Trauma exposure among cannabis use disorder individuals was associated with a craving-correlated non-habituating amygdala response to aversive cues.

The relationship of cannabis-use disorder and trauma exposure at the level of the brain is not well-understood. Cue-reactivity paradigms have largely focused on characterizing aberrant subcortical function by averaging across the entire task. However, changes across the task, including a non-habituating amygdala response (NHAR), may be a useful biomarker for relapse vulnerability and other pathology. This secondary analysis utilized existing fMRI data from a CUD population with (TR-Y, n = 18) or without trauma (TR-N, n = 15). Amygdala reactivity to novel and repeated aversive cues was examined between TR-Y vs. TR-N groups, using a repeated measures ANOVA. Analysis revealed a significant interaction between TR-Y vs. TR-N and amygdala response to novel vs. repeated cues in the amygdala (right: F (1,31) = 5.31, p = 0.028; left: F (1,31) = 7.42, p = 0.011). In the TR-Y group, a NHAR was evident, while the TR-N group exhibited amygdala habituation, resulting in a significant difference between groups of amygdala reactivity to repeated cues (right: p = 0.002; left: p < 0.001). The NHAR in the TR-Y (but not TR-N) group was significantly correlated with higher cannabis craving scores, yielding a significant group difference (z = 2.1, p = 0.018). Results suggest trauma interacts with the brain's sensitivity to aversive cues, offering a neural explanation for the relationship between trauma and CUD vulnerability. These findings suggest the importance of considering the temporal dynamics of cue reactivity and trauma history in future studies and treatment planning, as this distinction may help decrease relapse vulnerability.

Dorsolateral Striatal Task-initiation Bursts Represent Past Experiences More than Future Action Plans.

The dorsolateral striatum (DLS) is involved in learning and executing procedural actions. Cell ensembles in the DLS, but not the dorsomedial striatum (DMS), exhibit a burst of firing at the start of a well-learned action sequence ("task-bracketing"). However, it is currently unclear what information is contained in these bursts. Some theories suggest that these bursts should represent the procedural action sequence itself (that they should be about future action chains), whereas others suggest that they should contain representations of the current state of the world, taking into account primarily past information. In addition, the DLS local field potential shows transient bursts of power in the 50 Hz range (γ50) around the time a learned action sequence is initiated. However, it is currently unknown how bursts of activity in DLS cell ensembles and bursts of γ50 power in the DLS local field potential are related to each other. We found that DLS bursts at lap initiation in rats represented recently experienced reward locations more than future procedural actions, indicating that task-initiation DLS bursts contain primarily retrospective, rather than prospective, information to guide procedural actions. Furthermore, representations of past reward locations increased during periods of increased γ50 power in the DLS. There was no evidence of task-initiation bursts, increased γ50 power, or retrospective reward location information in the neighboring dorsomedial striatum. These data support a role for the DLS in model-free theories of procedural decision-making over planned action-chain theories, suggesting that procedural actions derive from representations of the current and recent past.SIGNIFICANCE STATEMENT While it is well-established that the dorsolateral striatum (DLS) plays a critical role in procedural decision-making, open questions remain about the kinds of representations contained in DLS ensemble activity that guide procedural actions. We found that DLS, but not DMS, cell ensembles contained nonlocal representations of past reward locations that appear moments before task-initiation DLS bursts. These retrospective representations were temporally linked to a rise in γ50 power that also preceded the characteristic DLS burst at task-initiation. These results support models of procedural decision-making based on associations between available actions and the current state of the world over models based on planning over action-chains.

Classic psychedelics in the treatment of substance use disorder: Potential synergies with twelve-step programs.

