Imaging pathophysiology examples from schizophrenia research Imaging dopamine receptors

Much research effort has focused on in vivo PET/SPET measurement of striatal dopamine D2-receptor number in schizophrenia following the initial post-mortem reports of increased striatal dopamine receptor number. Initially, using [ (11)C]N-methylspiperone as a radiotracer, a two- to threefold raised striatal D 2-receptor number in drug-naive schizophrenics was reported.(7) However, subsequently other investigators using [^Cjraclopride, [(11)C]N-methylspiperone, [(123)I]iodobenzamide, [(76)Br]bromolisuride failed to detect such elevations of striatal dopamine D 2-receptor number/89) The different radiotracer methodologies used, the selectivity of radiotracers for dopamine D2, D3, and D4 receptor subtypes, and the clinical characteristics of the patients studied have been advanced as possible explanations for the failure to replicate raised striatal dopamine D 2-receptor number. However, given these conflicting but essentially negative results, attention has shifted in recent years to reports of increased presynaptic dopaminergic function measured with [ ^F^opa^..0,) and decreased cortical dopamine D1 receptors measured with [(11)C]SCH 23390(11) in schizophrenia. These studies await further replication.

A novel extension to studies utilizing PET/SPET radiotracers for imaging dopamine D 2 receptors has been to index dopamine release during a pharmacological challenge in schizophrenia. Theoretically, PET/SPET has the potential to detect neurotransmitter release associated with behavioural and pharmacological challenges if sufficient endogenous neurotransmitter is released to cause appreciable change (via receptor occupancy) in the number of 'available' receptors that can be 'seen' by a radioligand/5) For example, pre-dosing animals and human subjects with D-amphetamine, which releases dopamine, results in decreased [(11)C]raclopride and [(123)I]iodobenzamide binding to dopamine D2 receptors/1.2) Recently enhanced release of striatal dopamine in acutely symptomatic patients with schizophrenia following pharmacological challenge has been reported by Laruelle et al.'(l3 In these studies the displacement of radiotracer (presumably reflecting increased release of dopamine) correlated with worsening of positive symptoms. Whether this important finding of increased dopaminergic responsivity will be prove to be reliable state or trait marker for schizophrenia remains to be fully established.

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