PHARMACOKINETICS OF PSYCHOSTIMULANTS AND REINFORCEMENT

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APPLICANT'S ABSTRACT: Cocaine and methylphenidate (MP) are both psychostimulant drugs. Yet cocaine is considered one of the most reinforcing and addictive drugs of abuse, while MP is widely used to treat attention deficit disorder in children. MP has a similar affinity for the dopamine transporter (DAT) as cocaine. Preliminary work from our laboratory using PET and [11C]cocaine and [11C]methylphenidate showed a striking similarity for the pattern of distribution of these two drugs in the human brain with competition for the same binding sites. However, they differ in their pharmacokinetics.MP's clearance from brain is significantly slower than that of cocaine. We hypothesize that the slow clearance of MP in brain will interfere with the magnitude of the response to a subsequent dose of MP, or cocaine, thus decreasing the likelihood of "bingeing" behavior. We propose to test these hypotheses by investigating the relation between the pharmacokinetics of MP in brain, its inhibition of the DATs and its behavioral effects after single and repeated administration.We will also investigate the effects of MP administration on the binding of cocaine in brain. We propose to use PET in conjunction with: [11C]methylphenidate to measure brain pharmacokinetics of MP, d-threo-[11C]methylphenidate to measure DAT occupancy after single and repeated iv MP administration and [11C]cocaine to evaluate binding inhibition by pharmacological doses of MP. For this last experiment we have chosen to use oral administration rather than iv because of the potential usefulness of a "slow release" form of MP in the treatment of cocaine addict. In parallel we will also evaluate the effects of oral MP on the behavioral response to a pharmacological dose of iv MP. Our working hypotheses are as follows: (1) The initial uptake of MP, as well as the fast inhibition of the DAT by MP, will be associated with the "high", but the continuous inhibition of the DAT will not. When a second dose is administered while the DATs are still inhibited, the "high" will be significantly decreased despite equivalent or even a larger percent of DAT inhibition. (2) Oral MP administration, will inhibit binding of [11C]cocaine and [11C]MP to a comparable extent and will decrease the magnitude of the iv MP-induced "high". Understanding the relation between MP's pharmacokinetics in brain, its length of occupation of the DAT and its psychoactive effects is important not only in understanding the addictive potential of MP and other psychostimulant drugs but also for the development of therapeutic strategies to treat cocaine addiction.