Neurochemical mechanisms underlying responses to psychostimulants.

It is proposed to undertake a study to determine if differences in dopa-minergic reactivity among individuals could explain the variability in response to psychostimulants and to assess the relation of this reactivity to mental state and personality characteristics. Investigation of these relations may provide clues to the association between brain biochemistry and predisposition for drug abuse. The underlying hypotheses are: 1. Behavioral response to a drug is not only a function of the chemical composition of the drug but also of the unique biochemical characteristics of an individual (Skrinskaya et al. 1992). 2. Personality and mental state of an individual reflect in part his/her unique metabolic and biochemical brain composition (Cloninger 1986). 3. Increased dopaminergic reactivity is associated with increased vulnerability for drug addiction (Deminiere et al. 1989). Positron emission tomography (PET) (Fowler et al. 1990) in conjunction with 11C-raclopride (Farde et al. 1985), a dopamine (DA) type 2 (D2) receptor ligand that is sensitive to endogenous DA (Inoue et al. 1989; Seeman et al. 1989; Young et al. 1991), will be used to measure DA reactivity. Responsivity of the DA system will be assessed by monitoring changes in 11C-raclopride binding induced by methylphenidate (MP) (Scheel-Kruger 1971). MP increases synaptic DA concentration by inhibiting the DA transporter (Schweri et al. 1985). Changes in DA concentration induced by MP or other drugs that increase synaptic DA concentration interfere with 11C-raclopride binding, and the degree of its inhibition is a measure of 323 relative changes in DA concentration. This method has been successfully used to measure drug-induced changes in DA concentration in response to pharmacological challenge in the baboon