Methylphenidate treatment during pre- and periadolescence alters behavioral responses to emotional stimuli at adulthood

Biological Psychiatry

Volumn 54, Issue 12, 2003, Pages 1317-1329

  Bolaños, Carlos A ^a   Barrot, Michel ^a   Berton, Olivier ^a   Wallace Black, Deanna ^a   Nestler, Eric J ^a,b  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

Attention deficit hyperactivity disorder; Depression; Development; Emotion; Methylphenidate

Indexed keywords

CORTICOSTERONE; METHYLPHENIDATE; SUCROSE;

ADOLESCENT; ANIMAL BEHAVIOR; ANIMAL EXPERIMENT; ANIMAL MODEL; ANXIETY; ARTICLE; ATTENTION DEFICIT DISORDER; AVERSION; BEHAVIOR; BRAIN DEVELOPMENT; CONTROLLED STUDY; CORTICOSTERONE BLOOD LEVEL; DRUG EXPOSURE; DRUG SENSITIVITY; EMOTION; FEMALE; LONG TERM CARE; MALE; NONHUMAN; PRIORITY JOURNAL; RAT; REWARD; SEXUAL BEHAVIOR; STIMULUS; STIMULUS RESPONSE; STRESS; TASK PERFORMANCE;

EID: 0345967827     PISSN: 00063223     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0006-3223(03)00570-5     Document Type: Article

References (114)

1. Andersen S.L., Arvanitogiannis A., Pliakas A.M., LeBlanc C., Carlezon W.A. Jr. Altered responsiveness to cocaine in rats exposed to methylphenidate during development. Nat Neurosci. 5:2002;13-14.
2. Bardo M.T., Bowling S.L., Pierce R.C. Changes in locomotion and dopamine neurotransmission following amphetamine, haloperidol, and exposure to novel environmental stimuli. Psychopharmacol (Berl). 101:1990;338-343.
3. Bardo M.T., Donohew R.L., Harrington N.G. Psychobiology of novelty seeking and drug seeking behavior. Behav Brain Res. 77:1996;23-43.
4. Barrot M., Olivier J.D., Perrotti L.I., DiLeone R.J., Berton O., Eisch A.J., et al. CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli. Proc Natl Acad Sci U S A. 99:2002;11435-11440.
5. Becker J.B., Rudick C.N., Jenkins W.J. The role of dopamine in the nucleus accumbens and striatum during sexual behavior in the female rat. J Neurosci. 21:2001;3236-3241.
6. Biederman J., Faraone S., Milberger S., Curtis S., Chen L., Marrs A. Predictors of persistence and remission of ADHD into adolescence Results from a four-year prospective follow-up study . J Am Acad Child Adolesc Psychiatry. 35:1996;343-351.
7. Biederman J., Wilens T., Mick E., Faraone S.V., Weber W., Curtis S., et al. Is ADHD a risk factor for psychoactive substance use disorders? Findings from a four-year prospective follow-up study. J Am Acad Child Adolesc Psychiatry. 36:1997;21-29.
8. Bolanos C.A., Garmsen G.M., Clair M.A., McDougall S.A. Effects of the kappa-opioid receptor agonist U-50,488 on morphine-induced place preference conditioning in the developing rat. Eur J Pharmacol. 317:1996;1-8.
9. Bolanos C.A., Glatt S.J., Jackson D. Subsensitivity to dopaminergic drugs in periadolescent rats A behavioral and neurochemical analysis . Brain Res Dev Brain Res. 111:1998;25-33.
10. Bolanos CA, Perrotti LP, Edwards S, Eisch AJ, Barrot M, Olson VG, et al (in press): Phospholipase C-gamma in distinct regions of the ventral tegmental area differentially modulates mood-related behaviors. J Neurosci.
11. Brandon C.L., Marinelli M., Baker L.K., White F.J. Enhanced reactivity and vulnerability to cocaine following methylphenidate treatment in adolescent rats. Neuropsychopharmacology. 25:2001;651-661.
