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Abstract

Objective The primary focus of previous addiction research was on the dopamine system, by which the rewarding and reinforcing effects of cocaine are mediated. However, over the past decade evidence from preclinical studies emerged showing that cocaine use also leads to long-lasting neuroadaptations in the corticostriatal glutamate system, in which the dopamine axon terminals are embedded (Kalivas, 2009). Disruption of the glutamate homeostasis seems to be particularly relevant for drug-seeking and relapse-related behaviors (McFarland et al., 2003; Reissner and Kalivas, 2010). The metabotropic glutamate receptor 5 (mGluR5) seems an interesting candidate to be investigated because mGluR5 null mutant mice did not self-administer cocaine and mGluR5 anatagonists attenuated self-administration and reinstatement of cocaine use in rodents (Backstrom and Hyytia, 2006; Chiamulera et al., 2001). Moreover, a human magnetic resonance spectroscopy (MRS) study with chronic cocaine users found lower glutamate levels in the ACC in comparison to controls (Yang et al., 2009). Interestingly, years of cocaine use correlated positively with glutamate levels possibly implying a compensatory neurobiological mechanism over time. Therefore, achieving a more in-depth understanding of cocaine-related glutamatergic alterations in humans may eventually lead to the development of novel drug treatment approaches. Methods Sixteen male cocaine users either with an occasional or chronic cocaine use pattern and 16 male controls will undergo [11C]-ABP688 positron emission tomography (PET) and 1H MRS. [11C]-ABP688 is a selective radioligand for the mGluR5, allowing to investigate potential group differences in mGluR5 densities in selected regions of interest such as the DLPFC, OFC, ACC, MPFC, and the striatum. Free in vivo glutamate concentrations of the perigenual ACC and the DLPFC will be acquired in MRS by means of a 2D JPRESS sequence and quantified by using ProFit. In addition, participants will complete a comprehensive neuropsychological test battery to relate putative neurobiological alterations to cognitive impairment.