Alcohol-induced dysregulation of stress-related circuitry: The search for novel targets and implications for interventions across the sexes.

While the ability to process fermented fruits and alcohols was once an adaptive trait that improved nutrition and quality of life, the availability and prevalence of high potency alcoholic drinks has contributed to alcohol abuse disorders in a vulnerable portion of the population. Although the neural reward systems take part in the initial response to alcohol, negative reinforcement and stress, which are normally adaptive responses, can intersect to promote continued alcohol use at all stages of the addiction cycle. Eventually a point is reached where these once adaptive responses become dysregulated resulting in uncontrolled intake that constitutes a clinically important condition termed alcohol use disorder (AUD). Current research is targeted at both the behavioral and molecular adaptations in AUDs in an effort to better develop novel approaches to intervention. In this review, historical context is provided demonstrating the societal burden of alcohol use and abuse disorders. The importance of gender in the mechanism of action of alcohol is discussed. Finally, the impact of alcohol on stress-related circuitry, uncovered by preclinical research, is outlined to provide insight into potential novel pharmacological approaches to the treatment of AUD.

Amygdalar neuronal plasticity and the interactions of alcohol, sex, and stress.

Alcohol abuse and alcoholism are major medical problems affecting both men and women. Previous animal studies reported a difference in c-Fos neuronal activation after chronic alcohol exposure; however, females remain an understudied population. To model chronic alcohol exposure match-pair fed adult male and female rats were administered 14 days of a liquid ethanol containing diet. Analysis focused on the central nucleus of the amygdala (CeA), a region integral to stress sensitivity and substance abuse. Immunocytochemical approaches identified cells containing ΔFosB, a marker of sustained neuronal activation, and activity patterns within the CeA were mapped by subdivision and rostral-caudal extent. Significant interactions were present between all groups, with gender differences noted among control groups, and ethanol exposed animals having the greatest number of ΔFosB immunoreactive cells indicating baseline dysregulation. Compared with c-Fos, a marker of recent neuronal activation, male ethanol treated animals had similar activity to controls, indicating a neuronal habituation not seen in females. Next, a cohort of animals were exposed to the forced swim test (FST), and c-Fos was examined in addition to FST behavior. Neuronal activity was increased in ethanol exposed animals compared to controls, and control females compared to males, indicating a potentiated stress response. Further, a population of activated neurons were shown to contain either corticotropin releasing factor or enkephalin. The present data suggest that dysregulation in the CeA neuronal activity may underlie some of the negative sequelae of alcohol abuse, and may, in part, underlie the distinctive response seen between genders to alcohol use.

Fabrication and operation of a two-dimensional ion-trap lattice on a high-voltage microchip.

Microfabricated ion traps are a major advancement towards scalable quantum computing with trapped ions. The development of more versatile ion-trap designs, in which tailored arrays of ions are positioned in two dimensions above a microfabricated surface, will lead to applications in fields as varied as quantum simulation, metrology and atom-ion interactions. Current surface ion traps often have low trap depths and high heating rates, because of the size of the voltages that can be applied to them, limiting the fidelity of quantum gates. Here we report on a fabrication process that allows for the application of very high voltages to microfabricated devices in general and use this advance to fabricate a two-dimensional ion-trap lattice on a microchip. Our microfabricated architecture allows for reliable trapping of two-dimensional ion lattices, long ion lifetimes, rudimentary shuttling between lattice sites and the ability to deterministically introduce defects into the ion lattice.

Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal.

Withdrawal from opiates, such as heroin or oral narcotics, is characterized by a host of aversive physical and emotional symptoms. High rates of relapse and limited treatment success rates for opiate addiction have prompted a search for new approaches. For many opiate addicts, achieving abstinence may be further complicated by poly-drug use and co-morbid mental disorders. Research over the past decade has shed light on the influence of endocannabinoids (ECs) on the opioid system. Evidence from both animal and clinical studies point toward an interaction between these two systems, and suggest that targeting the EC system may provide novel interventions for managing opiate dependence and withdrawal. This review will summarize the literature surrounding the molecular effects of cannabinoids and opioids on the locus coeruleus-norepinephrine system, a key circuit implicated in the negative sequelae of opiate addiction. A consideration of the trends and effects of marijuana use in those seeking treatment to abstain from opiates in the clinical setting will also be presented. In summary, the present review details how cannabinoid-opioid interactions may inform novel interventions in the management of opiate dependence and withdrawal.

