohol and drug dependence. Ann Clin Psychiatry. 1990; 3(1):79–89.CrossRefGoogle Scholar
  2. 2.
    Grinspoon L, Bakalar JB. Chronic cocaine abuse does not usually appear as a medical problem. In: Kaplan HI, Freedman AM, Sadock BJ, eds. Comprehensive Textbook of Psychiatry. Baltimore, Md: Williams & Wilkins; 1980.Google Scholar
  3. 3.
    Gawin F. Cocaine addiction: psychology and neurophysiology. Science. March 1991; 251:1580–1586.PubMedCrossRefGoogle Scholar
  4. 4.
    Calcagnetti DJ, Schechter MD. Conditioned place aversion following the central administration of a novel dopamine release inhibitor CGS 10746B. Pharmacol Biochem Behav. 1991; 40:255–259.PubMedCrossRefGoogle Scholar
  5. 5.
    Killam KF, Olds J, Sinclair J. Further studies on the effects of centrally acting drugs on self-stimulation. J Pharmacol Exp Ther. 1957; 119:157.Google Scholar
  6. 6.
    Gardner EL, Lowinson JH. Marijuana’s interaction with brain reward systems: update 1991. Pharmacol Biochem Behav. 1991; 40:571–580.PubMedCrossRefGoogle Scholar
  7. 7.
    Crow TJ. A map of the rat mesencephalon for electrical selfstimulation. Brain Res. 1972; 36:265–273.PubMedCrossRefGoogle Scholar
  8. 8.
    Wise RA, Bozarth MA. Brain substrates for reinforcement and drug self-administration. Prog Neuropsychopharmacol. 1981; 5:467–474.PubMedCrossRefGoogle Scholar
  9. 9.
    Wise RA, Rompre PP. Brain dopamine and reward. Annu Rev Psychol. 1989; 40:191–225.PubMedCrossRefGoogle Scholar
  10. 10.
    Dewit H, Wise RA. A blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide but not with the noradrenergic blockers phentolamine or phenoxybenzamine. Can. J. Psychol. 1977; 31:195.Google Scholar
  11. 11.
    Wise RA. Action of drugs of abuse on brain reward systems. Pharmacol Biochem Behav. 1980; 13(suppl. l):213–223.PubMedCrossRefGoogle Scholar
  12. 12.
    Wise RA. The dopamine synapse and the notion of “pleasure centers” in the brain. Trends Neurosci. 1980; 3:91–95.CrossRefGoogle Scholar
  13. 13.
    Dackis CA, Gold MS. Treatment strategies for cocaine detoxification. In: Lakoski JM, Galloway MP, White FJ, eds. Cocaine: Pharmacology, Physiology, and Clinical Strategies. Boca Raton, Fla: CRC Press; 1991.Google Scholar
  14. 14.
    Wise RA. The neurobiology of craving: implications for the understanding and treatment of addiction. J Abnormal Psychol. 1988; 97(2): 118–132.CrossRefGoogle Scholar
  15. 15.
    Miller NS, Gold MS. The relationship of addiction, tolerance, and dependence to alcohol and drugs: a neurochemical approach. J Substance Abuse Treatment. 1987;4:197–207.CrossRefGoogle Scholar
  16. 16.
    Iverson II. The Uptake and Storage of Noradrenaline in Sympathetic Nerves. London: Cambridge University Press; 1967.Google Scholar
  17. 17.
    Javaid J, Fischman MW, Schuster CR, Dekirmenjian H, Davis JM. Cocaine plasma concentrations: relationship to physiological and subjective effects in humans. Science. 1978;202:227–228.PubMedCrossRefGoogle Scholar
  18. 18.
    Resnick R, Schuyten-Resnick E. Clinical aspects of cocaine: assessment of cocaine abuse behavior in man. In: Mule SJ, ed. Cocaine. Boca Raton, Fla: CRC Press; 1977.Google Scholar
  19. 19.
    Denau GA, Yanagita T, Seevers MH. Self-administration of psychoactive substances by the monkey. Psychopharmacologia. 1969;16:30.Google Scholar
  20. 20.
