Glutamatergic Biomarkers for Cocaine Addiction: A Longitudinal Study Using MR Spectroscopy and mGluR5 PET in Self-Administering Rats.

Abstract

Cocaine addiction is a disorder that still lacks diagnostic biomarkers or effective pharmacotherapy. We present findings on a rat model of cocaine self-administration that was followed up longitudinally using the metabotropic glutamate receptor type 5 (mGluR5) tracer ¹⁸F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile (¹⁸F-FPEB) PET, proton MR spectroscopy (¹H-MRS), and behavioral tests. <b>Methods:</b> Forty-two Wistar rats were scanned with ¹⁸F-FPEB PET and ¹H-MRS before and after sucrose or intravenous cocaine self-administration, during withdrawal, and during relapse. All animals performed a rodent Iowa Gambling Task (rIGT) at baseline to evaluate decision making. Baseline values were used in a mixed model to assess associations with later cocaine use, and follow-up measurements were compared with the values before drug exposure. <b>Results:</b> Preexposure rIGT scores were significantly related to both cocaine and sucrose use during the drug-exposure phase. However, only cocaine self-administration induced a decrease in ¹⁸F-FPEB binding. This decrease was most pronounced bilaterally in the hippocampus, where mGluR5 availability correlated with the amount of cocaine used during relapse. Compared with the sucrose group, a larger decrease was observed in the hippocampo-prefrontal cortex pathway. Preexposure glutamate and glycine concentrations in the prefrontal cortex were significantly associated with cocaine use during the drug-exposure phase. Moreover, prefrontal glutamate exhibited a distinct, reversible decrease when animals had access to cocaine but not sucrose. <b>Conclusion:</b> Baseline values of prefrontal glutamate and glycine are associated with future cocaine use. Furthermore, baseline rIGT scores are associated with both sucrose and cocaine. Finally, both glutamate concentration and mGluR5 availability decrease during exposure to cocaine.