Dorothy J. Yamamoto

Continuous intracerebroventricular infusion of the competitive NMDA receptor antagonist, LY235959, facilitates escalation of cocaine self-administration and increases break point for cocaine in Sprague-Dawley rats.

Although escalation of consumption is an important characteristic of cocaine dependence, the neurobiological mechanisms that mediate this phenomenon have not been fully described. In this study, we used male, Sprague-Dawley rats to measure the effects of acute and continuous intracerebroventricular (ICV) administration of the competitive NMDA receptor antagonist, LY235959, on cocaine self-administration behavior under various schedules of reinforcement and access conditions. Single ICV infusions of LY235959 (0.03-0.3 microg/5 microl) produced dose-dependent and statistically significant decreases in the number of cocaine infusions earned under a progressive ratio schedule of reinforcement. In a second experiment, vehicle or LY235959 (0.2-0.3 microg/day) was continuously administered ICV to rats via surgically-implanted subcutaneous osmotic minipump/intracranial cannula assemblies. Both vehicle- and LY235959-treated rats significantly escalated cocaine self-administration over the 10 long access sessions; however, rats treated with LY235959 escalated cocaine self-administration faster and to a greater degree than vehicle-treated rats. There was a statistically significant increase in cocaine infusions earned under the PR schedule in LY235959-treated rats, but not vehicle-treated rats, after 10 long access cocaine self-administration sessions. These data support the hypothesis that escalation of cocaine consumption is mediated by hypo-glutamatergic tone in the central nervous system and this facilitation of escalation is associated with an increase in motivation to respond for cocaine.

Rats classified as low or high cocaine locomotor responders: A unique model involving striatal dopamine transporters that predicts cocaine addiction-like behaviors

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 cocaines 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.

Differences in Rat Dorsal Striatal NMDA and AMPA Receptors following Acute and Repeated Cocaine-Induced Locomotor Activation

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.

Influence of dorsolateral prefrontal cortex and ventral striatum on risk avoidance in addiction: a mediation analysis

BACKGROUND Alterations in frontal and striatal function are hypothesized to underlie risky decision making in drug users, but how these regions interact to affect behavior is incompletely understood. We used mediation analysis to investigate how prefrontal cortex and ventral striatum together influence risk avoidance in abstinent drug users. METHOD Thirty-seven abstinent substance-dependent individuals (SDI) and 43 controls underwent fMRI while performing a decision-making task involving risk and reward. Analyses of a priori regions-of-interest tested whether activity in dorsolateral prefrontal cortex (DLPFC) and ventral striatum (VST) explained group differences in risk avoidance. Whole-brain analysis was conducted to identify brain regions influencing the negative VST-risk avoidance relationship. RESULTS Right DLPFC (RDLPFC) positively mediated the group-risk avoidance relationship (p < 0.05); RDLPFC activity was higher in SDI and predicted higher risk avoidance across groups, controlling for SDI vs. CONTROLS Conversely, VST activity negatively influenced risk avoidance (p < 0.05); it was higher in SDI, and predicted lower risk avoidance. Whole-brain analysis revealed that, across group, RDLPFC and left temporal-parietal junction positively (p ≤ 0.001) while right thalamus and left middle frontal gyrus negatively (p < 0.005) mediated the VST activity-risk avoidance relationship. CONCLUSION RDLPFC activity mediated less risky decision making while VST mediated more risky decision making across drug users and controls. These results suggest a dual pathway underlying decision making, which, if imbalanced, may adversely influence choices involving risk. Modeling contributions of multiple brain systems to behavior through mediation analysis could lead to a better understanding of mechanisms of behavior and suggest neuromodulatory treatments for addiction.

Sex disparities in substance abuse research: Evaluating 23 years of structural neuroimaging studies

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.

Sex Differences in Gray Matter Changes and Brain-Behavior Relationships in Patients with Stimulant Dependence

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 = -0.364, P = .047; right: r = -0.407, P = .031) but not in men (left: r = -0.063, P = .737; right: r = -0.174, 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.

Temporal profile of fronto-striatal-limbic activity during implicit decisions in drug dependence.

BACKGROUND Substance dependence is associated with impaired decision-making and altered fronto-striatal-limbic activity. Both greater and lesser brain activity have been reported in drug users compared to controls during decision-making. Inconsistent results might be explained by group differences in the temporal profile of the functional magnetic resonance imaging (fMRI) response. While most previous studies model a canonical hemodynamic response, a finite impulse response (FIR) model measures fMRI signal at discrete time points without assuming a temporal profile. We compared brain activity during decision-making and feedback in substance users and controls using two models: a canonical hemodynamic response function (HRF) and a FIR model. METHODS 37 substance-dependent individuals (SDI) and 43 controls performed event-related decision-making during fMRI scanning. Brain activity was compared across group using canonical HRF and FIR models. RESULTS Compared to controls, SDI were impaired at decision-making. The canonical HRF model showed that SDI had significantly greater fronto-striatal-limbic activity during decisions and less activity during feedback than controls. The FIR model confirmed greater activity in SDI during decisions. However, lower activity in SDI during feedback corresponded to a lower post-stimulus undershoot of the hemodynamic response. CONCLUSIONS Greater activity in fronto-striatal-limbic pathways in SDI compared to controls is consistent with prior work, further supporting the hypothesis that abnormalities in these circuits underlie impaired decision-making. We demonstrate for the first time using FIR analysis that lower activity during feedback may simply reflect the tail end of the hemodynamic response to decision, the post-stimulus undershoot, rather than an actual difference in feedback response.

Top-Down Network Effective Connectivity in Abstinent Substance Dependent Individuals

Objective We 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. Methods 50 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. Results Compared 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. Conclusions Increased 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.

Behavioral approach and orbitofrontal cortical activity during decision-making in substance dependence

Behavioral approach, defined as behavior directed toward a reward or novel stimulus, when elevated, may increase ones vulnerability to substance use disorder. Behavioral approach has been associated with relatively greater left compared to right frontal activity; behavioral inhibition may be associated with relatively greater right compared to left frontal brain activity. We hypothesized that substance dependent individuals (SDI) would have higher behavioral approach than controls and greater prefrontal cortical activity during decision-making involving reward. We hypothesized that behavioral approach would correlate with left frontal activity during decision-making and that the correlation would be stronger in SDI than controls. 31 SDI and 21 controls completed the Behavioral Inhibition System/Behavioral Approach System (BIS/BAS) scales and performed a decision-making task during fMRI. Orbitofrontal (OFC) and dorsolateral prefrontal activity were correlated with BIS and BAS scores. Compared to controls, SDI had higher BAS Fun Seeking scores (p<0.001) and worse decision-making performance (p=0.004). BAS Fun Seeking correlated with left OFC activity during decision-making across group (r=0.444, p<0.003). The correlation did not differ by group. There was no correlation between BIS and right frontal activity. Left OFC may play a role in reward-related decision-making in substance use disorder especially in individuals with high behavioral approach.