    Pickens RL, Harris WC. Self-administration of d-amphetamine by rats. Psychopharmacologia. 1968;12:158.PubMedCrossRefGoogle Scholar
  21. 21.
    Carroll FI, Lewin AH, Boja JW, Kuhar MJ. Cocaine receptor: biochemical characteristics and structure-activity relationships of cocaine analogues at the dopamine transporter. J Medicinal Chem. 1992;35(6):969–981.CrossRefGoogle Scholar
  22. 22.
    Giros B, Eimestikawy S, Betrand L, Caron MG. Cloning and functional characterization of a cocaine-sensitive dopamine transporter. FEBS Lett. 1991;295(1,2,3):149–154.PubMedCrossRefGoogle Scholar
  23. 23.
    Ramsey NF, van Ree JM. Intracerebroventricular naltrexone treatment attenuates acquisition of intravenous cocaine self-administration in rats. Pharmacol Biochem Behav. 1991;40:807–810.PubMedCrossRefGoogle Scholar
  24. 24.
    Meert TF, Janssen PAJ. Ritanserin, a new therapeutic approach for drug abuse. Part 2: effects on cocaine. Drug Develop Res. 1992;25:39–53.CrossRefGoogle Scholar
  25. 25.
    Meert TF, Janssen PAJ. Ritanserin, a new therapeutic approach for drug abuse. Part 3: effects on fentanyl and sucrose. Drug Develop Res. 1992;25:55–66.CrossRefGoogle Scholar
  26. 26.
    Wolffgramm J. An ethopharmacological approach to the development of drug addiction. Neurosci Biobehav Rev. 1991;15:515–519.PubMedCrossRefGoogle Scholar
  27. 27.
    Curran T, Abate C, Cohne DR, et al. Inducible proto-oncogene transcription factors: third messengers in the brain? In: Cold Spring Harbor Symposia on Quantitative Biology. Cold Spring Harbor Press; 1990.Google Scholar
  28. 28.
    Cohen DR, Curran T. The structure and function of the fos proto-oncogene. Crit Rev Oncogen. 1989;1:65.Google Scholar
  29. 29.
    Goodwin FK. From the Alcohol, Drug Abuse, and Mental Health Administration. J Am Med Assoc. December 25, 1991;266(24):3403.CrossRefGoogle Scholar
  30. 30.
    Post R. Talk given at the American Society of Addiction Medicine’s 23rd Annual Medical-Scientific Conference, April 2-5, 1992. Washington, DC.Google Scholar
  31. 31.
    Bastos ML, Hoffman DB. Detection and identification of cocaine, its metabolites and its derivatives. In: Mule SJ, ed. Cocaine: Chemical, Biological, Clinical, Social and Treatment Aspects. Cleveland: CRC Press; 1976:45.Google Scholar
  32. 32.
    Chen J, Paredes W, Li J, Smith D, Gardner EL. In vivo brain microdialysis studies of delta9tetrahydrocannabinol on presynaptic dopamine efflux in nucleus accumbens of the Lewis rat. Soc Neurosci Abstr. 1989;15:1096.Google Scholar
  33. 33.
    Chen J, Paredes W, Li J, Smith D, Lowinson J, Gardner EL. Delta9tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis. Psychopharmacology (Berlin). 1990;102: 156–162.PubMedCrossRefGoogle Scholar
  34. 34.
    Matthews RT, German DC. Electrophysiological evidence for excitation of rat ventral tegmental area dopaminergic neurons by morphine. Neuroscience. 1984;11:617–626.PubMedCrossRefGoogle Scholar
  35. 35.
    Kosten TR. Neurobiology of abused drugs: opioids and stimulants. J Nervous Mental Dis. 1990;178(4):217–227.CrossRefGoogle Scholar
  36. 36.
    Jenck F, Graton A, Wise RA. Opposite effects of tegmental and periaqueductal gray morphine injections on lateral hypothalamic stimulation-induced feeding. Brain Res. 1986;399:24–32.PubMedCrossRefGoogle Scholar
  37. 37.
