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Abstract:
Introduction: Craving, as triggered by drug-related cues, is at the heart of addiction. Preclinical models describe that chronic cocaine administration in rodents leads to decreased glutamate (Glu) levels in the nucleus accumbens (NAcc), whereas cueinduced reinstatement of drug-seeking is accompanied by enhanced glutamatergic transmission [1]. However, little is known about such neurometabolic alterations in cocaine addiction in humans. Thus, we aim at investigating potential changes within the Glu homeostasis in the NAcc of cocaine-dependent individuals during rest and cue-induced cocaine craving by means of a novel proton magnetic resonance spectroscopy (1H-MRS) protocol for
small voxels [2].
Methods: The applied 1H-MRS comprised non-water suppressed
PRESS localization preceded by a metabolite-cycling
pulsecombined with inner-volumesaturation andwas performedon
a 3T Philips Achieva (TE/TR = 32/2500 ms, 512 averages,
2000 Hz bandwidth). This scheme allows frequency and phase
alignment before signal averaging by using the high signal-to-noiseratio (SNR) of thewater peak to increase spectral quality. The voxel was of 9.4 × 18.8 × 8.4 mmand covered the leftNAcc. For absolute quantification of metabolites, a method based on the principle of
reciprocity has been applied [3]. Metabolites were quantified with
LC Model [4] and concentrations with SNR > 10 and Cramér-Rao
lower bounds (CRLBs) <20 were considered reliable.
Spectra were obtained in 25 cocaine-dependent individuals
(CD), meeting the DSM-IV cocaine dependence criteria with an
average cocaine consumption of 5.71 g/week, and in 30 healthy
controls (HC) matched with respect to sex, age, verbal IQ, years of
education and smoking status. All participants refrained from
illicit drugs for 3 days and from alcohol for 2 days before the
measurement. Glu concentrations were assessed twice, first during
a neutral and subsequently during a craving state that was triggered
by audio-visual cocaine stimuli. Subjective cravings were rated on
a visual analogue scale.
Results: An average SNR of 17.29, a mean line width of
6.95 Hz and CRLB <10 indicate good spectral quality. During
neutral state, Glu concentrations were significantly reduced in
CDs (M = 0.011, SD = 0.002) compared to HCs (M = 0.013, SD
= 0.002), t(53) = 3.31, p = 0.002, d = 0.91.
Craving across session and groups were evaluated with
repeated-measures ANOVA. Craving was constantly higher in
CDs compared to HCs (group effect; F(1, 52) = 78.81, p < 0.001),
and elevated after the cocaine stimulus in relation to all previous
ratings (group × craving × time; F(1, 52) = 23.08, p < 0.001).
Moreover, repeated-measures ANOVA of Glu concentrations
revealed an opposing effect of cocaine stimuli in the two groups.
In CDs, Glu levels increased from the neutral to the craving state,
whereas Glu concentrations in HCs decreased (group × craving; F
(1, 52) = 7.07, p = 0.010).
Conclusion: Despite the small voxel size, our novel 1H-MRS
protocol achieves high data quality and, thus, finally allows a
reliable detection of glutamate in the human NAcc. For the first
time this reveals that, consistent with animal models, glutamatergic
alterations in the NAcc occur in cocaine-dependent humans
and might play a decisive role in the development and maintenance
of cocaine dependence. Hence, the glutamatergic system is a target
for future pharmacological treatment approaches.
