2010). In order to reconcile these contradictory findings, it has been proposed that the effects

of dopaminergic drugs depend on task demands as well as the residual level of endogenous dopamine in nigrostriatal and ventral tegmental area (VTA) PFC circuits (“dopamine overdose hypothesis”) (Cools 2006; Kehagia et al. 2010; de la Fuente-Fernandez 2012). Previous evidence also showed that the relation between dopaminergic neurotransmission and PFC Inhibitors,research,lifescience,medical function follows an inverted-U-shaped model (Williams and Goldman-Rakic 1995; Arnsten and Goldman-Rakic 1998). In other words, a drug that restores the function of a dopamine-depleted circuit might simultaneously overdose, and thus impair the function of a different network with a less severe dopaminergic deficit (Cools 2006; Kehagia

et al. 2010). Nonetheless, the complex relation between Inhibitors,research,lifescience,medical dopaminergic drugs and cognition in PD is far from being fully characterized and several questions remain open. For example, it is still unclear how Inhibitors,research,lifescience,medical dopamine agonists impact on cognition in PD and whether the brain responses associated with specific neuropsychological functions might be influenced by individual levels of nigrostriatal degeneration. This study investigated the effects of apomorphine, a potent and fast-acting dopamine agonist, on neural activity during working memory in PD patients with variable levels of nigrostriatal degeneration, as assessed by dopamine-transporter (DAT) imaging. Previous research in animal models of PD combined radio-isotopic Inhibitors,research,lifescience,medical and functional magnetic resonance imaging (fMRI) to investigate the relations between dopaminergic damage (tracked via DAT scan), D2 receptor sensitivity (measured with raclopride, a dopamine agonist), and blood oxygenation level–dependant (BOLD) response after infusion of apomorphine (Nguyen et al. 2000; Zhang et al. 2000, 2001, 2006).

These studies demonstrated that dopaminergic Inhibitors,research,lifescience,medical damage (i.e., reduced DAT levels) was associated with PI3K inhibitor enhanced striatal BOLD response to apomorphine (Nguyen et al. 2000; Zhang et al. 2000, 2001, 2006) and increased D2 receptor sensitivity Cediranib (AZD2171) (i.e., enhanced raclopride binding; Nguyen et al. 2000). Apomorphine is a nonselective dopamine agonist, although it exhibits a very high affinity for the D2 receptor family, and particularly the D4 receptor (Millan et al. 2002). At low doses (i.e., ~0.004 mg/kg), apomorphine reduces the dopamine release within the striatum via the inhibitory D2 receptors located presynaptically (i.e., on the nigrostriatal terminals) (Montoya et al. 2008; Schellekens et al. 2010). In contrast, at the higher (10-fold) doses used for PD treatment (i.e., ~0.04 mg/kg), apomorphine mainly stimulates the postsynaptic D2 receptors expressed by striatal neurons (Bowron 2004; LeWitt 2004).