Noradrenergic correlates of chronic cocaine craving: neuromelanin and functional brain imaging

Abstract

Preclinical studies have implicated noradrenergic (NA) dysfunction in cocaine addiction. In particular, the NA system plays a central role in motivated behavior and may partake in the regulation of craving and drug use. Yet, human studies of the NA system are scarce, likely hampered by the difficulty in precisely localizing the locus coeruleus (LC). Here, we used neuromelanin imaging to localize the LC and quantified LC neuromelanin signal (NMS) intensity in 44 current cocaine users (CU; 37 men) and 59 nondrug users (NU; 44 men). We also employed fMRI to investigate cue-induced regional responses and LC functional connectivities, as quantified by generalized psychophysiological interaction (gPPI), in CU. Imaging data were processed by published routines and the findings were evaluated with a corrected threshold. We examined how these neural measures were associated with chronic cocaine craving, as assessed by the Cocaine Craving Questionnaire (CCQ). Compared to NU, CU demonstrated higher LC NMS for all probabilistic thresholds defined of 50-90% of the peak. In contrast, NMS of the ventral tegmental area/substantia nigra (VTA/SN) did not show significant group differences. Drug as compared to neutral cues elicited higher activations of many cortical and subcortical regions, none of which were significantly correlated with CCQ score. Drug vs. neutral cues also elicited "deactivation" of bilateral parahippocampal gyri (PHG) and PHG gPPI with a wide array of cortical and subcortical regions, including the ventral striatum and, with small volume correction, the LC. Less deactivation of the PHG (r = 0.40, p = 0.008) and higher PHG-LC gPPI (r = 0.44, p = 0.003) were positively correlated with the CCQ score. In contrast, PHG-VTA/SN connectivity did not correlate with the CCQ score. Together, chronic cocaine exposure may induce higher NMS intensity, suggesting neurotoxic effects on the LC. The correlation of cue-elicited PHG LC connectivity with CCQ score suggests a noradrenergic correlate of chronic cocaine craving. Potentially compensating for memory functions as in neurodegenerative conditions, cue-elicited PHG LC circuit connectivity plays an ill-adaptive role in supporting cocaine craving.

Fig. 1. NMS of the LC and VTA/SNc in CU and NU.

A LC NMS intensities were significantly different between CU and NU across all thresholds. B VTA/SNc NMS intensities were not significantly different between CU and NU across the same thresholds. Histograms show mean ± SD of the NMS for CU and NU at each threshold. **p < 0.01; ***p < 0.001; two-sample two-tail t-test with age, sex, AUDIT and FTND scores as covariates.

Fig. 2. Cue-induced regional activations and functional connectivity.

A One-sample t test of drug vs. neutral cues in CU. Voxels showing higher activation during drug vs. neutral and neutral vs. drug are shown in warm and cool colors, respectively. Voxel p < 0.001, uncorrected. Clusters that met cluster p < 0.05, FWE-corrected are listed in Table 2. B (upper panel) Cue-induced functional connectivity (gPPI) with bilateral PHG in CU: one-sample t test of drug vs. neutral cues. Voxels showing higher gPPI during drug vs. neutral are shown in warm colors. Voxel p < 0.001, uncorrected. Clusters that met cluster p < 0.05, FWE-corrected are listed in Supplementary Table S1. No clusters showed higher gPPI in response to neutral vs. drug cues. B (lower panel) LC and VTA/SNc masks and linear regression of LC and VTA/SNc gPPI with PHG vs. CCQ scores in CU.