Several pilot studies have provided evidence supporting the potential of classic psychedelics like psilocybin in the treatment of substance use disorders (SUDs). If larger trials confirm efficacy, classic psychedelic-assisted psychotherapy may eventually be integrated into existing addiction treatments such as cognitive behavioral therapy, contingency management, and medication-assisted therapies. Many individuals seeking treatment for SUDs also join twelve-step facilitation (TSF) programs like Alcoholics Anonymous (AA), which are among the most widely available and accessed treatments for alcohol use disorder worldwide. For such individuals, engaging in classic psychedelic-assisted psychotherapy could be seen as controversial, as members of AA/TSF programs have historically rejected medication-assisted treatments in favor of a pharmacotherapy-free approach. We argue that classic psychedelics and the subjective experiences they elicit may represent a special, more compatible case than conventional medications. In support of this claim, we describe Bill Wilson's (the founder of AA) little known experiences with psychedelics and on this basis, we argue that aspects of classic psychedelic treatments could complement AA/TSF programs. We provide a review of clinical trials evaluating psychedelics in the context of SUDs and discuss their potential large-scale impact should they be ultimately integrated into AA/TSF.

Sustained brain response to repeated drug cues is associated with poor drug-use outcomes.

A threefold increase in fatal cocaine overdoses during the past decade highlights the critical lack of medications for cocaine use disorders. The brain response to drug cues can predict future drug use; however, results have been mixed. We present preliminary evidence that a sustained response to repeated cocaine cues within a single task is a significant predictor of drug-use outcomes. Seventy-three cocaine inpatients were administered a passive-viewing fMRI task, featuring 500 ms novel evocative (cocaine, sexual, aversive) and neutral comparator cues in the first half (Half1), which were then repeated in the second half (Half2). After the baseline scan, patients received eight outpatient treatment weeks with twice-weekly drug screens. Drug-use outcome groups were empirically defined based on cocaine-positive or missing urines averaged across the outpatient phase: GOOD (<40%), POOR (>85%), and Intermediate (INT, between 40% and 85%) outcomes. Differences of response to initial (Half1) and repeated (Half2) cues in a priori (cue-reactive) regions were tested between outcome groups (3 [Group] × 2 [Halves] ANOVA). An interaction was found in the brain response to drug (but not sex or aversive) cues, with a significant difference between the GOOD and POOR outcome groups in Half2, driven by a significant decrease in brain response by the GOOD outcome group and a sustained brain response by the POOR outcome group, to repeated cocaine cues. The brain response to repeated drug cues may be a useful predictor of future drug use, encouraging future intervention studies to restore a "healthy" (decreasing) response to the repeated presentation of drug cues.

Orbitofrontal sulcogyral morphology in patients with cocaine use disorder.

Orbitofrontal cortex (OFC) is thought to be involved in appropriate processing of rewarding stimuli, and abnormal OFC structure and function has been found in patients with substance use disorders. Atypical patterns of the H-sulcus in the OFC have been primarily identified with schizophrenia, but also with bipolar disorder, both of which are associated with comorbid substance use. Given the high rates of substance use within Axis I psychiatric disorders, it is reasonable to consider how frequencies of OFC patterns in populations with only substance use compare to controls. This information is crucial to disentangle whether atypical frequencies of H-sulcus sulcogyral patterns within psychopathology are associated with the psychiatric or substance use phenotype. Here, we present the first analysis of H-sulcus sulcogyral patterns in a population of adult black men with (n = 84) and without (n = 24) cocaine use disorder (CUD). We find that OFC sulcogyral patterns are not significantly different from the control group, indicating that OFC sulcogyral patterns are not disrupted in patients with CUD. As exploratory analyses, we describe OFC sulcogyral pattern subtypes in this cohort as well as an additional control group (n = 52), in order to add to the growing body of literature on OFC sulcogyral pattern characterization.

Clinical Trials for Stimulant Use Disorders: Addressing Heterogeneities That May Undermine Treatment Outcomes.

In recent years, use of cocaine and amphetamines and deaths associated with stimulants have been on the rise, and there are still no FDA-approved medications for stimulant use disorders. One contributing factor may involve heterogeneity. At the neurobiological level, dual dopamine dysfunction may be undermining medication efficacy, suggesting a need for combination pharmacotherapies. At the population level, individual variability is expressed in a number of ways and, if left unaddressed, may interfere with medication efficacy. This chapter reviews studies investigating medications to address dopamine dysfunction, and it also identifies several prominent heterogeneities associated with stimulant (and other substance) use disorders. The chapter has implications for improving interventions to treat stimulant use disorders, and the theme of individual heterogeneity may have broader application across substance use disorders.

