Abstract
Modafinil [(diphenyl-methyl)sulphinyl-2-acetamide] is a novel psychostimulant drug which is effective in the treatment of narcolepsy and idiopathic hypersomnia. It also has neuroprotective effects in animal models of striatal neuropathology. Although the cellular mechanisms of action of modafinil are poorly understood, it has been shown to have a profile of pharmacological effects that differs considerably from that of amphetamine-like stimulants. There is some evidence that modafinil has central α1-adrenergic agonist effects. In the present study modafinil was evaluated for cocaine-like discriminative stimulus effects in rats and for reinforcing effects in rhesus monkeys maintained on intravenous cocaine self-administration. Modafinil,l-ephedrine andd-amphetamine all produced dose dependent increases in cocaine-lever responding, with maximal levels of 67%, 82% and 100%, respectively. Modafinil produced full substitution in four out of the six rats tested while the highest levels of substitution were associated with substantial response rate decreasing effects. Little evidence was obtained that the discriminative stimulus effects of modafinil were produced by α1-adrenergic activation, based upon results of tests performed in combination with prazosin. In the self-administration procedure, modafinil andl-ephedrine functioned as reinforcers in rhesus monkeys. The reinforcing and discriminative stimulus effects of modafinil required very high doses: modafinil was over 200 times less potent thand-amphetamine and was also less potent thanl-ephedrine. These results show that modafinil has some cocaine-like discriminative stimulus effects and, like other abused stimulants, can serve as a reinforcer at high doses.
Similar content being viewed by others
References
Akaoka H, Roussel B, Lin J, Chouvet G, Jouvet M (1991) Effect of modafinil and amphetamine on the rat catecholaminergic neuron activity. Neurosci Lett 123:20–22
Baker LE, Riddle EE, Saunders RB, Appel JB (1993) The role of monoamine uptake in the discriminative stimulus effects of cocaine and related compounds. Behav Pharmacol 4:69–79
Balster RL (1991) Drug abuse potential evaluation in animals. Br J Addict 86:1549–1558
Balster RL, Schuster CR (1973) A comparison ofd-amphetamine,l-amphetamine and methamphetamine self-administration in rhesus monkeys. Pharmacol Biochem Behav 1:67–71
Balster RL, Woolverton WL (1982) Intravenous buspirone self-administration in rhesus monkeys. J Clin Psychiatry 43:34–37
Balster RL, Carroll FI, Graham JH, Mansbach RS, Rahman A, Lewin AH, Showalter VM (1991) Potent substituted-β-phenyltropane analogs of cocaine have cocaine-like discriminative stimulus effects. Drug Alcohol Depend 29:145–151
Bastuji H, Jouvet M (1988) Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil. Prog Neuropsychopharmacol Biol Psychiatry 12:695–700
Beardsley PM, Balster RL, Harris LS (1986) Self-administration of methylenedioxymethamphetamine (MDMA) by rhesus monkeys. Drug Alcohol Depend 18:149–157
Boivin DB, Montplaisir J, Petit D, Lambert C, Lubin S (1993) Effects of modafinil on symptomatology of human narcolepsy. Clin Neuropharmacol 16:46–53
Bruno A, Nolte KB, Chapin J (1993) Stroke associated with ephedrine use. Neurology 43:1313–1316
Carney JM, Uwaydah IM, Balster RL (1977) Evaluation of a suspension system for intravenous self-administration studies of water-insoluble compounds in the rhesus monkey. Pharmacol Biochem Behav 7:357–364
Chait LD (1994) Factors influencing the reinforcing and subjective effects of ephedrine in humans. Psychopharmacology 113:381–387
Deneau G, Yanagita T, Seevers MH (1969) Self-administration of psychoactive substances by the monkey. Psychopharmacology 16:30–43
Duteil J, Rambert FA, Pessonnier J, Hermant J, Gombert R, Assous E (1990) Central α1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals. Eur J Pharmacol 180:49–58
Fishman MW, Schuster CR, Resnekov L, Shick JFE, Krasnegor NA, Fennell W, Freedman DX (1976) Cardiovascular and subjective effects of intravenous cocaine administration in humans. Arch Gen Psychiatry 33:983–989
Fuxe K, Janson AM, Rosen L, Finnman U-B, Tanganelli S, Morari M, Goldstein M, Agnati LF (1992) Evidence for protective action of the vigilance promoting drug modafinil on the MPTP-induced degeneration of the nigrostriatal dopamine neurons in the black mouse: an immunocytochemical and biochemical analysis. Exp Brain Res 88:117–130
Gauvin DV, Harland RD, Michaelis RC, Holloway FA (1989) Caffeine-phenylethylamine combinations mimic the cocaine discriminative cue. Life Sci 44:67–73
Gauvin DV, Moore KR, Youngblood BD, Holloway FA (1993) The discriminative stimulus properties of legal, over-the-counter stimulants administered singly and in binary and ternary combinations. Psychopharmacology 110:309–319
