Testing PET-[ ¹¹ C]ABP688 as a tool to quantify glutamate release in vivo

The excitatory neurotransmitter glutamate plays a critical role inexperience-dependent neuroplasticity, including addiction-related processes. Todate, however, it is not possible to measure glutamate release in the livinghuman brain. Positron emission tomography (PET) with [¹¹C]ABP688, aselective allosteric antagonist of metabotropic type 5 glutamate (mGlu5)receptors, could offer an effective strategy. To test this proposition, weconducted a series of studies in rats using microdialysis and[¹¹C]ABP688 microPET imaging, and in humans using PET and magneticresonance spectroscopy (MRS). Significant calcium-dependent glutamate releasewas identified in the ventral striatum of awake rats (190.5 ± 34.7%,p< 0.05;n= 7) followingadministration of a low dose of ethanol (EtOH; 20%, 0.5 g/kg), a pharmacologicalchallenge readily translatable to human research. Simultaneous microdialysis andmicroPET studies in anesthetized rats yielded concurrent increases in glutamaterelease (126.9 ± 5.3%,p < 0.001;n= 11) and decreases in striatal[¹¹C]ABP688 binding (6.8 ± 9.6%,p <0.05). These latter two effects, however, were not significantlycorrelated (r= 0.25,p= 0.46).In humans, a laboratory stressor yielded significant changes in self-reportedmood (ps < 0.041), sympathetic system activations(ps < 0.042), and the MRS index of striatalglutamate reuptake following excitatory neurotransmission, Glx/Cr levels(p= 0.048). These effects, however, were notaccompanied by significant changes in [¹¹C]ABP688 BP_ND(ps > 0.21,n= 9) orcorrelated with each other (ps > 0.074). Together, thesestudies document EtOH-induced glutamate release from neurons, EtOH-induceddecreases in [¹¹C]ABP688 binding, and stress-induced changes inglutamate turnover, yet fail to provide evidence that the PET[¹¹C]ABP688 method can be exploited to quantify moderate changes inglutamate release. The results underscore the need for highly controlled testingconditions during PET measures of mGlu5 receptors.