12. Britton D.R., Britton K.T. A sensitive open field measure of anxiolytic drug activity. Pharmacol Biochem Behav. 15:1981;577-582.
13. Brown R.T., Freeman W.S., Perrin J.M., Stein M.T., Amler R.W., Feldman H.M., et al. Prevalence and assessment of attention-deficit/hyperactivity disorder in primary care settings. Pediatrics. 107:2001;E43.
14. Carlezon W.A. Jr, Boundy V.A., Haile C.N., Lane S.B., Kalb R.G., Neve R.L., Nestler E.J. Sensitization to morphine induced by viral-mediated gene transfer. Science. 277:1997;812-814.
15. Carlezon W.A. Jr, Thome J., Olson V.G., Lane-Ladd S.B., Brodkin E.S., Hiroi N., et al. Regulation of cocaine reward by CREB. Science. 282:1998;2272-2275.
16. Crawford C.A., McDougall S.A., Meier T.L., Collins R.L., Watson J.B. Repeated methylphenidate treatment induces behavioral sensitization and decreases protein kinase A and dopamine-stimulated adenylyl cyclase activity in the dorsal striatum. Psychopharmacology (Berl). 136:1998;34-43.
17. Cryan J.F., Markou A., Lucki I. Assessing antidepressant activity in rodents Recent developments and future needs . Trends Pharmacol Sci. 23:2002;238-245.
18. Damsma G., Pfaus J.G., Wenkstern D., Phillips A.G., Fibiger H.C. Sexual behavior increases dopamine transmission in the nucleus accumbens and striatum of male rats Comparison with novelty and locomotion . Behav Neurosci. 106:1992;181-191.
19. Datla K.P., Ahier R.G., Young A.M., Gray J.A., Joseph M.H. Conditioned appetitive stimulus increases extracellular dopamine in the nucleus accumbens of the rat. Eur J Neurosci. 16:2002;1987-1993.
20. Di Chiara G., North R.A. Neurobiology of opiate abuse. Trends Pharmacol Sci. 13:1992;185-193.
21. Emslie G.J., Mayes T.L. Mood disorders in children and adolescents Psychopharmacological treatment . Biol Psychiatry. 49:2001;1082-1090.
22. Everitt B.J. Sexual motivation A neural and behavioural analysis of the mechanisms underlying appetitive and copulatory responses of male rats . Neurosci Biobehav Rev. 14:1990;217-232.
23. Faraone S.V., Biederman J., Spencer T., Wilens T., Seidman L.J., Mick E., Doyle A.E. Attention-deficit/hyperactivity disorder in adults An overview . Biol Psychiatry. 48:2000;9-20.
24. Ferre P., Nunez J.F., Garcia E., Tobena A., Escorihuela R.M., Fernandez-Teruel A. Postnatal handling reduces anxiety as measured by emotionality rating and hyponeophagia tests in female rats. Pharmacol Biochem Behav. 51:1995;199-203.
25. File S.E. The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs. J Neurosci Methods. 2:1980;219-238.
26. File S.E., Hyde J.R. Can social interaction be used to measure anxiety? Br J Pharmacol. 62:1978;19-24.
27. Findling R.L., Dogin J.W. Psychopharmacology of ADHD Children and adolescents . J Clin Psychiatry. 59:(suppl7):1998;42-49.
28. Fink J.S., Smith G.P. Mesolimbicocortical dopamine terminal fields are necessary for normal locomotor and investigatory exploration in rats. Brain Res. 199:1980;359-384.
29. Fiorino D.F., Coury A., Phillips A.G. Dynamic changes in nucleus accumbens dopamine efflux during the Coolidge effect in male rats. J Neurosci. 17:1997;4849-4855.
30. Gaiardi M., Bartoletti M., Bacchi A., Gubellini C., Costa M., Babbini M. Role of repeated exposure to morphine in determining its affective properties Place and taste conditioning studies in rats . Psychopharmacology (Berl). 103:1991;183-186.