    Mucha RF, Iverson SD. Increased food intake after opioid microinjection into the nucleus accumbens and ventral tegmental area of rat. Brain Res. 1986;397:214–224.PubMedCrossRefGoogle Scholar
  38. 38.
    Geary N, Smith G. Pimozide decreases the positive reinforcing effect of sham fed sucrose in the rat. Pharmacol Biochem Behav. 1985;22:787–790.PubMedCrossRefGoogle Scholar
  39. 39.
    Gardner EL. Brain reward mechanism. In Lowinson JH, Substance Abuse: A Comprehensive Textbook. 2nd ed. Ruiz P, Millman RB, et al., eds. Baltimore, Md: Williams & Wilkins; 1992.Google Scholar
  40. 40.
    Stolerman IP, Schoaib M. The neurobiology of tobacco addiction. Trends Pharmacol Sci. 1991;12:467–473.PubMedCrossRefGoogle Scholar
  41. 41.
    Winkler A. Dynamics of drug dependence: implications of a conditioning theory for research. Arch Gen Psychiatry. 1973;28:611–619.CrossRefGoogle Scholar
  42. 42.
    Kosten TA, Marby DA, Nestler EJ. Cocaine conditioned place preference is attenuated by chronic buprenorphine treatment. Life Sci. 1991;49(24):201–206.CrossRefGoogle Scholar
  43. 43.
    Gawin FH, Kleber HD. Abstinence symptomatology and psychiatric diagnosis in cocaine abusers: clinical observations. Arch Gen Psychiatry. 1986;43:107–113.PubMedCrossRefGoogle Scholar
  44. 44.
    Satel SL, Price LH, Palumbo JM, et al. Clinical phenomenology and neurobiology of cocaine abstinence: a prospective inpatient study. Am J Psychiatry. 1991;148:1712–1716.PubMedGoogle Scholar
  45. 45.
    Dackis CA, Gold MS. Psychopharmacology of cocaine. Psychiatric Ann. 1988;18(9):528–530.Google Scholar
  46. 46.
    Pitts DK, Marwah J. Cocaine and central monaminergic neurotransmission: a review of electrophysiological studies and comparison to amphetamines and antidepressants. Life Sci. 1988;42:949–968.PubMedCrossRefGoogle Scholar
  47. 47.
    Morton BE. The utility of viewing the locus coeruleus as an alarm system. University of Hawaii School of Medicine. In press.Google Scholar
  48. 48.
    WHO Expert Committee on Mental Health and Alcohol. The craving for alcohol. Q J Stud Alcohol. 1955;16:53–66.Google Scholar
  49. 49.
    Ludwig A. The mystery of craving. Alcohol Health Res World. 1989;11:12–17.Google Scholar
  50. 50.
    Marlatt GA. Craving for alcohol, loss of control and relapse: cognitive behavioral analysis. In: Nathan PE, Marlatt GA, Loberg T, eds. Alcoholism: New Directions in Behavioral Research and Treatment. New York: Plenum Press; 1978:271–314.Google Scholar
  51. 51.
    Littmen GK, Stapleton J, Oppenheim AN. Situations related to alcoholism relapse. Br J Addict. 1983;78:381–389.CrossRefGoogle Scholar
  52. 52.
    Bradley BP, Phillips G, Green L, Gossop M. Circumstances surrounding the initial lapse to opiate use following detoxification. Br J Psychiatry. 1989;154:354–359.PubMedCrossRefGoogle Scholar
  53. 53.
    Wallace BC. Psychological and environmental determinants of relapse in crack cocaine smokers. J Subst Abuse Treat. 1989;6:95–106.PubMedCrossRefGoogle Scholar
  54. 54.
    Kennedy D. Pupillometrics as an aid in the assessment of motivation, impact of treatment and prognosis of chronic alcoholics. Unpublished doctoral dissertation. Salt Lake City: University of Utah; 1971.Google Scholar
  55. 55.
    Niaura RS, Roshenow DJ, Blinkoff JA, Monti P. Responses to smoking-related stimuli and early relapse to smoking. Addict Behav. 1989;14:419–428.PubMedCrossRefGoogle Scholar
  56. 56.
