Pregnenolone effects on parasympathetic response to stress and alcohol cue provocation in treatment-seeking individuals with alcohol use disorder.

Background: Chronic alcohol consumption in alcohol use disorder (AUD) is associated with autonomic nervous system dysregulation, increasing cardiovascular risk, and high alcohol cravings. Heart rate variability (HRV), a marker of autonomic nervous system responsiveness to stressors, may mediate alcohol's impact on the cardiovascular system. While pregnenolone (PREG) has been shown to normalize heart rate and blood pressure in individuals with AUD, its effects on sympathetic and parasympathetic components of HRV and related alcohol craving are not known.

Stability and Reliability of Repeated Plasma Pregnenolone Levels After Oral Pregnenolone Dosing in Individuals with Cocaine Use Disorder: Pilot Findings.

Substance use disorders (SUDs), including cocaine use disorder (CUD), have significant negative health risks and impose a substantial social burden, yet effective treatments are limited. Pregnenolone, a neuroactive steroid precursor, has been shown to reduce alcohol craving and normalize stress biology in individuals with CUD, but its clinical utility has been questioned due to limited data on bioavailability and the stability of blood levels in humans. Thus, this pilot study aimed to determine whether twice-daily oral pregnenolone (PREG) at 300 mg/day and 500 mg/day versus placebo in week two of PREG administration led to stable increased plasma pregnenolone levels in individuals with CUD.

Laboratory and Real-World Experimental Approaches to Understanding Alcohol Relapse.

Alcohol use disorder is highly prevalent and high risk of relapse remains a significant treatment challenge. Therefore, the utility of human laboratory models of relapse to further the understanding of psychobiological mechanisms that precipitate relapse risk and allow testing of novel interventions could be of benefit in expediting the development of effective treatments to target high relapse risk. Stress is a risk factor for the development of AUD and for relapse, and furthermore, chronic alcohol use leads to adaptations in central and peripheral stress biology.

Therapeutics for Substance-Using Women: The Need to Elucidate Sex-Specific Targets for Better-Tailored Treatments.

In the last decade, alcohol consumption in the US has risen by 84% in women compared with 35% in men. Furthermore, research has shown that sex- and gender-related differences may disadvantage women in terms of developing a range of psychological, cognitive, and medical problems considerably earlier in their drinking history than men, and despite consuming a similar quantity of substances. While this "telescoping" process has been acknowledged in the literature, a concomitant understanding of the underlying biobehavioral mechanisms, and an increase in the development of specific treatments tailored to women, has not occurred.

Hypothalamic-pituitary-adrenal and autonomic response to psychological stress in abstinent alcohol use disorder individuals with and without depressive symptomatology.

Background: Stress and depression have each been associated with relapse risk. In clinical practice, chronic alcohol use is often accompanied by poor emotional and self-regulatory processes. Tonic and phasic changes in stress responsivity impact an individual's relapse risk to alcohol.

Sex differences in neural responses to stress and drug cues predicts future drug use in individuals with substance use disorder.

Background: Substance use disorders (SUDs) are chronically recurring illnesses, where stress and drug cues significantly increase drug craving and risk of drug use recurrence. This study examined sex differences in functional magnetic resonance imaging (fMRI) brain responses to stress and drug cue exposure and assessed their prospective association with future drug use post-treatment.

Methods: Inpatient, treatment engaged men (N = 46) and women (N = 26) with SUDs, including alcohol, cocaine and/or cannabis use disorders, participated in an fMRI scan that assessed subjective (anxiety, drug craving), heart rate and neural responses to brief individualized script-driven imagery of stress, drug, and neutral-relaxing trials.

Pregnenolone effects on provoked alcohol craving, anxiety, HPA axis, and autonomic arousal in individuals with alcohol use disorder.

Rationale: Chronic alcohol intake down-regulates GABAergic transmission and reduces levels of neuroactive steroids. These changes are associated with greater stress dysregulation and high alcohol craving which in turn increases relapse risk.

Objectives: This study tested whether potentiation of the neurosteroid system with pregnenolone (PREG), a precursor to neuroactive steroids and known to increase GABAergic transmission, will normalize chronic alcohol-related stress adaptations in the hypothalamic-pituitary-adrenal (HPA) axis and autonomic responses and reduce alcohol craving to significantly impact relapse risk.

Pregnenolone Reduces Stress-Induced Craving, Anxiety, and Autonomic Arousal in Individuals with Cocaine Use Disorder.

Chronic cocaine use leads to adaptations in stress biology and in neuroactive steroid system. These adaptations are associated with high cocaine craving and increased relapse risk. This study tested whether potentiation of the neuroactive steroid system with the precursor pregnenolone (PREG) affects stress- and cue-induced cocaine craving, anxiety and autonomic response in individuals with cocaine use disorder (CUD).

Moderation of Prazosin's Efficacy by Alcohol Withdrawal Symptoms.

Objective: Alcohol use disorder (AUD) is a leading cause of global disease burden. Chronic, heavy use increases the likelihood of alcohol withdrawal symptoms and associated secondary outcomes of alcohol craving and mood, anxiety, and sleep disturbances, which are predictive of poor treatment outcomes. The authors examined whether alcohol withdrawal symptoms moderate the efficacy of prazosin in reducing alcohol intake and associated secondary outcomes.

Effects of Prazosin on Provoked Alcohol Craving and Autonomic and Neuroendocrine Response to Stress in Alcohol Use Disorder.