31. Gerasimov M.R., Franceschi M., Volkow N.D., Gifford A., Gatley S.J., Marsteller D., et al. Comparison between intraperitoneal and oral methylphenidate administration A microdialysis and locomotor activity study . J Pharmacol Exp Ther. 295:2000;51-57.
32. Gerasimov M.R., Franceschi M., Volkow N.D., Rice O., Schiffer W.K., Dewey S.L. Synergistic interactions between nicotine and cocaine or methylphenidate depend on the dose of dopamine transporter inhibitor. Synapse. 38:2000;432-437.
33. Gispen W.H., Colbern D.L., Spruijt B.M. Molecular transduction mechanisms in ACTH-induced grooming. Psychopharmacol Ser. 4:1988;215-231.
34. Gispen W.H., Isaacson R.L. ACTH-induced excessive grooming in the rat. Pharmacol Ther. 12:1981;209-246.
35. Goldman L.S., Genel M., Bezman R.J., Slanetz P.J. Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Council on Scientific Affairs, American Medical Association. JAMA. 279:1998;1100-1107.
36. Gordon N.S., Kollack-Walker S., Akil H., Panksepp J. Expression of c-fos gene activation during rough and tumble play in juvenile rats. Brain Res Bull. 57:2002;651-659.
37. Greenhill L.L., Pliszka S., Dulcan M.K., Bernet W., Arnold V., Beitchman J., et al. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry. 41:(suppl 2):2002;26S-49S.
38. Hajnal A., Norgren R. Accumbens dopamine mechanisms in sucrose intake. Brain Res. 904:2001;76-84.
39. Hogg S. A review of the validity and variability of the elevated plus-maze as an animal model of anxiety. Pharmacol Biochem Behav. 54:1996;21-30.
40. Hooks M.S., Kalivas P.W. The role of mesoaccumbens-pallidal circuitry in novelty-induced behavioral activation. Neuroscience. 64:1995;587-597.
41. Horger B.A., Giles M.K., Schenk S. Preexposure to amphetamine and nicotine predisposes rats to self-administer a low dose of cocaine. Psychopharmacology (Berl). 107:1992;271-276.
42. Horger B.A., Shelton K., Schenk S. Preexposure sensitizes rats to the rewarding effects of cocaine. Pharmacol Biochem Behav. 37:1990;707-711.
43. Hyman S.E. Mood disorders in children and adolescents An NIMH perspective . Biol Psychiatry. 49:2001;962-969.
44. Kabbaj M., Devine D.P., Savage V.R., Akil H. Neurobiological correlates of individual differences in novelty-seeking behavior in the rat Differential expression of stress-related molecules . J Neurosci. 20:2000;6983-6988.
45. Kapur S., Mann J.J. Role of the dopaminergic system in depression. Biol Psychiatry. 32:1992;1-17.
46. Kelley A.E., Berridge K.C. The neuroscience of natural rewards Relevance to addictive drugs . J Neurosci. 22:2002;3306-3311.
47. Kirby K., Rutman L.E., Bernstein H. Attention-deficit/hyperactivity disorder A therapeutic update . Curr Opin Pediatr. 14:2002;236-246.
48. Klein-Schwartz W. Abuse and toxicity of methylphenidate. Curr Opin Pediatr. 14:2002;219-223.
49. Kollins S.H., MacDonald E.K., Rush C.R. Assessing the abuse potential of methylphenidate in nonhuman and human subjects A review . Pharmacol Biochem Behav. 68:2001;611-627.
50. Koob G.F., Sanna P.P., Bloom F.E. Neuroscience of addiction. Neuron. 21:1998;467-476.
51. Koob G.F., Stinus L., Le Moal M. Hyperactivity and hypoactivity produced by lesions to the mesolimbic dopamine system. Behav Brain Res. 3:1981;341-359.
52. Kuczenski R., Segal D.S. Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine Comparison with amphetamine . J Neurochem. 68:1997;2032-2037.
53. Kuczenski R., Segal D.S. Locomotor effects of acute and repeated threshold doses of amphetamine and methylphenidate Relative roles of dopamine and norepinephrine . J Pharmacol Exp Ther. 296:2001;876-883.
