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Psychopharmacology

, Volume 119, Issue 2, pp 179–185 | Cite as

Serotonergic mechanisms of cocaine effects in humans

  • Sarah C. Aronson
  • Jed E. Black
  • Christopher J. McDougle
  • B. Ellen Scanley
  • George R. Heninger
  • Lawrence H. Price
  • Peter Jatlow
  • Thomas R. Kosten
Original Investigation

Abstract

The objective of this study was to investigate the role of serotonin (5-HT) in mediating the effects of cocaine in humans. To accomplish this, 12 subjects each participated in two randomized, double-blind test sessions separated by 1 week. In one session, subjects underwent acute depletion of the 5-HT amino acid precursor tryptophan (TRP), followed by a test dose of intranasal cocaine. In the other session, the cocaine test dose was preceded by sham depletion. Subject ratings of cocaine “high” were significantly lower following active TRP depletion than after the sham procedure. Subjects also showed an earlier but less sustained rise in self-rated nervousness during active TRP depletion. These findings are consistent with the hypothesis that 5-HT may be involved in mediating the euphorigenic and modulating the anxiogenic effects of cocaine in humans, either directly or through actions on other (e.g., dopaminergic) systems.

Key words

Cocaine Serotonin Tryptophan 

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References

  1. American Psychiatric Association (1987) Diagnostic and statistical manual of mental disorders, 3rd edn revised (DSM-III-R). Washington, D.C. American Psychiatric PressGoogle Scholar
  2. Aston-Jones G, Akaoka H, Charléty P, Chouvet G (1991) Serotonin selectively attenuates glutamate-evoked activation of noradrenergic locus coeruleus neurons. J Neurosci 11:760–769Google Scholar
  3. Barr LC, Goodman WK, McDougle CJ, Delgado PL, Heninger GR, Charney DS, Price LH (1994) Tryptophan depletion in patients with obsessive-compulsive disorder who respond to serotonin reuptake inhibitors. Arch Gen Psychiatry 51:309–317Google Scholar
  4. Batki SL, Manfredi LB, Jacob PI, Jones RT (1993) Fluoxetine for cocaine dependence in methadone maintenance: Quantitative plasma and urine cocaine/benzoylecgonine concentrations. J Clin Psychopharmacol 13:243–250Google Scholar
  5. Batki SL, Washburn A, Manfredi L, Murphy J, Herbst MD, Delucchi K, Jones T, Nanda N, Jacob P, Jones RT (1994) Fluoxetine in primary and secondary cocaine dependence: outcome using quantitative benzoylecgonine concentration. In: Harris LS (ed) Problems of drug dependence, 1993, vol II. NIDA Res Monogr 141, Rockville, MD, p 140Google Scholar
  6. Biggio G, Fadda F, Fanni P, Tagliamonte A, Gessa G (1974) Rapid depletion of serum tryptophan, brain tryptophan, serotonin and 5-hydroxyindoleacetic acid by a tryptophan-free diet. Life Sci 14:1321–1329Google Scholar
  7. Carroll ME, Lac ST, Asencio M, Kragh R (1990) Intravenous cocaine self-administration in rats is reduced by dietaryl-tryptophan. Psychopharmacology 100:293–300Google Scholar
  8. Corrigal WA, Coen K (1991) Cocaine self-administration is increased by both D1 and D2 antagonists. Pharmacol Biochem Behav 39:799–802Google Scholar
  9. Cregler LL, Mark H (1986) Medical complications of cocaine abuse. N Engl J Med 315:1495–1500Google Scholar
  10. Cunningham KA, Callahan PM (1991) Monoamine reuptake inhibitors enhance the discriminative state induced by cocaine in the rat. Psychopharmacology 104:177–180Google Scholar
  11. Cunningham KA, Lakoski JM (1990) The interaction of cocaine with serotonin dorsal raphe neurons. Single unit extracellular recording studies. Neuropsychopharmacology 3:41–50Google Scholar
  12. Cunningham KA, Paris JM, Goeders NE (1992) Chronic cocaine enhances serotonin autoregulation and serotonin uptake binding. Synapse 11:112–123Google Scholar
  13. Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR (1990) Serotonin function and the mechanism of antidepressant action. Arch Gen Psychiatry 47:411–418Google Scholar
  14. Delgado PL, Price LH, Miller HL, Salomon RM, Licinio J, Krystal JH, Heninger GR, Charney DS (1991) Rapid serotonin depletion as a provocative challenge test for patients with major depression: relevance to antidepressant action and the neurobiology of depression. Psychopharmacol Bull 27:321–330Google Scholar
