Effects of the partial agonist antipsychotic drug aripiprazole on dopamine synthesis in humans measured by PET with [C-11]DOPA

Objectives The partial agonist antipsychotic drugs of dopamine D2 receptors can modulate the dopaminergic neurotransmission as functional agonists or functional antagonists. Effects of antipsychotics on the presynaptic functions of dopaminergic neurotransmission might also be related to therapeutic effects of them. In the present study, changes in dopamine synthesis capacity by partial agonist antipsychotic drug aripiprazole were measured by PET.

Methods PET studies were performed on 12 healthy men under resting condition (baseline study) and oral administration of single dose of aripiprazole of 3-9 mg, (drug challenge study) on separate days. In each study, both PET scans with [C-11]raclopride and [C-11]DOPA were performed sequentially. The occupancy of dopamine D2 receptors by aripiprazole was calculated from binding potential values in the striatum for baseline and drug challenge studies with [C-11]raclopride determined by the SRTM method. The uptake rate constant, Ki, for [C-11]DOPA in the striatum indicating the dopamine synthesis capacity was estimated by the graphical analysis.

Results The occupancies of dopamine D2 receptors were 53%-77%. The dopamine synthesis capacity Ki were 0.0128±0.0016 and 0.0128±0.0014 (1/min) for the baseline and drug challenge studies, respectively, and no significant change in Ki by aripiprazole was observed. A significant negative correlation was observed between the baseline Ki and the change in Ki by aripiprazole (r=-0.65).

Conclusions The negative correlation between the baseline Ki and the change in Ki by aripiprazole, and smaller coefficient of variation of Ki in drug challenge studies than in baseline studies indicate that aripiprazole can be assumed to stabilize the level of dopamine synthesis capacity. Therapeutic effects of aripiprazole on schizophrenia might be related to stabilizing effects on dopaminergic neurotransmission responsivity in dopamine release