Cocaine craving is accompanied by glutamate imbalance in the reward system of the brain
Background: Craving is at the heart of addiction and its mechanisms seem to have rewired the reward circuitry in the brain profoundly. For decades, preclinical studies consistently reported glutamatergic adaptations in the nucleus accumbens (NAcc) after chronic substance abuse that is characterised by reduced glutamate levels after withdrawal and glutamatergic burst during drug-seeking reinstatement. However, the translational validity of this animal model of addiction has still not been elucidated and, thus, little is known about neurometabolic changes following cocaine addiction in humans, mainly due to methodological obstacles. Therefore, we aim at investigating potential glutamatergic changes in the NAcc in humans following chronic cocaine use applying a recently optimised proton magnetic resonance spectroscopy (1H-MRS) protocol. It allows quantifying metabolites such as glutamate even within small subcortical volumes that have been difficult to assess in humans yet.
Methods: Thus, by means of this dedicated 1H-MRS sequence, glutamate concentrations in the NAcc have been assessed in 26 cocaine dependent individuals (CD) and 29 matching healthy control subjects (HC) during a neutral condition and while presentation of cocaine stimuli to trigger cocaine craving.
Results: Cocaine craving was significantly increased due to cocaine stimuli in CD by contrast with neutral stimuli and in comparison to HC. Despite the small region of interest, glutamate levels were reliably detected and quantified in the human NAcc. Moreover, the basal glutamate concentration was significantly diminished in CD compared to HC, while glutamate levels in CD considerably increased during presentation of cocaine stimuli.
Conclusion: These findings are conform with changes of glutamate transmission described in substance-seeking reinstatement models in rodents. This indicates that accumbal glutamate signalling in human cocaine addiction is generally restricted but is augmented when craving is triggered. This verification of a disrupted glutamate homeostasis in cocaine dependent individuals suggests a major role of the glutamatergic system in the persistence of cocaine addiction and provides a target for future pharmacotherapies.