  15. Foltin RW, Fischman MW (1992) The cardiovascular and subjective effects of intravenous cocaine and morphine combinations in humans. J Pharmacol Exp Ther 261[2]:623–632Google Scholar
  16. Galloway MP (1990) Regulation of dopamine and serotonin synthesis by acute administration of cocaine. Synapse 6:63–72Google Scholar
  17. Gawin FH, Ellinwood EH (1988) Cocaine and other stimulants. Actions, abuse, and treatment. N Engl J Med 318:1173–1182Google Scholar
  18. Glass AR, Smallridge RC, Schaaf M, Dimond RC (1980) Absent prolactin response tol-tryptophan in normal and acromegalic subjects. Psychoneuroendocrinology 5:261–265Google Scholar
  19. Goddard AW, Charney DS, Germine M, Woods SW, Heninger GR, Krystal JH, Goodman WK, Price LH (1995) Effects of tryptophan depletion on responses to yohimbine in healthy human subjects. Biol Psychiatry (in press)Google Scholar
  20. Imperato A, Mele A, Scrocco MG, Puglisi-Allegra S (1992) Chronic cocaine alters limbic extracellular dopamine. Neurochemical basis for addiction. Eur J Pharmacol 212:299–300Google Scholar
  21. Jatlow P, Nadim H (1990) Determination of cocaine concentrations in plasma by high-performance liquid chromatography. Clin chemistry 36[8 14 1]:1436–1439Google Scholar
  22. Johanson CE, Fischman MW (1989) The pharmacology of cocaine related to its abuse. Pharmacol Rev 41[1]:3–52Google Scholar
  23. Kalivas PW, Duffy P (1990) Effect of acute and daily cocaine treatment on extracellular dopamine in the nucleus accumbens. Synapse 5:48–58Google Scholar
  24. Kleven MS, Woolverton WL (1993) Effects of three monoamine uptake inhibitors on behavior maintained by cocaine or food presentation in rhesus monkeys. Drug Alcohol Depend 31:149–158Google Scholar
  25. Kosten TR (1990) Neurobiology of abused drugs: opioids and stimulants. J Nerv Men Dis 176[4]:217Google Scholar
  26. Kuhar MJ, Ritz MC, Boja JW (1991) The dopamine hypothesis in the reinforcing properties of cocaine. Trends Neural Sci 14(7) 299–302Google Scholar
  27. Loh EA, Roberts DCS (1990) Break-points on a progressive ratio schedule reinforced by intravenous cocaine increase following depletion of forebrain serotonin. Psychopharmacology 101:262–266Google Scholar
  28. Malison RT, Price LH (1991) Panic disorder: neurobiological advances. Curr Opin Psychiatry 4:255–261Google Scholar
  29. McCance-Katz EF, Marek KL, Price LH (1992) Serotonergic dysfunction in depression associated with Parkinson's disease. Neurology 42:1813–1814Google Scholar
  30. McCance-Katz EF, Price LH, McDougle CJ, Kosten TR, Black JE, Jatlow PI (1993) Concurrent cocaine-ethanol ingestion in humans: pharmacology, physiology, behavior, and the role of cocaethylene. Psychopharmacology 111:39–46Google Scholar
  31. McDougle CJ, Black JE, Malison RT, Zimmermann RC, Kosten TR, Heninger GR, Price LH (1994) Noradrenergic dysregulation during cocaine abstinence in cocaine addicts: biochemical, behavioral, and cardiovascular correlates. Arch Gen Psychiatry 51:713–719Google Scholar
  32. McNair DM, Lorr M, Droppleman LF (1971) Profile of mood states (manual). Educational and Industrial Testing Services, San Diego, Calif.Google Scholar
  33. National Institute on Drug Abuse (1991) National Household Survey on Drug Abuse, Population Estimates, 1991 (DHHS Publication No. ADM 91-1732). US Government Printing Office, Washington, D.C.Google Scholar
  34. Oldendorf WH, Szabo J (1976) Amino acid assignment to one of three blood-brain barrier carriers. Am J Physiol 230:94–98Google Scholar
  35. Palfreyman MG, Schmidt CJ, Sorensen SM, Dudley MW, Kehne JH, Moser P, Gittos MW, Carr AA (1993) Electrophysiological, biochemical and behavioral evidence for 5-HT2 and 5-HT3 mediated control of dopaminergic function. Psychopharmacology 112:S60-S67Google Scholar
  36. Peltier R, Schenk S (1993) Effects of serotonergic manipulations on cocaine self-administration in rats. Psychopharmacology 110:390–394Google Scholar
  37. Pitts DK, Marwah J (1987) Cocaine modulation of central monoaminergic neurotransmission. Pharmacol Biochem Behav 26:453–461Google Scholar
