9-11 Despite decades of effort to validate these hypotheses, documentation of abnormalities of DA function in schizophrenia has remained elusive. Postmortem studies measuring DA and its metabolites and receptors in the brains of schizophrenic patients have yielded inconsistent, or inconclusive results
(for a review, see reference 11). The lack of clear evidence for altered dopaminergic indices in schizophrenia might, indicate that DA transmission is abnormal only relative to Inhibitors,research,lifescience,medical other systems, such as the glutamatergic system.12 On the other hand, the absence of data supporting the DA hypothesis of schizophrenia might be due to the difficulty in obtaining a direct measurement of DA transmission in the living human brain. However, over
the last, few years, progress in brain-imaging methods has enabled direct, measurement of DA transmission at the D2 receptor, and the application of these techniques to the study of schizophrenia has provided new insights into the nature and the Inhibitors,research,lifescience,medical role of DA function dysregulation in schizophrenia. This paper will briefly review these data, and explore the implications of these results in terms of pathophysiology and treatment. Brain imaging as a tool for measuring DA synaptic activities Neuroreceptor imaging with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are classically Inhibitors,research,lifescience,medical aimed at measuring neuroreceptor parameters in the living human brain. More recently, several groups have demonstrated that under specific conditions, in vivo neuroreceptor Inhibitors,research,lifescience,medical binding techniques can also be used to measure acute fluctuations in the concentration of the endogenous transmitters in the vicinity of radiolabeled
receptors.13-16 Competition between radiotracers and transmitters for binding to neuroreceptors is the principle underlying this technique, though other mechanisms such as agonist-induced receptor internalization might also play a role (for a review, see Inhibitors,research,lifescience,medical reference 17). So far, applications of this new paradigm have been developed mainly to study DA transmission at D2 receptors. Endogenous competition between DA and radiolabeled D2 receptor ligands found was initially documented in ex vivo studies performed in rodents. Amphetamine, which releases DA and thereby increases endogenous DA synaptic concentration,18,19 reduced the in vivo binding of the D2 agonist [3H]-N-propylnorapomorphine20,21 and the D2 antagonist [3H]raclopride.22,23 Reduced in vivo accumulation of D2 tracers was also reported KPT-330 clinical trial following pretreatment with the DA uptake inhibitors amfonelic acid and methylphenidate.21 The opposite effect, (ie, increased tracer accumulation) was induced by drugs that decrease DA endogenous concentration, such as reserpine and γ-butyrolactone.21,23-26 These interactions suggested that PET and SPECT could be used to measure acute fluctuations in endogenous DA.