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.
Similar content being viewed by others
References
American Psychiatric Association (1987) Diagnostic and statistical manual of mental disorders, 3rd edn revised (DSM-III-R). Washington, D.C. American Psychiatric Press
Aston-Jones G, Akaoka H, Charléty P, Chouvet G (1991) Serotonin selectively attenuates glutamate-evoked activation of noradrenergic locus coeruleus neurons. J Neurosci 11:760–769
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 51:309–317
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 13:243–250
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 140
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 14:1321–1329
Carroll ME, Lac ST, Asencio M, Kragh R (1990) Intravenous cocaine self-administration in rats is reduced by dietaryl-tryptophan. Psychopharmacology 100:293–300
Corrigal WA, Coen K (1991) Cocaine self-administration is increased by both D1 and D2 antagonists. Pharmacol Biochem Behav 39:799–802
Cregler LL, Mark H (1986) Medical complications of cocaine abuse. N Engl J Med 315:1495–1500
Cunningham KA, Callahan PM (1991) Monoamine reuptake inhibitors enhance the discriminative state induced by cocaine in the rat. Psychopharmacology 104:177–180
Cunningham KA, Lakoski JM (1990) The interaction of cocaine with serotonin dorsal raphe neurons. Single unit extracellular recording studies. Neuropsychopharmacology 3:41–50
Cunningham KA, Paris JM, Goeders NE (1992) Chronic cocaine enhances serotonin autoregulation and serotonin uptake binding. Synapse 11:112–123
Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR (1990) Serotonin function and the mechanism of antidepressant action. Arch Gen Psychiatry 47:411–418
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 27:321–330
Foltin RW, Fischman MW (1992) The cardiovascular and subjective effects of intravenous cocaine and morphine combinations in humans. J Pharmacol Exp Ther 261[2]:623–632
Galloway MP (1990) Regulation of dopamine and serotonin synthesis by acute administration of cocaine. Synapse 6:63–72
Gawin FH, Ellinwood EH (1988) Cocaine and other stimulants. Actions, abuse, and treatment. N Engl J Med 318:1173–1182
Glass AR, Smallridge RC, Schaaf M, Dimond RC (1980) Absent prolactin response tol-tryptophan in normal and acromegalic subjects. Psychoneuroendocrinology 5:261–265
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)
Imperato A, Mele A, Scrocco MG, Puglisi-Allegra S (1992) Chronic cocaine alters limbic extracellular dopamine. Neurochemical basis for addiction. Eur J Pharmacol 212:299–300
Jatlow P, Nadim H (1990) Determination of cocaine concentrations in plasma by high-performance liquid chromatography. Clin chemistry 36[8 14 1]:1436–1439
Johanson CE, Fischman MW (1989) The pharmacology of cocaine related to its abuse. Pharmacol Rev 41[1]:3–52
Kalivas PW, Duffy P (1990) Effect of acute and daily cocaine treatment on extracellular dopamine in the nucleus accumbens. Synapse 5:48–58
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 31:149–158
Kosten TR (1990) Neurobiology of abused drugs: opioids and stimulants. J Nerv Men Dis 176[4]:217
Kuhar MJ, Ritz MC, Boja JW (1991) The dopamine hypothesis in the reinforcing properties of cocaine. Trends Neural Sci 14(7) 299–302
Loh EA, Roberts DCS (1990) Break-points on a progressive ratio schedule reinforced by intravenous cocaine increase following depletion of forebrain serotonin. Psychopharmacology 101:262–266
Malison RT, Price LH (1991) Panic disorder: neurobiological advances. Curr Opin Psychiatry 4:255–261
McCance-Katz EF, Marek KL, Price LH (1992) Serotonergic dysfunction in depression associated with Parkinson's disease. Neurology 42:1813–1814
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 111:39–46
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 51:713–719
McNair DM, Lorr M, Droppleman LF (1971) Profile of mood states (manual). Educational and Industrial Testing Services, San Diego, Calif.
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.
Oldendorf WH, Szabo J (1976) Amino acid assignment to one of three blood-brain barrier carriers. Am J Physiol 230:94–98
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-S67
Peltier R, Schenk S (1993) Effects of serotonergic manipulations on cocaine self-administration in rats. Psychopharmacology 110:390–394
Pitts DK, Marwah J (1987) Cocaine modulation of central monoaminergic neurotransmission. Pharmacol Biochem Behav 26:453–461
Pradhan SN, Bhattacharyya AK, Pradhan S (1978) Serotonergic manipulation of the behavioral effects of cocaine in rats. Commun Psychopharmacol 2:481–486
Reith MEA, Fischette CT (1991) Sertraline and cocaine-induced locomotion in mice. II. Chronic studies. Psychopharmacology 103:306–313
Reith MEA, Wiener HL, Fischette CT (1991) Sertraline and cocaine-induced locomotion in mice. I. Acute studies. Psychopharmacology 103:306–313
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 49:833–840
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 97:535–538
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 172–192
Satel SL, Delgado PL, Charney DS (1991) Serotonin mediation of cue-induced craving. Soc Neuroscience Annual Meeting (abstract) #348.15, p 888
Segal M (1979) Serotonergic innervation of the locus coeruleus from the dorsal raphe and its action on responses to noxious stimuli. J Physiol 286:401–415
Sherer MA, Kumor KM, Jaffe JH (1988) Effects of intravenous cocaine are partially attenuated by haloperidol. Psychiatry Res 27:117–125
Spealman RD (1993) Modification of behavioral effects of cocaine by selective serotonin and dopamine uptake inhibitors in squirrel monkeys. Psychopharmacology 112:93–99
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 12:1–13
Weltzin TE, Fernstrom JD, McConaha C, Kaye WH (1994) Acute tryptophan depletion in bulimia: effects on large neutral amino acids. Biol Psychiatry 35:388–397
White FJ, Hu X-T, Henry DJ (1993) Electrophysiological effects of cocaine in the rat nucleus accumbens: microiontophoretic studies. J Pharmacol Exp Ther 266:1075–1084
Wise RA (1987) The role of reward pathways in the development of drug dependence. Pharmacol Ther 35:227–263
Woolverton WL, Johnson KM (1992) Neurobiology of cocaine abuse. Trends Pharmacol Sci 13:193–200
Young SN, Smith SE, Phihl RD, Ervin FR (1985) Tryptophan depletion causes a rapid lowering of mood in normal males. Psychopharmacology 87:173–177
Young SN, Ervin FR, Pihl RO, Finn P (1989) Biochemical aspects of tryptophan depletion in primates. Psychopharmacology 95:508–511
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 18:567–578
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 76:1160–1164
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Aronson, S.C., Black, J.E., McDougle, C.J. et al. Serotonergic mechanisms of cocaine effects in humans. Psychopharmacology 119, 179–185 (1995). https://doi.org/10.1007/BF02246159
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02246159