Lower prefrontal cortical synaptic vesicle binding in cocaine use disorder: An exploratory 11 C-UCB-J positron emission tomography study in humans

Abstract

Preclinical studies have revealed robust and long-lasting alterations in dendritic spines in the brain following cocaine exposure. Such alterations are hypothesized to underlie enduring maladaptive behaviours observed in cocaine use disorder (CUD). The current study explored whether synaptic density is altered in CUD. Fifteen individuals with DSM-5 CUD and 15 demographically matched healthy control (HC) subjects participated in a single ¹¹ C-UCB-J positron emission tomography scan to assess density of synaptic vesicle glycoprotein 2A (SV2A). The volume of distribution (V_T ) and the plasma-free fraction-corrected form of the total volume of distribution (V_T /f_P ) were analysed in the anterior cingulate cortex (ACC), dorsomedial and ventromedial prefrontal cortex (PFC), lateral and medial orbitofrontal cortex (OFC) and ventral striatum. A significant diagnostic-group-by-region interaction was observed for V_T and V_T /f_P . Post hoc analyses revealed no differences on V_T , while for V_T /f_P showed lower values in CUD as compared with HC subjects in the ACC (-10.9%, p = 0.02), ventromedial PFC (-9.9%, p = 0.02) and medial OFC (-9.9%, p = 0.04). Regional V_T /f_P values in CUD, though unrelated to measures of lifetime cocaine use, were positively correlated with the frequency of recent cocaine use (p = 0.02-0.03) and negatively correlated with cocaine abstinence (p = 0.008-0.03). These findings provide initial preliminary in vivo evidence of altered (lower) synaptic density in the PFC of humans with CUD. Cross-sectional variation in SV2A availability as a function of recent cocaine use and abstinence suggests that synaptic density may be dynamically and plastically regulated by acute cocaine, an observation that merits direct testing by studies using more definitive longitudinal designs.

Keywords: PET imaging; addictive behaviours; anterior cingulate cortex; cocaine use disorder; medial orbitofrontal cortex; synaptic vesicle glycoprotein 2A; ventromedial prefrontal cortex.

Figure 1.. Regional synaptic density (V_T/f_P) in HC and CUD subjects

Values are raw individual values for each group (15 HC and 15 CUD). CS is presented as a control/region of interest representative of white matter. Abbreviations: HC, healthy control; CUD, cocaine use disorder; V_T/f_P, free fraction corrected volume of distribution; ACC, anterior cingulate cortex; vmPFC, ventromedial prefrontal cortex; mOFC, medial orbitofrontal cortex; CS, centrum semiovale.

Figure 2.. Significant relationships between synaptic density (V_T/f_P), grey-matter volume (GMV) and cocaine use variables in anterior cingulate cortex (ACC)

V_T/f_P ¹¹C-UCB-J binding in the ACC was positively correlated with frequency (days per month) of cocaine use (Figure 2A) and negatively correlated with duration (days) of abstinence (Figure 2B) at the time of PET scanning. By comparison, gray-matter volume (GMV) in the ACC was negatively correlated with years of lifetime cocaine use (Figure 2C). GMV relationships plotted as partial correlations adjusting for total intracranial volume (TIV). Abbreviations: V_T/f_P, free fraction corrected volume of distribution; ACC, anterior cingulate cortex; GMV, gray matter volume.

Figure 3.. Exploratory voxel-wise analyses of 11C-UCB-J V_T/f_P and V_T between groups.

Sagittal views (x=−2) of exploratory voxel-wise analyses to visualize group differences of lower 11C-UCB-J in CUD relative to HC subjects. V_T/f_P (left) displayed at uncorrected thresholds of voxel p<0.01 and cluster p<0.05. V_T (right) displayed at uncorrected p<0.05, with an extent threshold of k>200.