Verica Milivojevic

Neural Correlates of Impulse Control During Stop Signal Inhibition in Cocaine-Dependent Men

Altered impulse control is associated with substance use disorders, including cocaine dependence. We sought to identify the neural correlates of impulse control in abstinent male patients with cocaine dependence (PCD). Functional magnetic resonance imaging (fMRI) was conducted during a stop signal task that allowed trial-by-trial evaluation of response inhibition. Fifteen male PCD and 15 healthy control (HC) subjects, matched in age and years of education, were compared. Stop signal reaction time (SSRT) was derived on the basis of a horse race model. By comparing PCD and HC co-varied for stop success rate, task-related frustration rating, and post-error slowing, we isolated the neural substrates of response inhibition, independent of attentional monitoring (of the stop signal) and post-response processes including affective responses and error monitoring. Using region of interest analysis, we found no differences between HC and PCD who were matched in stop signal performance in the pre-supplementary motor area (pre-SMA) previously shown to be associated with SSRT. However, compared with HC, PCD demonstrated less activation of the rostral anterior cingulate cortex (rACC), an area thought to be involved in the control of stop signal inhibition. The magnitude of rACC activation also correlated negatively with the total score and the impulse control subscore of the Difficulty in Emotion Regulation Scale in PCD. The current study thus identified the neural correlates of altered impulse control in PCD independent of other cognitive processes that may influence stop signal performance. Relative hypoactivation of the rACC during response inhibition may represent a useful neural marker of difficulties in impulse control in abstinent cocaine-dependent men who are at risk of relapse.

Gender differences in cardiovascular and corticoadrenal response to stress and drug cues in cocaine dependent individuals

RationaleExtensive research suggests that gender may affect neuroendocrine and cardiovascular arousal mechanisms underlying biological responses to stress.ObjectiveTo examine the impact of gender on response to stress and to drug-cue exposure in treatment-seeking cocaine abusers.MethodsFifty recently abstinent cocaine dependent individuals (25F/25M), who were matched on cocaine use history, were exposed to a brief guided-imagery procedure that involved imagining a recent personal stressful situation, a personal drug-related situation and neutral-relaxing situation, one imagery per session, presented in random order. Subjective craving and anxiety, cardiovascular measures and plasma adrenocorticotrophic hormone (ACTH), cortisol and prolactin were assessed.ResultsMales showed significantly higher levels of ACTH, cortisol, and SBP, both at baseline and following all three imagery conditions. Females showed significantly higher basal heart rate and prolactin, although no gender differences were observed following imagery. No gender differences were seen in subjective anxiety or cocaine craving.ConclusionsResults indicate significant gender differences in baseline sensitivity and subsequent variations in hypothalamus–pituitary–adrenal (HPA) and cardiovascular response to imagery challenge. Such gender-specific responses could have implications for the development of pharmacological treatments that address stress and drug-cue-related relapse in cocaine-abusing individuals.

Neuroimaging study of sex differences in the neuropathology of cocaine abuse

BACKGROUND Female and male substance abusers differ in their disease patterns and clinical outcomes. An important question in addiction neuroscience thus concerns the neural substrates underlying these sex differences. OBJECTIVE This article aims to examine what is known of the neural mechanisms involved in the sex differences between substance abusers. METHODS We reviewed neuroimaging studies that addressed sex differences in cerebral perfusion deficits after chronic cocaine use and in regional brain activation during pharmacologic challenge and cue-induced craving. We also present results from a preliminary study in which cocaine-dependent men and women participated in script-guided imagery of stress- and drug cue-related situations while blood oxygenation level-dependent signals of their brain were acquired in a 1.5T scanner. Spatial pre-processing and statistical analysis of brain images were performed. Regional brain activation was compared between stress and drug cue trials in men versus women. RESULTS The results of our study showed greater activation in the left uncus and right claustrum (both, statistical threshold of P = 0.01, uncorrected; extent = 10 voxels) in men (n = 5) during drug cue trials compared with stress trials. No brain regions showed greater activation during stress trials compared with drug cue trials. In contrast, women (n = 6) showed greater activation in the right medial and superior frontal gyri during stress trials compared with drug cue trials at the same statistical threshold. No brain regions showed more activation during drug cue trials than during stress trials. CONCLUSIONS The studies reviewed underscore the need to consider sex-related factors in examining the neuropathology of cocaine addiction. Our preliminary results also suggest important sex differences in the effect of stress- and drug cue-associated brain activation in individuals with cocaine use disorder.

