Measuring Neurotransmitter Release with PET: Methodological Issues

The objective of this study is to develop a method of measuring the release of neurotransmitter in the human brain based on the premise that endogenous neurotransmitter competes with a positron emission tomography neuroreceptor tracer for binding at the receptor site. A graphical method was used to estimate the change in distribution volume of the opiate antagonist [ 11 C]diprenorphine in response to stimuli intended to promote the release of opioid peptides in the brain. Six subjects inhaled the anesthetic agent nitrous oxide, which is thought to promote opioid peptide release. There was generalized displacement of the tracer throughout the brain in three out of six subjects. However, simulations showed that changes in cerebral blood flow (CBF) due to the stimulus could act as a confounding factor by causing significant displacement of radiotracer, and that this would be indistinguishable from effects attributed to endogenous transmitter release. Moreover, these studies also suffered from significant motion artifacts despite conventional head restraints. Standard realignment algorithms were applied to correct for motion; however, they introduced systematic errors (false displacements) due to the changing distribution of radioligand during the course of the scan. It was concluded that (1) in a displacement protocol, CBF changes in response to activation may mimic the effects of endogenous transmitter release; and (2) false positives may also result from slight subject motion. Motion correction algorithms, developed for [ 15 O]water activation studies, cannot be applied to dynamic radioligand images.