Cognitive impairment in substance use disorders.

Cognitive impairments in substance use disorders have been extensively researched, especially since the advent of cognitive and computational neuroscience and neuroimaging methods in the last 20 years. Conceptually, altered cognitive function can be viewed as a hallmark feature of substance use disorders, with documented alterations in the well-known "executive" domains of attention, inhibition/regulation, working memory, and decision-making. Poor cognitive (sometimes referred to as "top-down") regulation of downstream motivational processes-whether appetitive (reward, incentive salience) or aversive (stress, negative affect)-is recognized as a fundamental impairment in addiction and a potentially important target for intervention. As addressed in this special issue, cognitive impairment is a transdiagnostic domain; thus, advances in the characterization and treatment of cognitive dysfunction in substance use disorders could have benefit across multiple psychiatric disorders. Toward this general goal, we summarize current findings in the abovementioned cognitive domains of substance use disorders, while suggesting a potentially useful expansion to include processes that both precede (precognition) and supersede (social cognition) what is usually thought of as strictly cognition. These additional two areas have received relatively less attention but phenomenologically and otherwise are important features of substance use disorders. The review concludes with suggestions for research and potential therapeutic targeting of both the familiar and this more comprehensive version of cognitive domains related to substance use disorders.

Women at Greater Sexual Risk for STIs/HIV Have a Lower Mesolimbic and Affective Bias Response to Sexual Stimuli.

Young adult women in the United States have high rates of sexually transmitted infections, increasing the risk of human immunodeficiency virus (HIV). The underlying neurobiology of behaviors that increase the probability of contracting sexually-transmitted diseases (STIs) and HIV is just beginning to be explored. The current study assessed the link between sexual risk and the brain and behavioral response to sexual cues in emerging adult women. Our hypothesis was that women with more activity in reward/motivational circuitry would report higher sexual risk behaviors and would evidence higher positive affective bias to visual sexual stimuli. Women (n = 52; age = 18-24 years) who had protected sex 100% of the time (n = 17) vs. those who did not (n = 35), in the past 3 months, were compared on their brain response to 500 ms evocative (sex, aversive, food) vs. neutral cues in a blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) fast event-related design. Based on existing literature, an a priori anatomical "cue-reactive" mask was used to constrain the analyses. Self-reported sexual activity and the affective bias scores to sexual cues were examined as correlates with the brain response to cues. In contrast to our initial hypothesis, the higher sexual risk (Unprotected) group had significantly less activation in mesolimbic brain regions and lower (less positive) affective bias scores to sexual cues compared to the lower risk (Protected) group. As predicted, the brain response was positively correlated with sexual bias. Follow-up analyses showed an effect of partner "risk" (e.g., more vs. less knowledge of partner's STIs/HIV status). This evidence suggests that women who have protected sex may view sexual-related stimuli more positively, reflected by a neural response in reward/motivational regions and more positive sexual bias scores. In contrast, young women at increased risk for STIs/HIV may feel more negatively about sexual-related stimuli, evidenced by a lower mesolimbic response and a less positive affective bias to sexual cues. These data may help identify young women who are at greatest risk for acquiring STIs and/or HIV, which carries added importance with the availability of new medications that can prevent HIV.

Emotional, physical and sexual abuse are associated with a heightened limbic response to cocaine cues.

Drug-reward cues trigger motivational circuitry, a response linked to drug-seeking in animals and in humans. Adverse life events have been reported to increase sensitivity to drug rewards and to bolster drug reward signaling. Therefore, we hypothesized that cocaine-dependent individuals with prior emotional, physical and sexual abuse might have a heightened mesolimbic brain response to cues for drug reward in a new brief-cue probe. Cocaine-dependent human individuals (N = 68) were stabilized in an inpatient setting and then completed an event-related blood-oxygen-level dependent functional magnetic resonance imaging task featuring 500-ms evocative (cocaine, sexual, aversive) and comparator (neutral) cues. Responses to three questions about emotional, physical and sexual abuse from the Addiction Severity Index were used to divide the patients into subgroups (history of Abuse [n = 40] versus No Abuse [n = 28]). When subjects were grouped by the historical presence or absence of emotional, physical or sexual abuse, the Abuse group showed a heightened midbrain, thalamic, caudate, and caudal orbitofrontal cortex response to cocaine cues; a similar result was found in other evocative cues, as well. These findings are the first reported for a 500-ms cocaine-cue probe, and they highlight the ability of very brief evocative cues to activate the brain's motivational circuitry. Although all participants had severe cocaine use disorders, individuals reporting prior abuse had a heightened mesolimbic response to evocative cues. To our knowledge, this is the first study in humans linking a history of abuse to a brain vulnerability (heightened mesolimbic response to drug cues) previously shown to contribute to drug-seeking.