Effects of progesterone stimulated allopregnanolone on craving and stress response in cocaine dependent men and women

OBJECTIVES Fluctuations in progesterone levels during the menstrual cycle have been shown to affect physiological and subjective effects of cocaine. Furthermore, our laboratory has demonstrated that following drug-cue exposure, cocaine dependent women with high levels of circulating progesterone display lower diastolic and systolic blood pressure responses and report lower levels of anxiety and drug craving compared to cocaine dependent women with low levels of progesterone. In the current study we examined the role of the progesterone derived neuroactive steroid allopregnanolone (ALLO) on stress arousal, inhibitory control and drug craving in cocaine dependent subjects. METHODS Plasma levels of ALLO were measured using GC/MS in 46 treatment-seeking cocaine dependent men and women on day 5 of a 7-day treatment regimen of micronized progesterone (15M/8F) (400mg/day) or placebo (14M/9F) administered in a double blind, randomized manner. As a control, levels of the testosterone derived neurosteroid androstanediol (ADIOL) were also measured. All subjects participated in laboratory sessions on days 5-7 of progesterone/placebo administration in which they were exposed to a series of 5-min personalized guided imagery of either a stressful situation, cocaine use or of a neutral setting and dependent variables including subjective craving, mood, Stroop task as a measure of inhibitory control performance and plasma cortisol were assessed. Participants were grouped by high or low ALLO level and levels of dependent variables compared between ALLO groups. RESULTS Progesterone relative to placebo significantly increased ALLO levels with no sex differences. There were no effects of micronized progesterone on the testosterone derived ADIOL. Individuals in the high versus the low ALLO group showed decreased levels of cortisol at baseline, and a higher cortisol response to stress; higher positive mood scores at baseline and improved Stroop performance in the drug-cue and stress conditions, and reduced cocaine craving across all imagery conditions. CONCLUSIONS As expected, cocaine dependent individuals administered progesterone showed significantly higher ALLO plasma levels. High levels of ALLO appeared to normalize basal and stress response levels of cortisol, decrease cocaine craving and also contribute to improvements in positive emotion and Stroop performance in response to stress and drug-cue exposures. These findings suggest that the neuroactive steroid ALLO plays a significant role in mediating the positive effects of progesterone on stress arousal, cognitive performance and drug craving in cocaine dependence.

Recent cannabis abuse decreased stress-induced BOLD signals in the frontal and cingulate cortices of cocaine dependent individuals

Previous neuroimaging studies showed that use of marijuana can alter patterns of cortical activation during rest or a task challenge. We used functional magnetic resonance imaging to examine whether recent cannabis abuse contributed to stress-induced blood-oxygen-level-dependent (BOLD) contrast in a group of cocaine-dependent individuals. Emotional stress was induced using the script-guided imagery paradigm, in which subjects imagined being in a real-life stressful situation and, as a control, in a neutral situation, while BOLD signals of their brain were acquired with a 1.5 T scanner. Abstinent cocaine-dependent subjects with recent marijuana abuse (n=8) were compared with abstinent cocaine-dependent subjects who had not abused marijuana recently (n=18). The two groups were otherwise matched in their demographic characteristics and drug use history. All subjects were abstinent for at least 15 days and drug free as confirmed by urine drug screening before the imaging session. Recent cannabis abusers demonstrated hypo-activation in frontal cortical areas including the perigenual anterior cingulate during increased emotional stress. In contrast, at the same statistical threshold, no brain regions showed increased activation in recent cannabis abusers compared with non-abusers. The group difference in the perigenual anterior cingulate remained even when lifetime cocaine and alcohol consumption was accounted for in covariance analysis. These results provide evidence that recent cannabis abuse is associated with decreased activation in the frontal cortex during an emotional stress task. The results suggest an abnormal cognitive control mechanism during affective processing in association with heavy cannabis use.

Alcohol Effects on Stress Pathways: Impact on Craving and Relapse Risk

A significant amount of neurobiological research regarding the development of alcohol use disorders (AUDs) has focused on alcohol-related activation and long-term alterations in the mesocortical dopaminergic reward pathways. However, alcohol does not only interact with brain reward systems. Many of its acute and chronic effects may be related to allostatic adaptations in hypothalamic and extrahypothalamic stress regulation pathways. For example, acute binge intoxication is associated with hypothalamically driven increases in blood cortisol, norepinephrine, and sex steroid metabolite levels. This may contribute to the development of mesocortical sensitization to alcohol. Furthermore, chronic alcohol exposure is associated with systemic dysregulation of the hypothalamic pituitary adrenal axis, sympathetic adrenal medullary system, and sex steroid systems. This dysregulation appears to manifest as neuroendocrine tolerance. In this review, we first summarize the literature suggesting that alcohol-induced alterations in these hypothalamic systems influence craving and contribute to the development of AUDs. We note that for women, the effects of alcohol on these neuroendocrine stress regulation systems may be influenced by the rhythmic variations of hormones and steroids across the menstrual cycle. Second, we discuss how changes in these systems may indicate progression of AUDs and increased risk of relapse in both sexes. Specifically, neuroendocrine tolerance may contribute to mesocortical sensitization, which in turn may lead to decreased prefrontal inhibitory control of the dopaminergic reward and hypothalamic stress systems. Thus, pharmacological strategies that counteract alcohol-associated changes in hypothalamic and extrahypothalamic stress regulation pathways may slow the development and progression of AUDs.

