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

Abstract

Abstract The excitatory neurotransmitter glutamate plays a critical role in experience-dependent neuroplasticity, including addiction-related processes. To date, however, it is not possible to measure glutamate release in the living human brain. Positron emission tomography (PET) with [11C]ABP688, a selective allosteric antagonist of metabotropic type 5 glutamate (mGlu5) receptors, could offer an effective strategy. To test this proposition, we conducted a series of studies in rats using microdialysis and [11C]ABP688 microPET imaging, and in humans using PET and magnetic resonance spectroscopy (MRS). Significant calcium-dependent glutamate release was identified in the ventral striatum of awake rats (190.5 ± 34.7%, p < 0.05; n = 7) following administration of a low dose of ethanol (EtOH; 20%, 0.5 g/kg), a pharmacological challenge readily translatable to human research. Simultaneous microdialysis and microPET studies in anesthetized rats yielded concurrent increases in glutamate release (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 significantly correlated (r = 0.25, p = 0.46). In humans, a laboratory stressor yielded significant changes in self-reported mood (ps < 0.041), sympathetic system activations (ps < 0.042), and the MRS index of striatal glutamate reuptake following excitatory neurotransmission, Glx/Cr levels (p = 0.048). These effects, however, were not accompanied by significant changes in [11C]ABP688 BPND (ps > 0.21, n = 9) or correlated with each other (ps > 0.074). Together, these studies document EtOH-induced glutamate release from neurons, EtOH-induced decreases in [11C]ABP688 binding, and stress-induced changes in glutamate turnover, yet fail to provide evidence that the PET [11C]ABP688 method can be exploited to quantify moderate changes in glutamate release. The results underscore the need for highly controlled testing conditions during PET measures of mGlu5 receptors.