Dissociable rate-dependent effects of oral methylphenidate on impulsivity and D2/3 receptor availability in the striatum.
We have previously shown that impulsivity in rats is linked to decreased dopamine D2/3 receptor availability in the ventral striatum. In the present study, we investigated, using longitudinal positron emission tomography (PET), the effects of orally administered methylphenidate (MPH), a first-line treatment for attention deficit hyperactivity disorder, on D2/3 receptor availability in the dorsal and ventral striatum and related these changes to impulsivity. Rats were screened for impulsive behavior on a five-choice serial reaction time task. After a baseline PET scan with the D2/3 ligand [(18)F]fallypride, rats received 6 mg/kg MPH, orally, twice each day for 28 d. Rats were then reassessed for impulsivity and underwent a second [(18)F]fallypride PET scan. Before MPH treatment, we found that D2/3 receptor availability was significantly decreased in the left but not the right ventral striatum of high-impulse (HI) rats compared with low-impulse (LI) rats. MPH treatment increased impulsivity in LI rats, and modulated impulsivity and D2/3 receptor availability in the dorsal and ventral striatum of HI rats through inverse relationships with baseline levels of impulsivity and D2/3 receptor availability, respectively. However, we found no relationship between the effects of MPH on impulsivity and D2/3 receptor availability in any of the striatal subregions investigated. These findings indicate that trait-like impulsivity is associated with decreased D2/3 receptor availability in the left ventral striatum, and that stimulant drugs modulate impulsivity and striatal D2/3 receptor availability through independent mechanisms.
Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224.
Daniele
D
Caprioli
Behavioural and Clinical Neuroscience Institute, and Department of Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom.
Bianca
B
Jupp
Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom.
Young T
YT
Hong
Behavioural and Clinical Neuroscience Institute, and Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom.
Stephen J
SJ
Sawiak
Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom.
Valentina
V
Ferrari
Behavioural and Clinical Neuroscience Institute, and Department of Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom.
Laura
L
Wharton
Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom.
David J
DJ
Williamson
School of Pharmacy, University of Auckland, Auckland 1142, New Zealand.
Carolyn
C
McNabb
Epilepsy Society, Chalfont St Peter SL9 0RJ, United Kingdom, and.
David
D
Berry
Behavioural and Clinical Neuroscience Institute, and Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom.
Franklin I
FI
Aigbirhio
Behavioural and Clinical Neuroscience Institute, and Department of Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom.
Trevor W
TW
Robbins
Behavioural and Clinical Neuroscience Institute, and Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom.
Tim D
TD
Fryer
Behavioural and Clinical Neuroscience Institute, and Department of Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom, Department of Psychiatry, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 2QQ, United Kingdom jwd20@cam.ac.uk.
Jeffrey W
JW
Dalley
D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D007175:Impulsive Behavior / Q000187:drug effects*; D008297:Male; D008774:Methylphenidate / Q000031:analogs & derivatives / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D050637:Receptors, Dopamine D3 / Q000187:drug effects*
D000697:Central Nervous System Stimulants; D018765:Dopamine Uptake Inhibitors; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D008774:Methylphenidate; C009189:ritalinic acid
addiction; attention-deficit hyperactivity disorder; dopamine; methylphenidate; nucleus accumbens; positron emission tomography