54. Ladd C.O., Huot R.L., Thrivikraman K.V., Nemeroff C.B., Meaney M.J., Plotsky P.M. Long-term behavioral and neuroendocrine adaptations to adverse early experience. Prog Brain Res. 122:2000;81-103.
55. Laviola G., Adriani W., Terranova M.L., Gerra G. Psychobiological risk factors for vulnerability to psychostimulants in human adolescents and animal models. Neurosci Biobehav Rev. 23:1999;993-1010.
56. LeFever G.B., Dawson K.V., Morrow A.L. The extent of drug therapy for attention deficit-hyperactivity disorder among children in public schools. Am J Public Health. 89:1999;1359-1364.
57. Lucki I. The forced swimming test as a model for core and component behavioral effects of antidepressant drugs. Behav Pharmacol. 8:1997;523-532.
58. Marinelli M., White F.J. Enhanced vulnerability to cocaine self-administration is associated with elevated impulse activity of midbrain dopamine neurons. J Neurosci. 20:2000;8876-8885.
59. McDougall S.A., Bolanos C.A. Behavioral effects of the reversible dopamine antagonist flupenthixol are not potentiated by N-ethoxycarbonyl-2- ethoxy-1,2-dihydroquinoline in the preweanling rat. Pharmacol Biochem Behav. 50:1995;127-131.
60. McDougall S.A., Collins R.L., Karper P.E., Watson J.B., Crawford C.A. Effects of repeated methylphenidate treatment in the young rat Sensitization of both locomotor activity and stereotyped sniffing . Exp Clin Psychopharmacol. 7:1999;208-218.
61. McDougall S.A., Crawford C.A., Nonneman A.J. Effects of irreversible dopamine receptor inactivation on locomotor activity and grooming in the 17- and 90-day-old rat. Psychopharmacology (Berl). 106:1992;502-510.
62. Meririnne E., Kankaanpaa A., Seppala T. Rewarding properties of methylphenidate Sensitization by prior exposure to the drug and effects of dopamine D1- and D2-receptor antagonists . J Pharmacol Exp Ther. 298:2001;539-550.
63. Miller K.J., Castellanos F.X. Attention deficit/hyperactivity disorders. Pediatr Rev. 19:1998;373-384.
64. Naranjo C.A., Tremblay L.K., Busto U.E. The role of the brain reward system in depression. Prog Neuropsychopharmacol Biol Psychiatry. 25:2001;781-823.
65. Nestler E.J. Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci. 2:2001;119-128.
66. Nestler E.J., Barrot M., DiLeone R.J., Eisch A.J., Gold S.J., Monteggia L.M. Neurobiology of depression. Neuron. 34:2002;13-25.
67. Newton S.S., Thome J., Wallace T.L., Shirayama Y., Schlesinger L., Sakai N., et al. Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect. J Neurosci. 22:2002;10883-10890.
68. Panksepp J., Herman B.H., Vilberg T., Bishop P., DeEskinazi F.G. Endogenous opioids and social behavior. Neurosci Biobehav Rev. 4:1980;473-487.
69. Panksepp J., Siviy S., Normansell L. The psychobiology of play Theoretical and methodological perspectives . Neurosci Biobehav Rev. 8:1984;465-492.
70. Papp M., Willner P., Muscat R. An animal model of anhedonia Attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress . Psychopharmacology (Berl). 104:1991;255-259.
71. Pierce R.C., Crawford C.A., Nonneman A.J., Mattingly B.A., Bardo M.T. Effect of forebrain dopamine depletion on novelty-induced place preference behavior in rats. Pharmacol Biochem Behav. 36:1990;321-325.
72. Pierre P.J., Vezina P. Predisposition to self-administer amphetamine The contribution of response to novelty and prior exposure to the drug . Psychopharmacology (Berl). 129:1997;277-284.
