Cocaine is considered as one of the most reinforcing and addictive drugs Of abuse. The reinforcing properties of cocaine appear to be associated with its inhibition of the dopamine transporter (DAT). Methylphenidate (NIP), a drug given to children for the treatment of attention deficit disorder, has similar properties at the DAT as those of cocaine, and concerns have been raised about its abuse liability. Though the abuse of NIP has been reported, it is rare, and it predominantly occurs via intravenous administration. We postulate that while inhibition of the DAT by cocaine and MP is indispensable for their reinforcing effects, it is their pharmacokinetics that modulate their addictive potential. More specifically, we suggest that while the rate for peak uptake in brain will influence the intensity of the initial response, the rate of clearance will affect the intensity to subsequent responses during repeated administration. The purpose of this grant is to compare cocaine and NIP with respect to: their regional brain pharmacokinetics, degree of DAT inhibition and potency to change synaptic DA concentration after single and after repeated administration. We propose to use PET in conjunction with [11C]cocaine and [11C]methylphenidate to measure binding parameters and brain pharmacokinetics, [11C]d-threo-methylphenidate to measure DAT occupancy and [11C]raclopride to measure changes in synaptic dopamine (DA) concentration in response to cocaine and NIP. Our working hypothesis are as follows: 1)[11C]cocaine and [11C]methylphenidate will be of similar potency in inhibiting binding to the DAT. (2)Peak uptake and time to reach peak uptake in brain will be similar for [11C]MP and for [11C]cocaine, but clearance of [11C]MP will be significantly slower than that of [11C]cocaine. Slower clearance will lead to a longer period of DAT inhibition for NIP than for cocaine. (3 After single administration both drugs will induce similar increases in synaptic DA(as measured by inhibition of [11C]raclopride binding) whereas with sequential drug administrations (at 20 and 60 minutes intervals), NIP will induce a smaller response than cocaine. Preliminary work from our laboratory support these working hypotheses. Despite the widespread use of NIP in the treatment of attention deficit disorder, very little is known about its pharmacokinetics in brain as well as its abuse liability. In addition to being valuable in understanding the pharmacokinetics and the potential addictive properties of NIP, these studies are relevant in understanding the role of pharmacokinetics of drugs of abuse and therapeutic drugs in their ability to induce repeated self administration.
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| Wang, Gene-Jack; Volkow, Nora D; Telang, Frank et al. (2009) Evidence of gender differences in the ability to inhibit brain activation elicited by food stimulation. Proc Natl Acad Sci U S A 106:1249-54 |
| Tomasi, Dardo; Wang, Gene-Jack; Wang, Ruiliang et al. (2009) Association of body mass and brain activation during gastric distention: implications for obesity. PLoS One 4:e6847 |
| Woicik, Patricia A; Moeller, Scott J; Alia-Klein, Nelly et al. (2009) The neuropsychology of cocaine addiction: recent cocaine use masks impairment. Neuropsychopharmacology 34:1112-22 |
| Volkow, Nora D; Wang, Gene-Jack; Telang, Frank et al. (2009) Inverse association between BMI and prefrontal metabolic activity in healthy adults. Obesity (Silver Spring) 17:60-5 |
| Volkow, Nora D; Wang, Gene-Jack; Telang, Frank et al. (2008) Dopamine increases in striatum do not elicit craving in cocaine abusers unless they are coupled with cocaine cues. Neuroimage 39:1266-73 |
| Volkow, Nora D; Fowler, Joanna S; Wang, Gene-Jack et al. (2007) Dopamine in drug abuse and addiction: results of imaging studies and treatment implications. Arch Neurol 64:1575-9 |
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