Dopaminergic Dysfunction in Schizophrenia: Salience Attribution Revisited

Abstract

A dysregulation of the mesolimbic dopamine system in schizophrenia patients may lead to aberrant attribution of incentive salience and contribute to the emergence of psychopathological symptoms like delusions. The dopaminergic signal has been conceptualized to represent a prediction error that indicates the difference between received and predicted reward. The incentive salience hypothesis states that dopamine mediates the attribution of ''incentive salience'' to conditioned cues that predict reward. This hypothesis was initially applied in the context of drug addiction and then transferred to schizophrenic psychosis. It was hypothesized that increased firing (chaotic or stress associated) of dopaminergic neurons in the striatum of schizophrenia patients attributes incentive salience to otherwise irrelevant stimuli. Here, we review recent neuroimaging studies directly addressing this hypothesis. They suggest that neuronal functions associated with dopaminergic signaling, such as the attribution of salience to reward-predicting stimuli and the computation of prediction errors, are indeed altered in schizophrenia patients and that this impairment appears to contribute to delusion formation.Key words: psychosis/delusion/reward/ventral striatum/ fMRI/FDOPA It has long been suggested that dopamine dysfunction plays a major role in the pathogenesis of schizophrenic psychosis.1 First studies with positron emission tomography (PET) suggested that dopamine D2 receptors are indeed upregulated in schizophrenia patients 2 ; however, this finding was not confirmed in further studies.3 Also, studies on dopamine D2 receptor genotype failed to find an association between functional variance and schizophrenia. 4 It was not until 1996 that in vivo imaging studies first found convincing evidence of dopamine dysregulation in acute psychosis: Laruelle et al 5 and Breier et al 6 used the fact that radioligands, such as raclopride, are displaced by endogenous dopamine due to competition for binding at dopamine D2 receptors ( figure 1 and figure 2). They applied psychostimulants to release dopamine and observed increased displacement of dopamine D2 receptor ligands in unmedicated schizophrenia patients compared with healthy controls, suggesting that the pool of releasable dopamine is increased in patients suffering from schizophrenic psychosis. This hypothesis was further supported by studies using the radioligand [ 18 F]fluoro-3,4-dihydroxyphenyl-Lalanine (FDOPA), which is absorbed by dopaminergic neurons and metabolized into dopamine and subsequently stored in the presynaptic terminal. Studies with this radioligand suggested increased striatal dopamine synthesis capacity in unmedicated schizophrenia patients [8][9][10] ; a recent study by Kumakura et al 11 used a refined technology that takes into account that presynaptical dopamine is not simply trapped but instead released into the extracellular space in association with neuronal activation. This study found considerable differences in dopamine storage capacity between schizophreni...

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