    Tiffany ST. A cognitive model of drug urges and drug use behavior. Psychol Rev. 1990;97:147–168.PubMedCrossRefGoogle Scholar
  57. 57.
    Gold MS, Miller NS: Dissociation of Craving and Relapse in Alcohol and Cocaine Dependence. Soc Biol Psychiatry, in press, 1993.Google Scholar
  58. 58.
    Juston-Lyons D, Kornetsky C. Brain-stimulation reward as a model of drug-induced euphoria: comparison of cocaine and opiates. In Lakowski J, Galloway MP, White FJ, eds. Cocaine: Pharmacology, Physiology, and Clinical Strategies. Boca Raton, FL: CRC Press, 1992.Google Scholar
  59. 59.
    Berger PS, Elsworth JD, Arroyo J, Roth RH. Soc Neurosci Abstr. 1988;14:765.Google Scholar
  60. 60.
    Ritz MC, Lamb RJ, Goldberg, H Kuhar MJ. Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science. 1987;237:1219–1223.PubMedCrossRefGoogle Scholar
  61. 61.
    Koob GF, Thai Le H, Creese I. The D1 dopamine receptor antagonist SHC 23390 increases cocaine self-administration in the rat. Neurosci Let. 1987;79:315–320.CrossRefGoogle Scholar
  62. 62.
    Zito KA, Vickers G, Roberts DCS. Pharmacol Biochem Behav. 1985;23:1029–1036.PubMedCrossRefGoogle Scholar
  63. 63.
    Roberts DCS, Zito KA. Methods of Assessing the Reinforcing Properties of Abused Drugs. New York: Springer-Verlag; 1987;87–103.CrossRefGoogle Scholar
  64. 64.
    Lyness WH, Friedle NM, Moore KE. Pharmacol Biochem Behav. 1979;11:553–556.PubMedCrossRefGoogle Scholar
  65. 65.
    Pettit HO, Ettenberg A, Bloom FE, Koob GF. Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration. Psychopharmacology. 1984;84:167–173.PubMedCrossRefGoogle Scholar
  66. 66.
    Nakajima S. Subtypes of dopamine receptors involved in the mechanism of reinforcement. Neurosci Biobehav Rev. 1989;13:123–128.PubMedCrossRefGoogle Scholar
  67. 67.
    Stellar JR, Corbett D. Regional neuroepileptic microinjections indicate a role for the nucleus accumbens in lateral hypothalamic self-stimulation reward. Brain Res. 1989;477:126–143.PubMedCrossRefGoogle Scholar
  68. 68.
    Nakamura S, Sakaguchi T. Development and plasticity of the locus coeruleus: a review of recent physiological and pharmacological experimentation. Prog Neurobiol. 1990;34:505–526.PubMedCrossRefGoogle Scholar
  69. 69.
    Gold MS, Dackis CA, Pottash ALC, et al. Naltrexone, opiate addiction and endorphins. Med Res Rev. 1982;2(3):211–246.PubMedCrossRefGoogle Scholar
  70. 70.
    Amaral DG, Sinnamon HM. The locus coeruleus: neurobiology of a central noradrenergic nucleus. Prog Neurobiol. 1977;9:147–196.PubMedCrossRefGoogle Scholar
  71. 71.
    Gold MS, Redmond DE Jr, Kleber HD. Clonidine in opiate withdrawal. Lancet. 1978;1(8070):929–930.PubMedCrossRefGoogle Scholar
  72. 72.
    Grant SJ, Huang YH, Redmond YH. Behavior of monkeys during opiate withdrawal and locus coeruleus stimulation. Pharmacol Biochem Behav. 1988;30:13–19.PubMedCrossRefGoogle Scholar
  73. 73.
    Valentino RJ, Wehby RG. Locus coeruleus discharge characteristics of morphine-dependent rats: effects of naltrexone. Brain Res. 1989;488:126–134.PubMedCrossRefGoogle Scholar
  74. 74.