Hippocampus and subregions of the dorsal striatum respond differently to a behavioral strategy change on a spatial navigation task.

Goal-directed and habit-based behaviors are driven by multiple but dissociable decision making systems involving several different brain areas, including the hippocampus and dorsal striatum. On repetitive tasks, behavior transitions from goal directed to habit based with experience. Hippocampus has been implicated in initial learning and dorsal striatum in automating behavior, but recent studies suggest that subregions within the dorsal striatum have distinct roles in mediating habit-based and goal-directed behavior. We compared neural activity in the CA1 region of hippocampus with anterior dorsolateral and posterior dorsomedial striatum in rats on a spatial choice task, in which subjects experienced reward delivery changes that forced them to adjust their behavioral strategy. Our results confirm the importance of the hippocampus in evaluating predictive steps during goal-directed behavior, while separate circuits in the basal ganglia integrated relevant information during automation of actions and recognized when new behaviors were needed to continue obtaining rewards.

Contingency Management and Deliberative Decision-Making Processes.

Contingency management is an effective treatment for drug addiction. The current explanation for its success is rooted in alternative reinforcement theory. We suggest that alternative reinforcement theory is inadequate to explain the success of contingency management and produce a model based on demand curves that show how little the monetary rewards offered in this treatment would affect drug use. Instead, we offer an explanation of its success based on the concept that it accesses deliberative decision-making processes. We suggest that contingency management is effective because it offers a concrete and immediate alternative to using drugs, which engages deliberative processes, improves the ability of those deliberative processes to attend to non-drug options, and offsets more automatic action-selection systems. This theory makes explicit predictions that can be tested, suggests which users will be most helped by contingency management, and suggests improvements in its implementation.

Cocaine-, caffeine-, and stress-evoked cocaine reinstatement in high vs. low impulsive rats: treatment with allopregnanolone.

BACKGROUND: Previous research indicates that individual differences in traits such as impulsivity, avidity for sweets, and novelty reactivity are predictors of several aspects of drug addiction. Specifically, rats that rank high on these behavioral measures are more likely than their low drug-seeking counterparts to exhibit several characteristics of drug-seeking behavior. In contrast, initial work suggests that the low drug-seeking animals are more reactive to negative events (e.g., punishment and anxiogenic stimuli). The goal of this study was to compare high and low impulsive rats on reinstatement of cocaine-seeking behavior elicited by cocaine (COC) and by negative stimuli such as the stress-inducing agent yohimbine (YOH) or a high dose of caffeine (CAFF). An additional goal was to determine whether treatment with allopregnanolone (ALLO) would reduce reinstatement (or relapse) of cocaine-seeking behavior under these priming conditions. METHODS: Female rats were selected as high (HiI) or low (LoI) impulsive using a delay-discounting task. After selection, they were allowed to self-administer cocaine for 12 days. Cocaine was then replaced with saline, and rats extinguished lever responding over 16 days. Subsequently, rats were pretreated with either vehicle control or ALLO, and cocaine seeking was reinstated by injections of COC, CAFF, or YOH. RESULTS: While there were no phenotype differences in maintenance and extinction of cocaine self-administration or reinstatement under control treatment conditions, ALLO attenuated COC- and CAFF-primed reinstatement in LoI but not HiI rats. CONCLUSIONS: Overall, the present findings suggest that individual differences in impulsive behavior may influence efficacy of interventions aimed to reduce drug-seeking behavior.

Cocaine self-administration punished by i.v. histamine in rat models of high and low drug abuse vulnerability: effects of saccharin preference, impulsivity, and sex.

