Summary:The authors developed a novel positron emission tomography method to estimate changes in the synaptic level of dopamine ([DA]) induced by direct dopamine agonists (for example, apomorphine) in patients with Parkinson disease. The method is based on the typical asymmetry of the nigrostriatal lesion that often occurs in Parkinson disease. Using the between-side difference (ipsilateral (I) and contralateral (C) putamen to the more affected body side) of the inverse of the putamen [ 11 C]raclopride binding potential (BP), the authors obtainedat baseline (that is, before apomorphine administration) andafter apomorphine administration (assuming the concentration of apomorphine is equal in both putamina). The between-side difference in the estimated synaptic concentration of dopamine (diff [DA]) should remain constant unless apomorphine affects dopamine release differently between the two sides. The authors found that apomorphine given subcutaneously at doses of 0.03 and 0.06 mg/kg induced significant changes in their estimate of diff[DA] (P < 0.05). Such changes were more pronounced when only patients with a stable response to levodopa were considered (P < 0.01). These findings provide in vivo evidence that direct dopamine agonists can inhibit the release of endogenous dopamine. The authors propose that this effect is mainly mediated by the activation of presynaptic D 2 /D 3 dopamine receptors. Key Words: Dopamine release-Motor complications-Parkinson disease-Presynaptic inhibition-PET-Raclopride.The progression of Parkinson disease (PD) is invariably accompanied by changes in the therapeutic response to levodopa (Marsden and Parkes, 1976) and to dopamine agonists such as apomorphine (Verhagen Metman et al., 1997). In the case of apomorphine, such changes include a shortened response duration, a steeper doseresponse curve, and a narrower therapeutic window (Verhagen Metman et al., 1997).The physiologic alterations underlying these changes have been the subject of some studies. One hypothesis is that they are primarily caused by postsynaptic alterations in receptor density or sensitivity (Bravi et al., 1994;Verhagen Metman et al., 1997;Zigmond et al., 1990). However, some recent studies suggest that changes in presynaptic autoregulatory function may accompany disease progression and that these changes may contribute to the development of altered therapeutic response (Ekesbo et al., 1999;Tedroff et al., 1996). These studies were based on the idea that dopamine synthesis, storage, and release are "autoregulated" in such a way as to maintain the synaptic concentration of dopamine. There is substantial evidence for this autoregulation and for its mediation by dopamine receptors. For 1151instance, in studies of the nigrostriatal system in various species, dopamine agonists have been shown to negatively regulate tyrosine hydroxylase activity (Cho et al., 1997), aromatic amino acid decarboxylase activity (Hadjiconstantinou et al., 1993), electrical firing (Bunney et al., 1973), and cerebrospinal fluid dopamine levels...