    Rasmussen K, Beitner-Johnson DB, Krystal JH, Aghajanian GK, Nestler EJ. Opiate withdrawal and the rat locus coeruleus: behavioral, electrophysiological and biochemical correlates. J Neurosci. 1990;10:2308–2317.PubMedGoogle Scholar
  75. 75.
    Christie MJ, Williams JT, North AR. Cellular mechanism of opioid tolerance: studies in single brain neurons. Mol Pharmacol. 1987; 32:633–638.PubMedGoogle Scholar
  76. 76.
    Rasmussen KL, Aghajanian GK. Withdrawal-induced activation of locus coeruleus neurons in opiate-dependent rats: attenuation by lesions of the nucleus paragigantocellularis. Brain Res. 1989;505:346–350.PubMedCrossRefGoogle Scholar
  77. 77.
    Akaoka H, Aston-Jones G. Opiate withdrawal-induced hyperactivity of locus coeruleus neurons is substantially mediated by augmented excitatory amino acid input. J Neurosci. 1991; 11(12):3830–3839.PubMedGoogle Scholar
  78. 78.
    Tung CS, Grenhoff J, Svensson TH. Morphine withdrawal responses of rat locus coeruleus neurons are blocked by an excitatory amino acid antagonist. Acta Physiol Scand. 1990;138:581–582.PubMedCrossRefGoogle Scholar
  79. 79.
    Rasmussen K, Fuller RW, Stockton ME, Perry KW, Swinford RM, Ornstein PL. NMD A receptor antagonists suppress behaviors but no norepinephrine turnover or locus coeruleus unit activity induced by opiate withdrawal. Eur J Pharmacol. 1991;197:9–16.PubMedCrossRefGoogle Scholar
  80. 80.
    Poherecky LA, Brick J. Activity of neurons in the locus coeruleus of the rat: inhibition by ethanol. Brain Res. 1977;131:171–179.Google Scholar
  81. 81.
    Strahlendorf JC, Strahlendorf HK. Response of locus coeruleus neurons to direct application of ethanol. Neurosci Abstr. 1984;7:312.Google Scholar
  82. 82.
    Baumgartner GR, Rowen RC. Clonidine vs. chlordiazepoxide in the management of acute alcohol withdrawal syndrome. Arch Intern Med. 1987;147:1223–1226.PubMedCrossRefGoogle Scholar
  83. 83.
    Gold MS, Miller NS. Seeking pleasure and avoiding pain: the neuroanatomy of reward and withdrawal. Psychiatric Ann. 1992;22(8):430–435.Google Scholar
  84. 84.
    Verbanck P, Seutin V, Massotte L, Dresse A. Yohimbine can induce ethanol tolerance in an in vitro preparation on rat locus coeruleus. Alcoholism: Clin Experiment Res. 1991;15(6): 1036–1039.CrossRefGoogle Scholar
  85. 85.
    Mello NK, Mendelson JH, Kuehnle JC, et al. Operant analysis of human heroin self-administration and the effects of naltrexone. J Pharmacol Exp Ther. 1980;216:45–54.Google Scholar
  86. 86.
    Meyer RE, Mirrin SV, Altman JL, et al. A behavioral paradigm for the evaluation of narcotic antagonists. Arch Gen Psychiatry. 1976;33:371–377.PubMedCrossRefGoogle Scholar
  87. 87.
    Griffiths RR, Bigelow GE, Henningfield JE. Similarities in animal and human drug-taking behavior. In: Mello NK, ed. Advances in Substance Abuse. vol 1. Greenwich, Conn: JAI Press; 1980.Google Scholar
  88. 88.
    U. S. Department of Health and Human Services. Alcohol and Health. Seventh Special Report to the U. S. Congress, January 1990. DHHS Publication # (ADM) 90–1656.Google Scholar
  89. 89.
    Woolverton WL, Johnson KM. Neurobiology of cocaine abuse. TiPs (13):193–200. May 1992.PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1993

Authors and Affiliations

  • Mark S. Gold
    • 1
  1. 1.Departments of Neuroscience and PsychiatryUniversity of Florida College of MedicineGainesvilleUSA

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