Background Sex differences in brain structure and clinical course of substance use disorders underscores the need to include women in structural brain imaging studies. The NIH has supported the need for research to address sex differences. We evaluated female enrollment in substance abuse structural brain imaging research and the methods used to study sex differences in substance effects. Methods Structural brain imaging studies published through 2016 (n=230) were evaluated for number of participants by sex and substance use status and methods used to evaluate sex differences. Temporal trends in the numbers of participants by sex and substance use status were analyzed. We evaluated how often sex effects were appropriately analyzed and the proportion of studies that found sex by substance interactions on volumetric measures. Results Female enrollment increased over time, but remained significantly lower than male enrollment (p=0.01), with the greatest bias for alcohol and opiate studies. 79% of studies included both sexes; however, 74% did not evaluate sex effects or used an analytic approach that precluded detection of sex by substance use interactions. 85% of studies that stratified by sex reported different substance effects on brain volumes. Only 33% of studies examining two-way interactions found significant interactions, highlighting that many studies were underpowered to detect interactions. Conclusions Although female participation in substance use studies of brain morphometry has increased, sex disparity persists. Studying adequate numbers of both sexes and employing correct analytic approaches is critical for understanding sex differences in brain morphometric changes in substance abuse.

Individual differences are a hallmark of drug addiction. Here, we describe a rat model based on differential initial responsiveness to low dose cocaine. Despite similar brain cocaine levels, individual outbred Sprague-Dawley rats exhibit markedly different magnitudes of acute cocaine-induced locomotor activity and, thereby, can be classified as low or high cocaine responders (LCRs or HCRs). LCRs and HCRs differ in drug-induced, but not novelty-associated, hyperactivity. LCRs have higher basal numbers of striatal dopamine transporters (DATs) than HCRs and exhibit marginal cocaine inhibition of in vivo DAT activity and cocaine-induced increases in extracellular DA. Importantly, lower initial cocaine response predicts greater locomotor sensitization, conditioned place preference and greater motivation to self-administer cocaine following low dose acquisition. Further, outbred Long-Evans rats classified as LCRs, versus HCRs, are more sensitive to cocaine’s discriminative stimulus effects. Overall, results to date with the LCR/HCR model underscore the contribution of striatal DATs to individual differences in initial cocaine responsiveness and the value of assessing the influence of initial drug response on subsequent expression of addiction-like behaviors.

).q RSNA, 2015 Purpose:To investigate whether sex modulates the effects of stimulant dependence on gray matter volume (GMV) in patients who have achieved long-term abstinence and to characterize how sex modulates GMV according to specific behavioral measures, such as dependence symptom count, behavioral approach, and impulsivity. Materials and Methods:Colorado Multiple Institutional Review Board approval and informed consent were obtained. In this prospective parallel group study, 127 age-and sex-matched participants (68 control subjects [28 women, 40 men] and 59 patients with stimulant dependence [28 women, 31 men]) underwent T1-weighted spoiled gradient-echo inversion recovery magnetic resonance imaging of the brain at 3 T. Images were segmented by using voxel-based morphometric software. After adjustment for age, education, and head size, the effects of group according to sex on GMV and main effects were analyzed throughout the whole brain by using an analysis of covariance family-wise cluster corrected for multiple comparisons, with a threshold P value of less than .05. Dependence symptom count and behavioral measurements were correlated with GMV in the whole brain and in five a priori regions of interest. Results:The effects of group according to sex on GMV were significant in numerous regions (P , .001). Compared with female control subjects, women with stimulant dependence had significantly lower GMV in widespread brain regions (P , .001). There were no significant differences in GMV between male control subjects and men with stimulant dependence (P = .625). Dependence symptom count negatively correlated with GMV in the nucleus accumbens in women (left: r = 20.364, P = .047; right: r = 20.407, P = .031) but not in men (left: r = 20.063, P = .737; right: r = 20.174, P = .349). Behavioral approach (P = .002) and impulsivity (P = .013) correlated negatively with frontal and temporal GMV changes in women with stimulant dependence but not in the other groups. Conclusion:Vast changes in GMV were observed in women with stimulant dependence after prolonged abstinence, but were not observed in men. Sexual dimorphism in drug-related neuroanatomic changes and brain-behavior relationships may be mechanisms underlying the difference in clinical profiles of addiction between women and men.q RSNA, 2015

ObjectiveWe hypothesized that compared to healthy controls, long-term abstinent substance dependent individuals (SDI) will differ in their effective connectivity between large-scale brain networks and demonstrate increased directional information from executive control to interoception-, reward-, and habit-related networks. In addition, using graph theory to compare network efficiencies we predicted decreased small-worldness in SDI compared to controls.Methods50 SDI and 50 controls of similar sex and age completed psychological surveys and resting state fMRI. fMRI results were analyzed using group independent component analysis; 14 networks-of-interest (NOI) were selected using template matching to a canonical set of resting state networks. The number, direction, and strength of connections between NOI were analyzed with Granger Causality. Within-group thresholds were p<0.005 using a bootstrap permutation. Between group thresholds were p<0.05, FDR-corrected for multiple comparisons. NOI were correlated with behavioral measures, and group-level graph theory measures were compared.ResultsCompared to controls, SDI showed significantly greater Granger causal connectivity from right executive control network (RECN) to dorsal default mode network (dDMN) and from dDMN to basal ganglia network (BGN). RECN was negatively correlated with impulsivity, behavioral approach, and negative affect; dDMN was positively correlated with impulsivity. Among the 14 NOI, SDI showed greater bidirectional connectivity; controls showed more unidirectional connectivity. SDI demonstrated greater global efficiency and lower local efficiency.ConclusionsIncreased effective connectivity in long-term abstinent drug users may reflect improved cognitive control over habit and reward processes. Higher global and lower local efficiency across all networks in SDI compared to controls may reflect connectivity changes associated with drug dependence or remission and requires future, longitudinal studies to confirm.

Sprague-Dawley rats can be classified as low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor activity induced by an acute low dose of cocaine. Upon repeated cocaine exposure, LCRs display greater locomotor sensitization, reward, and reinforcement than HCRs. Altered glutamate receptor expression in the brain reward pathway has been linked to locomotor sensitization and addiction. To determine if such changes contribute to the differential development of locomotor sensitization, we examined protein levels of total, phosphorylated, and cell surface glutamate N-methyl D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors (Rs) following acute or repeated cocaine (10 mg/kg, i.p.) in LCRs, HCRs and saline controls. Three areas involved in the development and expression of locomotor sensitization were investigated: the ventral tegmental area (VTA), nucleus accumbens (NAc) and dorsal striatum (dSTR). Our results revealed differences only in the dSTR, where we found that after acute cocaine, GluN2BTyr-1472 phosphorylation was significantly greater in LCRs, compared to HCRs and controls. Additionally in dSTR, after repeated cocaine, we observed significant increases in total GluA1, phosphorylated GluA1Ser-845, and cell surface GluA1 in all cocaine-treated animals vs. controls. The acute cocaine-induced increases in NMDARs in dSTR of LCRs may help to explain the more ready development of locomotor sensitization and susceptibility to addiction-like behaviors in rats that initially exhibit little or no cocaine-induced activation, whereas the AMPAR increases after repeated cocaine may relate to recruitment of more dorsal striatal circuits and maintenance of the marked cocaine-induced locomotor activation observed in all of the rats.