73. Pliakas A.M., Carlson R.R., Neve R.L., Konradi C., Nestler E.J., Carlezon W.A. Jr. Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens. J Neurosci. 21:2001;7397-7403.
74. Porsolt R.D., Le Pichon M., Jalfre M. Depression A new animal model sensitive to antidepressant treatments . Nature. 266:1977;730-732.
75. Ramos A., Mormede P. Stress and emotionality A multidimensional and genetic approach . Neurosci Biobehav Rev. 22:1998;33-57.
76. Rebec G.V., Christensen J.R., Guerra C., Bardo M.T. Regional and temporal differences in real-time dopamine efflux in the nucleus accumbens during free-choice novelty. Brain Res. 776:1997;61-67.
77. Robbins T.W., Cador M., Taylor J.R., Everitt B.J. Limbic-striatal interactions in reward-related processes. Neurosci Biobehav Rev. 13:1989;155-162.
78. Robbins T.W., Everitt B.J. Neurobehavioural mechanisms of reward and motivation. Curr Opin Neurobiol. 6:1996;228-236.
79. Robinson T.E., Berridge K.C. The neural basis of drug craving An incentive-sensitization theory of addiction . Brain Res Brain Res Rev. 18:1993;247-291.
80. Sampson D., Muscat R., Phillips G., Willner P. Decreased reactivity to sweetness following chronic exposure to mild unpredictable stress or acute administration of pimozide. Neurosci Biobehav Rev. 16:1992;519-524.
81. Schenk S., Davidson E.S. Stimulant preexposure sensitizes rats and humans to the rewarding effects of cocaine. NIDA Res Monogr. 169:1998;56-82.
82. Schenk S., Izenwasser S. Pretreatment with methylphenidate sensitizes rats to the reinforcing effects of cocaine. Pharmacol Biochem Behav. 72:2002;651-657.
83. Schweri M.M., Skolnick P., Rafferty M.F., Rice K.C., Janowsky A.J., Paul S.M. [3H]Threo-(+/-)-methylphenidate binding to 3,4-dihydroxyphenylethylamine uptake sites in corpus striatum: Correlation with the stimulant properties of ritalinic acid esters. J Neurochem. 45:1985;1062-1070.
84. Seeman P., Bzowej N.H., Guan H.C., Bergeron C., Becker L.E., Reynolds G.P., et al. Human brain dopamine receptors in children and aging adults. Synapse. 1:1987;399-404.
85. Self D.W., Genova L.M., Hope B.T., Barnhart W.J., Spencer J.J., Nestler E.J. Involvement of cAMP-dependent protein kinase in the nucleus accumbens in cocaine self-administration and relapse of cocaine-seeking behavior. J Neurosci. 18:1998;1848-1859.
86. Self D.W., Nestler E.J. Molecular mechanisms of drug reinforcement and addiction. Annu Rev Neurosci. 18:1995;463-495.
87. Shimura T., Kamada Y., Yamamoto T. Ventral tegmental lesions reduce overconsumption of normally preferred taste fluid in rats. Behav Brain Res. 134:2002;123-130.
88. Shippenberg T.S., Heidbreder C., Lefevour A. Sensitization to the conditioned rewarding effects of morphine Pharmacology and temporal characteristics . Eur J Pharmacol. 299:1996;33-39.
89. Silver L.B. Attention-deficit/hyperactivity disorder in adult life. Child Adolesc Psychiatr Clin North Am. 9:2000;511-523.
90. Sodersten P., Damassa D.A., Smith E.R. Sexual behavior in developing male rats. Horm Behav. 8:1977;320-341.
91. Spear L.P. The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev. 24:2000;417-463.
92. Spear L.P., Brake S.C. Periadolescence Age-dependent behavior and psychopharmacological responsivity in rats . Dev Psychobiol. 16:1983;83-109.
93. Spencer T., Biederman J., Wilens T., Harding M., O'Donnell D., Griffin S. Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle. J Am Acad Child Adolesc Psychiatry. 35:1996;409-432.