Background: Chronic alcohol use results in changes to stress biology and autonomic arousal contributing to acute alcohol withdrawal symptoms, neuroendocrine tolerance of the hypothalamic-pituitary-adrenal axis responses, high stress-induced craving, and risk of alcohol relapse. Thus, stress coping and recovery from alcohol during early abstinence may be jeopardized by such stress system dysfunction. Significant preclinical evidence suggests that noradrenergic disruption may contribute to these alcohol-related stress arousal changes and that alpha-1 adrenergic antagonists, such as prazosin, may normalize these stress system adaptations and reduce alcohol intake.

Stress-related suppression of peripheral cytokines predicts future relapse in alcohol-dependent individuals with and without subclinical depression.

Chronic alcohol abuse and depressive symptoms are both associated with peripheral cytokine changes. Despite this, cytokine adaptations have not been assessed in co-morbid populations or prospectively as predictors of relapse. We examine cytokine responses to stress in alcohol-dependent individuals and social drinkers, both with and without subclinical depression.

Neuroactive steroid levels and cocaine use chronicity in men and women with cocaine use disorder receiving progesterone or placebo.

Background And Objectives: Neuroactive steroids (NAS) may play a role in addiction, with observed increases in response to acute stress and drug use, but decreases with chronic substance use, suggesting that NAS neuroadaptations may occur with chronic substance use. However, levels of NAS in addicted individuals have not been systematically examined. Here, we evaluated a panel of NAS in men and women with cocaine use disorder (CUD) who participated in a clinical laboratory study of progesterone.

Sexual dimorphism in the neural impact of stress and alcohol.

Alcohol use disorder is a widespread mental illness characterized by periods of abstinence followed by recidivism, and stress is the primary trigger of relapse. Despite the higher prevalence of alcohol use disorder in males, the relationship between stress and behavioral features of relapse, such as craving, is stronger in females. Given the greater susceptibility of females to stress-related psychiatric disorders, understanding sexual dimorphism in the relationship between stress and alcohol use is essential to identifying better treatments for both male and female alcoholics.

Central and Peripheral Biomarkers of Stress Response for Addiction Risk and Relapse Vulnerability.

Substance use disorders (SUDs) are marked by heterogeneity in clinical symptomatology and high relapse rates following treatment. Here, we describe specific peripheral and central stress responses associated with the pathophysiology of SUDs. We outline potential stress response measures, including hypothalamus-pituitary-adrenal axis markers, autonomic responses, and central structural and functional brain alterations that could be exploited as putative biomarkers in SUDs.

Sex differences in guanfacine effects on stress-induced stroop performance in cocaine dependence.

Aims: Chronic drug abuse leads to sex-specific changes in drug cue and stress physiologic and neuroendocrine reactivity as well as in neural responses to stress and cue-related challenges and in executive function such as inhibitory control, cognitive flexibility and self control. Importantly, these functions have been associated with high risk of relapse and treatment. Alpha-2 agonism may enhance inhibitory cognitive processes in the face of stress with sex-specific effects, however this has not been previously assessed in cocaine dependence.

Peripheral immune system suppression in early abstinent alcohol-dependent individuals: Links to stress and cue-related craving.

Background: Peripheral immune system cytokines may play an integral role in the underlying sensitized stress response and alcohol craving during early alcohol withdrawal. To date, the nature of these immune changes during early abstinence have not been examined.

Methods: A total of 39 early abstinent, treatment-seeking, alcohol-dependent individuals and 46 socially drinking controls were exposed to three guided imageries: stress, alcohol cue and neutral.

Peripheral Immune System Adaptations and Motivation for Alcohol in Non-Dependent Problem Drinkers.

Background: Increasing evidence suggests that levels of pro-inflammatory and anti-inflammatory cytokines are dysfunctional in alcohol dependence. Moreover, some initial findings demonstrate that these adaptations in peripheral inflammation may contribute to motivation for alcohol and problem drinking via possible direct effects or the indirect effects of stress responsivity. Importantly, the role of pro-inflammatory and anti-inflammatory cytokines in the progression from healthy to problem drinking is not well understood.

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.

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.

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

Objective: 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).

Methods: Study 1: The Mayer, Salovey, and Caruso Emotional Intelligence Test (MSCEIT) was administered to 98 CDA (55 M/43 F) and 56 healthy (28 M/28 F) individuals. Performance in women was also assessed by MC phase.

Variation in AKR1C3, which encodes the neuroactive steroid synthetic enzyme 3α-HSD type 2 (17β-HSD type 5), moderates the subjective effects of alcohol.

Rationale: Animal models suggest that neuroactive steroids contribute to alcohol's acute effects. We previously reported that a common nonsynonymous polymorphism, AKR1C3 2 in the gene encoding the enzyme 3α-HSD2/17β-HSD5, and a synonymous single nucleotide polymorphism (SNP), rs248793, in SRD5A1, which encodes 5α-reductase, were associated with alcohol dependence (AD).

Objectives: The aim of the study was to investigate whether these polymorphisms moderate subjective effects of alcohol in humans and whether AKR1C3 2 affects neuroactive steroid synthesis.

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.

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.

Variation in genes encoding the neuroactive steroid synthetic enzymes 5α-reductase type 1 and 3α-reductase type 2 is associated with alcohol dependence.

Background: Studies of alcohol effects in rodents and in vitro implicate endogenous neuroactive steroids as key mediators of alcohol effects at GABA(A) receptors. We used a case-control sample to test the association with alcohol dependence (AD) of single nucleotide polymorphisms in the genes encoding two key enzymes required for the generation of endogenous neuroactive steroids: 5α-reductase, type I (5α-R), and 3α-hydroxysteroid dehydrogenase, type 2 (3α-HSD), both of which are expressed in human brain.

Methods: We focused on markers previously associated with a biological phenotype.