Zusammenfassung
Introduction:
Drug addiction is accompanied by reduced appraisal of natural rewards and consequently by a shift towards drug-associated behaviors. The development of these maladaptive behaviors that sustain addictive disorders, seem to be decisively determined by neuroplastic changes in brain circuits involved in reward processing (Koob, 2010). Animal models revealed that chronic cocaine administration is tightly linked to decreased basal levels of extracellular glutamate (Glu) at prefrontal projections to the nucleus accumbens (NAcc), a key structure within the reward circuitry (Kalivas, 2009). Reinstatement of drug-seeking, in turn, results in enhanced Glu transmission (Kalivas, 2009).
However, little is known about neurometabolic changes in humans due to methodological obstacles. We thus aim at investigating potential Glu-ergic changes in the human NAcc following chronic cocaine use applying a recently developed proton magnetic resonance spectroscopy (1H-MRS) protocol (Hock, 2014). It allows quantifying metabolites such as Glu within small subcortical volumes that have been difficult to assess in humans yet. Since there is currently no approved pharmacological treatment for cocaine addiction, we aim at investigating whether 1H-MRS will allow to assess the potential impact of future pharmacological challenges targeting such metabolic changes. The purpose of this pilot study was to examine the feasibility of optimized 1H-MRS to detect basal and pharmacologically induced Glu-ergic alterations in cocaine addiction. Therefore, we aimed at verifying the intra-individual consistency of metabolic concentrations in the small volume of the NAcc over time by sequential 1H-MRS measurements.
Methods:
To detect potential individual fluctuation, five non-water suppressed PRESS localization combined with inner-volume saturation using a 3T Philips Achieva system (TE/TR=31.6/2500ms, 512 averages, 2000Hz band width) was performed in one healthy volunteer at five different time points. MRS spectra were obtained from the left NAcc as the region of interest (voxel size=9.4x18.8x8.4mm). Metabolite concentration ratios to creatine (Cr) based on fitting results (LCModel; Provencher, 1993) with Cramer-Rao lower bounds (CRLB)<20 were considered reliable.
Results:
Single and average spectra (N=5), LCModel fit, and the fit-residual of the five measurements indicate good spectral quality (mean/averaged SNR: 12.6/27, mean/averaged line width: 4.9/4.9 Hz). Further, the fits of single spectra show equivalent quality over all time points and compared to the average spectrum.
The metabolic concentration ratios over all measurement points as shown in Cr, N-acetyl-aspartate (NAA), Glu and the sum of Glu and glutamine (Glu+Gln), and choline (Cho) could be quantified reliably with CRLB<11. Further, the within-subject concentration ratios of Glu and Glu+Gln are relatively stable over time.
Conclusions:
Despite small voxel size, the applied 1H-MRS allows the detection of metabolite markers in NAcc with high data quality. Furthermore, intra-individual metabolic concentrations remain relatively constant across measurements and thus provide a feasible and robust measure to test for differences in Glu-ergic metabolism between healthy controls and cocaine users as observed in preclinical models of cocaine addiction. We expect that this procedure will also allow to assess the potential restoration of the Glu homeostasis as induced pharmacological interventions in substance use disorders.