94. Sproson E.J., Chantrey J., Hollis C., Marsden C.A., Fonel K.C. Effect of repeated methylphenidate administration on presynaptic dopamine and behaviour in young adult rats. J Psychopharmacol. 15:2001;67-75.
95. Spruijt B.M., Welbergen P., Brakkee J., Gispen W.H. An ethological analysis of excessive grooming in young and aged rats. Ann N Y Acad Sci. 525:1988;89-100.
96. Swanson J.M., Sergeant J.A., Taylor E., Sonuga-Barke E.J., Jensen P.S., Cantwell D.P. Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet. 351:1998;429-433.
97. Taylor F.B., Russo J. Comparing guanfacine and dextroamphetamine for the treatment of adult attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 21:2001;223-228.
98. Teicher M.H., Andersen S.L., Hostetter J.C. Jr. Evidence for dopamine receptor pruning between adolescence and adulthood in striatum but not nucleus accumbens. Brain Res Dev Brain Res. 89:1995;167-172.
99. Teicher M.H., Andersen S.L., Polcari A., Anderson C.M., Navalta C.P. Developmental neurobiology of childhood stress and trauma. Psychiatr Clin North Am. 25:2002;397-426.
100. Vanderschuren L.J., Niesink R.J., Van Ree J.M. The neurobiology of social play behavior in rats. Neurosci Biobehav Rev. 21:1997;309-326.
101. Vanderschuren L.J., Stein E.A., Wiegant V.M., Van Ree J.M. Social isolation and social interaction alter regional brain opioid receptor binding in rats. Eur Neuropsychopharmacol. 5:1995;119-127.
102. Vezina P., Pierre P.J., Lorrain D.S. The effect of previous exposure to amphetamine on drug-induced locomotion and self-administration of a low dose of the drug. Psychopharmacology (Berl). 147:1999;125-134.
103. Volkow N.D., Wang G., Fowler J.S., Logan J., Gerasimov M., Maynard L., et al. Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. J Neurosci. 21:2001;RC121.
104. Volkow N.D., Wang G.J., Fowler J.S., Gatley S.J., Logan J., Ding Y.S., et al. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry. 155:1998;1325-1331.
105. Volkow N.D., Wang G.J., Fowler J.S., Logan J., Gatley S.J., Wong C., et al. Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors. J Pharmacol Exp Ther. 291:1999;409-415.
106. Wargin W., Patrick K., Kilts C., Gualtieri C.T., Ellington K., Mueller R.A., et al. Pharmacokinetics of methylphenidate in man, rat and monkey. J Pharmacol Exp Ther. 226:1983;382-386.
107. Wilens T.E., Biederman J., Spencer T.J. Attention deficit/hyperactivity disorder across the lifespan. Annu Rev Med. 53:2002;113-131.
108. Willner P., Towell A., Sampson D., Sophokleous S., Muscat R. Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology (Berl). 93:1987;358-364.
109. Wise R.A., Bozarth M.A. A psychomotor stimulant theory of addiction. Psychol Rev. 94:1987;469-492.
110. Wolraich M.L., Lindgren S., Stromquist A., Milich R., Davis C., Watson D. Stimulant medication use by primary care physicians in the treatment of attention deficit hyperactivity disorder. Pediatrics. 86:1990;95-101.
111. Yadid G., Overstreet D.H., Zangen A. Limbic dopaminergic adaptation to a stressful stimulus in a rat model of depression. Brain Res. 896:2001;43-47.
112. Zavala A.R., Yoshida S.T., Osburn J.R., McDougall S.A. Paradoxical locomotor activating effects of kappa-opioid receptor stimulation in the preweanling rat Role of the ventromedial thalamus and superior colliculus . Brain Res Dev Brain Res. 139:2002;301-306.
113. Zito J.M. Five burning questions. J Dev Behav Pediatr. 23:(suppl 1):2002;S23-30.
114. Zito J.M., Safer D.J., dosReis S., Gardner J.F., Boles M., Lynch F. Trends in the prescribing of psychotropic medications to preschoolers. JAMA. 283:2000;1025-1030.