Influence of Amphetamine-induced Sensitization on Dopamine Synthesis and Release

Positron emission tomography (PET) studies have consistently shown increased brain dopamine (DA) synthesis and enhanced d-amphetamine-induced DA release in patients with schizophrenia. Repeated administration of d-amphetamine leads to an increased subjective and behavioral drug-response. This effect, termed "sensitization", is paralleled by an increase in dopamine release to levels akin to those observed in schizophrenia. Schizophrenia thus goes along with a state of 'natural sensitization' towards amphetamines. However, while it is known that DA synthesis and release are both enhanced in schizophrenia, it is unknown whether sensitization changes indices of presynaptic DA synthesis in the striatum of healthy subjects. Thus, for the first time, this project will study the effects of repeated d-amphetamine on uptake of the DA precursor \[18F\]FDOPA and on d-amphetamine-induced changes in binding of the D2/3 receptor agonist radioligand \[11C\]-(+)PHNO in a within-subject design. Before and after amphetamine sensitization by repeated intermittent administration subjects will receive an \[18F\]FDOPA and and a \[11C\]-(+)PHNO PET scan. For the investigation of the influence of functional and structural cortical properties on dopamine synthesis and release, functional and structural magnet resonance imaging will be performed before and after sensitization.