Hermant J-F, Rambert FA, Duteil J (1991) Awakening properties of modafinil: effect on nocturnal activity in monkeys (Macaca mulatta) after acute and repeated administration. Psychopharmacology 103:28–32
Holtzman SG (1990) Discriminative stimulus effects of drugs: relationship to abuse liability. In: Adler MW, Cowan A (eds) Testing and evaluation of drugs of abuse. Modern methods in pharmacology, vol. 6. Wiley-Liss, New York, pp. 193–210
Huang J, Ho BT (1974) Discriminative stimulus properties ofd-amphetamine and related compounds in rats. Pharmacol Biochem Behav 2:669–673
Johanson CE, Balster RL (1978) A summary of the results of a drug self-administration study using substitution procedures in rhesus monkey. Bull Narc 30:43–54
Kamien JB, Woolverton WL (1989) A pharmacological analysis of the discriminative stimulus properties ofd-amphetamine in rhesus monkeys. J Pharmacol Exp Ther 248:938–946
Lagarde D, Milhaud C (1990) Electroencephalographic effects of modafinil, an alpha-1-adrenergic psychostimulant, on the sleep of rhesus monkeys. Sleep 13:441–448
Lamb RJ, Griffiths RR (1990) Self-administration in baboons and the discriminative stimulus effects in rats of bupropion, nomifensine, diclofensine and imipramine. Psychopharmacology 102:183–190
Lin JS, Roussel B, Akaoka H, Fort P, Debilly G, Jouvet M (1992) Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat. Brain Res 591:319–326
Mansbach RS, Balster RL (1993) Effects of mazindol on behaviors maintained or occasioned by cocaine. Drug Alcohol Depend 31:183–191
Mansbach RS, Sannerud CA, Griffiths RR, Balster RL, Harris LS (1990) Intravenous self-administration of 4-methylaminorex in primates. Drug Alcohol Depend 26:137–144
Martin WR, Sloan MD, Sapira JD, Jasinski DR (1971) Physiologic, subjective and behavioral effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and methylphenidate in man. Clin Pharmacol Ther 12:245–258
Mignot E, Nishino S, Guilleminault C, Dement WC (1994) Modafinil binds to the dopamine uptake carrier site with low affinity. Sleep 17:436–437
Pigeau R, Natioh P, Buguet A, McCann C, Baranski J, Taylor M, Thompson M, Mack I (1995) Modafinil,d-amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature. J Sleep Res 4:212–218
Rambert FA, Pessonnier J, Duteil J (1990) Modafinil, amphetamine and methylphenidate-induced hyperactivities in mice involve different mechanisms. Eur J Pharmacol 183:455–456
Simon P, Panissaud C, Costentin J (1994) The stimulant effect of modafinil on wakefulness is not associated with an increase in anxiety in mice. Psychopharmacology 114:597–600
Snoddy AM, Tessel RE (1983) Nisoxetine and amphetamine share discriminative stimulus properties in mice. Pharmacol Biochem Behav 19:205–210
Terry P, Witkin JM, Katz JL (1994) Pharmacological characterization of the novel discriminative stimulus effects of a low dose of cocaine. J Pharmacol Exp Ther 270:1041–1048
Touret M, Sallanon-Moulin M, Jouvet M (1995) Awakening properties of modafinil without paradoxical sleep rebound: comparative study with amphetamine in the rat. Neurosci Lett 189:43–46
Ueki A, Rosen L, Agnati LF, Hallstrom A, Goiny M, Tanganelli S, Ungerstedt U, Fuxe K (1993a) Evidence for a preventive action of the vigilance-promoting drug modafinil against striatal ischemic injury induced by endothelin-1 in the rat. Exp Brain Res 96:89–99
Ueki A, Rosen L, Andbjer B, Finnman U-B, Altamimi U, Janson AM, Goldstein M, Agnati LF, Fuxe K (1993b) The vigilance-promoting drug modafinil counteracts the reduction of tyrosine hydroxylase immunoreactivity and of dopamine stores in nigrostriatal dopamine neurons in the male rat after a partial transection of the dopamine pathway. Exp Brain Res 93:259–270
Woodward JJ, Mansbach RS, Carroll FI, Balster RL (1991) Cocaethylene inhibits dopamine uptake and produces cocaine-like actions in drug discrimination studies. Eur J Pharmacol 197:235–236
Woolverton WL (1991) Discriminative stimulus effects of cocaine. In: Glennon RA, Jarbe TUC, Frankenheim J (eds) Drug discrimination: applications to drug abuse research. NIDA Research Monograph Series 116, DHHS Publication number (ADM)92-1878, pp 61–74
Woolverton WL, Nader MA (1990) Experimental evaluation of the reinforcing effects of drugs. In: Adler MW, Cowan A (eds) Testing and evaluation of drugs of abuse. Modern methods in pharmacology, vol. 6. Wiley-Liss, New York, pp 165–192
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Gold, L.H., Balster, R.L. Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil. Psychopharmacology 126, 286–292 (1996). https://doi.org/10.1007/BF02247379
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02247379