  38. Pradhan SN, Bhattacharyya AK, Pradhan S (1978) Serotonergic manipulation of the behavioral effects of cocaine in rats. Commun Psychopharmacol 2:481–486Google Scholar
  39. Reith MEA, Fischette CT (1991) Sertraline and cocaine-induced locomotion in mice. II. Chronic studies. Psychopharmacology 103:306–313Google Scholar
  40. Reith MEA, Wiener HL, Fischette CT (1991) Sertraline and cocaine-induced locomotion in mice. I. Acute studies. Psychopharmacology 103:306–313Google Scholar
  41. Richardson NR, Roberts DCS (1991) Fluoxetine pre-treatment reduces breaking points on a progressive ratio schedule reinforced by intravenous cocaine self-administration in the rat. Life Sci 49:833–840Google Scholar
  42. Roberts DCS, Loh EA, Vickers G (1989) Self-administration on a progressive ratio schedule in rats: dose-response relationship and effect of haloperidol pre-treatment. Psychopharmacology 97:535–538Google Scholar
  43. Satel S (1992) Craving for and fear of cocaine: A phenomenologic update on cocaine craving and paranoia. In: Kosten TR, Kleber HD (eds) Clinician's guide to cocaine addiction. Guilford Press, New York, pp 172–192Google Scholar
  44. Satel SL, Delgado PL, Charney DS (1991) Serotonin mediation of cue-induced craving. Soc Neuroscience Annual Meeting (abstract) #348.15, p 888Google Scholar
  45. Segal M (1979) Serotonergic innervation of the locus coeruleus from the dorsal raphe and its action on responses to noxious stimuli. J Physiol 286:401–415Google Scholar
  46. Sherer MA, Kumor KM, Jaffe JH (1988) Effects of intravenous cocaine are partially attenuated by haloperidol. Psychiatry Res 27:117–125Google Scholar
  47. Spealman RD (1993) Modification of behavioral effects of cocaine by selective serotonin and dopamine uptake inhibitors in squirrel monkeys. Psychopharmacology 112:93–99Google Scholar
  48. Van Dyke C, Ungerer J, Jatlow P, Barash P, Byck R (1982) Intranasal cocaine: dose relationships of psychological effects and plasma levels. Int J Psychiatry Med 12:1–13Google Scholar
  49. Weltzin TE, Fernstrom JD, McConaha C, Kaye WH (1994) Acute tryptophan depletion in bulimia: effects on large neutral amino acids. Biol Psychiatry 35:388–397Google Scholar
  50. White FJ, Hu X-T, Henry DJ (1993) Electrophysiological effects of cocaine in the rat nucleus accumbens: microiontophoretic studies. J Pharmacol Exp Ther 266:1075–1084Google Scholar
  51. Wise RA (1987) The role of reward pathways in the development of drug dependence. Pharmacol Ther 35:227–263Google Scholar
  52. Woolverton WL, Johnson KM (1992) Neurobiology of cocaine abuse. Trends Pharmacol Sci 13:193–200Google Scholar
  53. Young SN, Smith SE, Phihl RD, Ervin FR (1985) Tryptophan depletion causes a rapid lowering of mood in normal males. Psychopharmacology 87:173–177Google Scholar
  54. Young SN, Ervin FR, Pihl RO, Finn P (1989) Biochemical aspects of tryptophan depletion in primates. Psychopharmacology 95:508–511Google Scholar
  55. Zimmermann RC, McDougle CJ, Schumacher M, Olcese J, Heninger GR, Price LH (1993a) Urinary 6-hydroxymelatonin sulfate as a measure of melatonin secretion during acute tryptophan depletion. Psychoneuroendocrinology 18:567–578Google Scholar
  56. Zimmermann RC, McDougle CJ, Schumacher M, Olcese J, Mason JW, Heninger GR, Price LH (1993b) Effects of acute tryptophan depletion on nocturnal melatonin secretion in humans. J Clin Endocrinol Metab 76:1160–1164Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • Sarah C. Aronson
    • 1
  • Jed E. Black
    • 1
  • Christopher J. McDougle
    • 1
  • B. Ellen Scanley
    • 1
  • George R. Heninger
    • 1
  • Lawrence H. Price
    • 1
  • Peter Jatlow
    • 2
    • 3
  • Thomas R. Kosten
    • 2
    • 4
  1. 1.Clinical Neuroscience Research Unit, Abraham Ribicoff Research Facilities, Department of PsychiatryYale University School of MedicineNew HavenUSA
  2. 2.Department of PsychiatryYale University School of MedicineNew HavenUSA
  3. 3.Department of Laboratory MedicineYale University School of MedicineNew HavenUSA
  4. 4.Substance Abuse Treatment UnitConnecticut Mental Health CenterNew HavenUSA

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