Alcohol Exposure During Late Adolescence Increases Drinking in Adult Wistar Rats, an Effect that is not Reduced by Finasteride

AIMS We tested whether an exposure to alcohol in late adolescence, an age of rapid increase in neuroactive steroid precursors, would increase voluntary alcohol consumption in adult rats and whether this effect would be modulated by finasteride, an inhibitor of neuroactive steroid synthesis. METHODS In Experiment 1, we exposed male Wistar rats to 8% alcohol during the dark cycle for 1 week during late adolescence [postnatal days (PNDs) 51-58], and then measured voluntary alcohol consumption 1 month later in adulthood (PNDs 91-104). In Experiment 2, finasteride was administered during the forced alcohol exposure in late adolescence and, in Experiment 3, during voluntary alcohol consumption in adulthood. Plasma was collected at the end of each finasteride treatment to confirm the reduction of plasma neuroactive steroid levels. RESULTS We found that a daily 12-h exposure to alcohol for 7 days in late adolescence significantly increased voluntary alcohol consumption (4-fold) a month later during adulthood. Finasteride administration in late adolescence increased group alcohol intake in late adolescence but did not block the effect of adolescent alcohol exposure on increasing alcohol preference in adulthood. There was no effect of finasteride treatment in adulthood on alcohol preference. CONCLUSIONS A daily 12-h exposure to alcohol for 7 days in late adolescence was sufficient to induce chronically increased alcohol preference in adulthood, indicating that this age may be sensitive to the effects of alcohol.

Enforced Pax6 Expression Rescues Alcohol-Induced Defects of Neuronal Differentiation in Cultures of Human Cortical Progenitor Cells

BACKGROUND Alcohol is the most widely consumed substance of abuse, and its use during pregnancy can lead to serious disorders of brain development. The precise molecular action of alcohol on human brain development, however, is still unknown. We previously enriched multipotent progenitor cells, radial glia (RG) cells, from human fetal forebrain and demonstrated that they express transcription factor Pax6 that is necessary for their neurogenic fate. METHODS Enriched human fetal RG cells were maintained in vitro as either control or Pax6-expressing retrovirus infected cells. Cultures were treated with increasing doses of alcohol to evaluate Pax6 expression, proliferation, and differentiation of RG cells by immunocytochemistry, Western blot, and RT-PCR methods. RESULTS In vitro treatment with alcohol reduced the expression of transcription factor Pax6 and proliferation of RG cells, which decreased neurogenesis. Consistent with this finding, the overexpression of Pax6 in RG cells under alcohol treatment rescued cell proliferation and restored the generation of neurons. In contrast to this effect on neurogenesis, the overexpression of Pax6 inhibits the generation of astroglia regardless of alcohol treatment, implying lineage-specific effects. CONCLUSIONS These findings suggest that the effect of alcohol on human neurogenesis is partially due to the reduced expression of transcription factor Pax6 in RG cells.

Effects of endogenous and exogenous progesterone on emotional intelligence in cocaine-dependent men and women who also abuse alcohol.

As sex differences in substance dependence may impinge upon the perception and regulation of emotion, we assess emotional intelligence (EI) as a function of gender, menstrual cycle (MC) phase and hormonal changes in early abstinent cocaine‐dependent individuals who abuse alcohol (CDA).

Targeting Stress Pathophysiology to Improve Alcoholism Relapse Outcomes

Excessive alcohol use is one of the top behavioral causes of global disease burden. A major factor contributing to this burden is the alcohol relapse risk during treatment and recovery from alcoholism. Clinical studies suggest that stress is one of the key factors that contributes to these high-relapse rates (Blaine et al, 2016). Changes in hypothalamic pituitary adrenal (HPA) axis responses, altered and blunted amygdala response to fear/threat potentiated startle in heavy drinkers compared with light social drinkers and autonomic imbalance in sympathetic/parasympathetic systems, have been reported with increased alcohol use (Sinha et al, 2011a). Furthermore, acute alcohol intake stimulates the HPA axis and increases cortisol levels (see Blaine et al (2016) for review), but chronic alcohol abuse is associated with blunted stress cortisol responses (Lovallo et al, 2000). In addition, alcohol withdrawal is associated with elevated basal cortisol (Blaine et al, 2016).