Abstract
1866a
Objectives Alcohol use disorders (AUD, as defined in DSM-V) are serious public health problems and significant contributors to the global burden of disease. Currently, a limited number of medications have been approved for treatment. Recently, research on AUD has implicated the glutamate system, particularly mGluR5, as key receptor in use, withdrawal, and relapse after abstinence. (Szumlinski et al, 2008; Paterson, et al, 2003). Currently, there are several PET ligands which are specific for mGluR5 - e.g 18F-FPEB and 11C-ABP688. Here, we use these two radiotracers to investigate changes in the mgluR5 system following chronic administration of alcohol in mice, by utilizing microPET and bio-distribution analysis.
Methods Imaging: A total of eight (8) C57-B6 mice were split into two groups 1. treatment group (n=4) , which received 2.5 g/kg i.p of ethanol (EtOH) for 14 days; and 2.a control group (n=4),that received an equivalent volume/kg of saline (sal) IP for 14 days. Within two hours of the final dose, the mice were scanned with 18F-FPEB (2 EtOH and 2 sal) or 11C-ABP (2 EtOH and 2 sal), on a GE Vista microPET scanner. All mice were scanned for a duration of 60 minutes, starting immediately after tail vein injection of 150-200 microCuries of FPEB/ABP. PET images were quantified using previously described methods (Nandi, et al, 2013). Biodistribution: An additional twelve (12) mice were studied for radiotracer brain biodistribution. Six mice (3 EtOH, 3 sal) were each injected with ABP or FPEB, then sacrificed 60 minutes after tracer injection;specific brain regions were dissected out and counted on a gamma counter.
Results Both imaging and biodistribution studies showed evidence for increased mGluR5 receptor density after chronic ethanol administration. Specifically, microPET imaging with both FPEB and ABP radiotracers, showed an increase in mGluR5 binding in cortex, hippocampus and striatum, which can be seen in the summed PET images of EtOH and saline treated mice . The biodistribution studies confirmed these results—specifically, in the EtOH treated mice there was a significant increase in binding in striatum, hippocampus and frontal cortex (p < 0.05). Therefore, using two different radiotracers and two methods of quantifying mGluR5 density, we demonstrated that chronic EtOH treatment robustly increases mGluR5.
Conclusions These results confirm a central role for mGluR5 in the chronic abuse of alcohol using two different mGluR5 ligands and two analytical methods (microPET, biodistribution). Our results are in line with the growing clinical evidence that glutamate signaling has a central role in the development and relapse from AUD. Future studies will investigate the time course of changes in mGluR5 density after cessation of alcohol use. References: Paterson, N. E., et al. (2003). Psychopharmacology (Berl), 167, 257-64. Szumlinski, K.K., et al. (2008) Biochem Pharmacol.;75:112-133 Nandi A, et al. (2013) J Nucl Med 54 (Supplement 2) [abstract] Grant Support : RO1AA023483-01A1