A key feature of substance use disorders is continued drug consumption despite aversive consequences. This has been modeled in the animal laboratory by pairing drug self-administration with electric shock, thereby punishing drug intake (Deroche-Gamonet et al. 2004). In the present experiments, we examined the effects of punishment on i.v. cocaine self-administration by adding histamine to the cocaine solution with three different animal models of high and low vulnerability to drug abuse: rats selectively bred for high (HiS) and low (LoS) saccharin consumption, rats selected for high (HiI) and low (LoI) impulsivity, and sex differences. Animals were allowed to self-administer cocaine (0.4 mg/kg/infusion) to establish a baseline of operant responding. Histamine (4.0mg/kg/infusion) was then added directly into the cocaine solution and its consequent effects on self-administration were compared to baseline. The histamine+cocaine solution was then replaced with a cocaine-only solution, and the rats' operant responding was again compared to baseline. Concurrent histamine exposure was effective in reducing cocaine consumption in all groups of rats; however, LoS and female rats took longer to return to baseline levels of cocaine consumption after histamine was removed compared to HiS and male rats. These data suggest that the reduction of drug self-administration by aversive consequences may differ in groups that vary in drug use vulnerability . Such results may inform pharmacological strategies that enhance the negative aspects of drug consumption.

Cocaine-induced c-Fos expression in rats selectively bred for high or low saccharin intake and in rats selected for high or low impulsivity.

Sweet preference and impulsivity are predictors of cocaine self-administration; however, no research has been conducted to investigate neuronal activation in key brain reward areas after first time exposure to cocaine in rats that differ in their propensity for cocaine-seeking and -taking behavior. In this study we used rats that had been selectively bred for high vs. low saccharin intake and rats selected for high vs. low impulsivity for food. The goal of this study was to investigate whether there are differences of c-Fos reactivity between high and low phenotypes and determine whether these differences are similar between the two animal models. A group of rats was bred for high or low saccharin intake. Another group of rats was selected as high or low impulsive based on performance in a delay-discounting task. Subsequently, rats were given an acute injection of cocaine or saline and then c-Fos expression was observed and analyzed in several brain regions. The low reward-seeking phenotypes showed higher cocaine-induced c-Fos expression in several of these regions. Low saccharin preferring rats showed higher cocaine-induced c-Fos expression in the nucleus accumbens shell, and low impulsive rats showed higher cocaine-induced c-Fos expression in the orbitofrontal cortex and cingulate gyrus 1 area. In addition, both low impulsive and low saccharin rats had higher cocaine-induced c-Fos in the dorsal medial and dorsal lateral caudate putamen. The results indicate that individual differences in neuronal reactivity exist prior to chronic exposure to drugs of abuse. Furthermore, similar differences between the two animal models may be indicative of a common mechanism underlying vulnerability to drugs of abuse.

Interactions between deliberation and delay-discounting in rats.

When faced with decisions, rats sometimes pause and look back and forth between possible alternatives, a phenomenon termed vicarious trial and error (VTE). When it was first observed in the 1930s, VTE was theorized to be a mechanism for exploration. Later theories suggested that VTE aided the resolution of sensory or neuroeconomic conflict. In contrast, recent neurophysiological data suggest that VTE reflects a dynamic search and evaluation process. These theories make unique predictions about the timing of VTE on behavioral tasks. We tested these theories of VTE on a T-maze with return rails, where rats were given a choice between a smaller reward available after one delay or a larger reward available after an adjustable delay. Rats showed three clear phases of behavior on this task: investigation, characterized by discovery of task parameters; titration, characterized by iterative adjustment of the delay to a preferred interval; and exploitation, characterized by alternation to hold the delay at the preferred interval. We found that VTE events occurred during adjustment laps more often than during alternation laps. Results were incompatible with theories of VTE as an exploratory behavior, as reflecting sensory conflict, or as a simple neuroeconomic valuation process. Instead, our results were most consistent with VTE as reflecting a search process during deliberative decision making. This pattern of VTE that we observed is reminiscent of current navigational theories proposing a transition from a deliberative to a habitual decision-making mechanism.