Vol 2 n° 4 - Schizophrenia: General Findings
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Recent developments in positron emission tomography (PET) and single-photon emission computed tomogra- phy (SPECT) imaging have enabled functional measure- ments of dopamine (DA) transmission at dopamine D2 receptors in the living human brain. Studies using these techniques have demonstrated that, in schizophrenia, increased DA stimulation of striatal D2 receptors is asso- ciated with the first episode of illness and subsequent episodes of illness exacerbation. While this dysregula- tion of DA function is not associated with the severity of positive symptoms per se, increased synaptic DA activity is predictive of good therapeutic response to antipsy- chotic treatment. Abnormalities of DA function were not detected during periods of illness remission. These findings are integrated into a clinical model proposing that, in schizophrenia, neurodevelopmental abnormali- ties of cortico-subcortical connectivity result in a vulner- ability of the mesolimbic DA system to the development of a process of endogenous sensitization, and that the resulting  sustained  hyperstimulation  of  D2  receptors induces neuroplastic changes within corticostriatal-thal- amocortical loops, perturbing information processing and underlying the psychotic experience. The “classical” dopamine (DA) hypothesis of schizophrenia proposed that hyperactivity of DA trans- mission is responsible for the positive symptoms (hallu- cinations,  delusions)  observed  in  this  disorder.1 This hypothesis was supported by the correlation between clinical doses of antipsychotic drugs and their potency for blocking DA D2 receptors,2,3 and by the psychoto- genic effects of DA-enhancing drugs (for reviews, see references  4  and  5).  These  critical  pharmacological observations suggested, but did not establish, a dysregu- lation of DA systems in schizophrenia. On the other hand, negative and cognitive symptoms are generally resistant to treatment by antipsychotic drugs. Impairment in higher cognitive functions, such as working memory, is one of the most enduring symptoms of schizophrenia and a strong predictor of poor clinical outcome.6 Functional brain-imaging studies suggested that these symptoms are associated with a dysfunction of the prefrontal cortex (PFC).7-9 Studies in nonhuman pri- mates demonstrated that deficit in DA transmission in the PFC and lack of stimulation of D1 receptors (the main DA receptor subtype in the PFC) induce cogni- tive  impairments  reminiscent  of  those  observed  in patients with schizophrenia.10 Together, these observa- tions suggest that a deficit in DA transmission at D1 receptors in the PFC might be implicated in the cogni- tive impairments presented by these patients.9 Thus, the current view on DA and schizophrenia proposes that schizophrenia might be associated with a dopamin- ergic imbalance involving an excess of subcortical DA and a deficit in cortical DA function: subcortical mesolim- bic DA projections might be hyperactive (resulting in Dopamine in the history of the schizophrenic brain:recent contributions of brain-imaging studies Marc Laruelle, MD;  Anissa Abi-Dargham, MD Keywords: dopamine agonist; dopamine D2 receptor; positron emission tomography; psychostimulant; schizophrenia; sensitization; single-photon emission computed tomography Author affiliations: Departments of Psychiatry and Radiology, Columbia University College of Physicians and Surgeons and New York State Psychiatric Institute, New York, NY, USA Address for correspondence: Marc Laruelle, Department of Psychiatry, Colum-bia University, New York State Psychiatric Institute, 1051 Riverside Drive, Unit 42, New York, NY 10032, USA
(e-mail: ml393@columbia.edu)

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