Relationship between psychostimulant-induced "high" and dopamine transporter occupancy.

Abstract

The ability ofcocaine to inhibit the dopamine transporter (DAT) appears to be crucial for its reinforcing properties. The potential use of drugs that produce longlasting inhibition of the DAT as a mean of preventing the "high" and reducing drug-seeking behavior has become a major strategy in medication development. However, neither the relation between the high and DAT inhibition nor the ability to block the high by prior DAT Cocaine addiction is one of the most devastating of the behavioral diseases. Despite its seriousness, there are no effective treatment medications. This has prompted a major effort in the development of pharmacological agents to treat cocaine addiction. One of the main strategies is the development of medications that would interfere with cocaine binding to the dopamine transporter (DAT) and block its effects (1). This "cocaine substitute" strategy is based on the good correlation found between the affinities of cocaine and cocaine like drugs for the DAT and their reinforcing effects (2, 3) and the fact that the "high" is associated with the fast uptake of these drugs in brain but not with their continuous presence (4). However, neither the relation between the high and acute DAT inhibition nor the ability to block the high by long lasting DAT inhibitors has ever been demonstrated.In this study we evaluated the relationship between DAT blockade and the high using methylphenidate (MP) as the pharmacological challenge. MP was used because it has similar reinforcing properties to those of cocaine (5, 6) [its affinity for DAT is about twice that of cocaine (2)], its intravenous administration induces a high indistinguishable from that of cocaine (7), and it has longer pharmacokinetics than cocaine (half life in striatum >90 min versus 20 min for cocaine) which allows its repeated administration while there is still significant DAT blockade (4). We tested the ability to block or attenuate the high by prior DAT blockade by comparing the responses between the first and the second of two MP doses given 60 min apart. At 60 min the high from MP has returned to baseline, but the brain retains 75-80% of the peak drug concentration (4). Thus the two sequential dose strategy allowed us to evaluate the effects that DAT inhibition by the first dose had on the perception of the high induced by the second dose. We also assessed the relation between DAT occupancy and the subjective perception of the high after single and after two sequential doses of MP. Occupation of DAT by MP was measured with positron-emission tomography (PET) using [11C]d-threo-MP (the labeled active isomer of MP) as a DAT ligand (8). Four scans, including a baseline, were obtained in each subject to estimate MP-induced DAT occupancies at the times when the high induced after a single and after two sequential doses of MP occurs and to estimate DAT occupancies at 60 min after MP, which was the time selected to give the second of the two sequential MP doses. METHODSSubjects. Subjects were nine normal healthy male volunteers (25-35...

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

“…In addition, drug-induced increases in striatal DA have been linked with subjective feelings of euphoria [115,116]. The firing of DA cells that accompanies drug use encodes a number of reward properties, including reward expectancy [117], reward learning [118], and the consolidation of contextual memories [119].…”

Pet Imaging Studies in Drug Abuse Research

“…Each drug was as a tracer for DAT occupancy, it was found that an intravenous dose of 0.075 mg/kg of MP was required to occupy 50% of DAT (Volkow et al, 1996). This is in the same range as intravenously administered cocaine which occupies 50% of the DAT at a dose of 0.13 mg/kg.…”

“…In the case of cocaine, its rapid uptake and clearance paralleled the short-lived, selfreports of U high" induced by the drug . In the case of MP, the fast uptake of the drug paralleled only the ascending limb of the time course for the U high", which returned to baseline rapidly even though MP had not cleared from brain (Volkow et al, 1996). The rapid uptake of intravenously administered [?…”

“…]cocaine and ["Clmethylphenidate in the brain contrasts to the slow brain uptake of orally administered ["C]methylphenidate which takes about 60 minutes to reach peak uptake in the brain (Volkow et al, 1998) (Figure 5). It has been postulated that this slow brain uptake is the reason why MP does not induce a " high" when administered orally since the rapidity at which drugs of abuse exert their effects has been shown to be crucial in their reinforcing effects (Balster et al, 1973 as a tracer for DAT occupancy, it was found that an intravenous dose of 0.075 mg/kg of MP was required to occupy 50% of DAT (Volkow et al, 1996). This is in the same range as intravenously administered cocaine which occupies 50% of the DAT at a dose of 0.13 mg/kg.…”

“…These comparative PET studies draw a compelling picture of the importance of drug pharmacokinetics -. and route of administration as major contributing factors in drug abuse versus drug therapy.Indeed, when MP is given intravenously, it also produces a " high" that most cocaine abusers cannot distinguish from that produced by cocaine (Volkow et al, 1996). Such studies measuring pharmacokinetics and DAT occupancy provide important knowledge in the continuing effort to develop a pharmacologic strategy for treating cocaine abuse (O'Brien et al, 1997).…”