Chronic treatment with extended release methylphenidate does not alter dopamine systems or increase vulnerability for cocaine self-administration: a study in nonhuman primates.
Despite the widespread use of stimulant medications for the treatment of attention deficit hyperactivity disorder, few studies have addressed their long-term effects on the developing brain or susceptibility to drug use in adolescence. Here, we determined the effects of chronic methylphenidate (MPH) treatment on brain dopamine (DA) systems, developmental milestones, and later vulnerability to substance abuse in juvenile nonhuman primates. Male rhesus monkeys (approximately 30 months old) were treated daily with either a sustained release formulation of MPH or placebo (N=8 per group). Doses were titrated to achieve initial drug blood serum levels within the therapeutic range in children and adjusted throughout the study to maintain target levels. Growth, including measures of crown-rump length and weight, was assessed before and after 1 year of treatment and after 3-5 months washout. In addition, positron emission tomography scans were performed to quantify binding availability of D2/D3 receptors and dopamine transporters (DATs). Distribution volume ratios were calculated to quantify binding of [¹⁸F]fluoroclebopride (DA D2/D3) and [¹⁸F]-(+)-N-(4-fluorobenzyl)-2β-propanoyl-3β-(4-chlorophenyl)tropane (DAT). Chronic MPH did not differentially alter the course of weight gain or other measures of growth, nor did it influence DAT or D2/D3 receptor availability after 1 year of treatment. However, after washout, the D2/D3 receptor availability of MPH-treated animals did not continue to decline at the same rate as control animals. Acquisition of intravenous cocaine self-administration was examined by first substituting saline for food reinforcement and then cocaine doses (0.001-0.1 mg/kg per injection) in ascending order. Each dose was available for at least five consecutive sessions. The lowest dose of cocaine that maintained response rates significantly higher than saline-contingent rates was operationally defined as acquisition of cocaine reinforcement. There were no differences in rates of acquisition, overall response rates, or cocaine intake as a function of cocaine dose between groups. In an animal model that closely mimics human development; chronic treatment with therapeutic doses of sustained release MPH did not have a significant influence on the regulation of DATs or D2/D3 receptors, or on standard measures of growth. Furthermore, this treatment regimen and subsequent drug washout did not have an impact on vulnerability to cocaine abuse.
Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, NC, USA.
Kathryn E
KE
Gill
Peter J
PJ
Pierre
James
J
Daunais
Allyson J
AJ
Bennett
Susan
S
Martelle
H Donald
HD
Gage
James M
JM
Swanson
Michael A
MA
Nader
Linda J
LJ
Porrino
D000818:Animals; D000697:Central Nervous System Stimulants / Q000008:administration & dosage* / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D019970:Cocaine-Related Disorders / Q000523:psychology*; D003216:Conditioning, Operant / Q000187:drug effects; D003692:Delayed-Action Preparations; D004298:Dopamine / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D006128:Growth / Q000187:drug effects; D007091:Image Processing, Computer-Assisted; D008253:Macaca mulatta; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage* / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011954:Receptors, Dopamine / Q000187:drug effects; D012054:Reinforcement, Psychology; D012646:Self Administration
D000697:Central Nervous System Stimulants; D003692:Delayed-Action Preparations; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D011954:Receptors, Dopamine; D008774:Methylphenidate; D004298:Dopamine