Cocaine withdrawal-induced anxiety in females: impact of circulating estrogen and potential use of delta-opioid receptor agonists for treatment.

Sex differences in cocaine addiction warrants further research focused on examining the growing population of female cocaine addicts. As demonstrated in both clinical and preclinical research, females are more susceptible to drug relapse with anxiety being a contributing factor. In support of this, a recent clinical study from our laboratory highlights the importance of menstrual cycle phase and anxiety at treatment admission for cocaine addiction on treatment retention. In support of these trends in the clinical population, the purpose of the present study was to design an animal model to directly test the role of circulating hormone levels during cocaine withdrawal. To directly measure the influence of estrogen on anxiety-like behavior during early stages of withdrawal, both ovariectomized and intact female rodent models were employed. The elevated-plus maze and elevated-zero maze were used to assess anxiety-like behavior. Recent evidence in male rodents highlights a potential role for the delta opioid-receptor (DOR) system in the modulation of cocaine withdrawal-induced anxiety. In addition to the evaluation of hormonal effects, a potential anxiolytic specific for DOR was tested for its efficacy in females withdrawn from cocaine. Our results support the use of DOR agonists as a potential anxiolytic in females and highlight the importance of estrogen and other circulating hormones during all phases of cocaine addiction.

The effect of therapist/patient race- and sex-matching in individual treatment.

AIMS: Equivocal findings of the effect that therapist and patient similarity plays in treatment outcome led us to examine the impact of race- and sex-matching on treatment retention and outcome for a sample of people seeking outpatient substance abuse treatment. DESIGN: Patient and therapist characteristics were crossed in a 2 x 2 factorial design. Matching effects were then tested using retrospective data. PARTICIPANTS: Participants were 116 African-American cocaine-dependent people. SETTING: The study site was a university-sponsored outpatient treatment facility located in an economically depressed area of a large Northeastern US city. MEASUREMENTS: Follow-up data were drawn from the Addiction Severity Index, the Risk for AIDS Behavior Inventory and a questionnaire measuring post-discharge need for treatment, employment and education. Retention was defined as the number of days inclusive between the last date of service and the date admitted. FINDINGS: No meaningful effects in favor of matching were observed on outcome measures. CONCLUSION: While matching therapists and drug-dependent people does not appear to be essential in promoting positive retention and outcome, limitations of this study that include sample size and the homogeneous demographic nature of those seeking therapeutic services at our facility lead us to conclude that replication with a larger number of therapists and patients is needed. In a different therapeutic setting, with a different population presenting for treatment, the mismatching of patients and therapists with respect to factors such as those explored here might well yield differing results.

Correlates of employment: a cohort study.

Employment is often viewed as a potent indicator of substance abuse treatment outcome. This study was conducted to determine if personality and/or demographic characteristics of a cohort of unemployed substance dependent persons presenting for addiction treatment might predict employment 9 months postadmission. By using stepwise discriminant function analysis, seven variables predictive of employment were identified. The positive value of employment was clearly documented. Those who gained employment were functioning better with regard to social and drug-use parameters than those who did not.

Does intensive outpatient cocaine treatment reduce AIDS risky behaviors?

The purposes of this study were: (1) to examine the characteristics of 447 cocaine dependent, first admission outpatients in relation to their AIDS risky behavior at intake; (2) to ascertain whether there was a reduction in risky behavior at follow-up 9 months after admission; and (3) to determine whether reductions in risky behavior were related to patient characteristics, group as compared to individual treatment, or time in treatment. In this sample of cocaine dependent patients entering outpatient treatment, those engaging in higher AIDS risky behaviors were not characterized by any particular demographic profile or by a lack of knowledge about HIV/AIDS. They did have higher scores on the SCL-90-R symptom scales, the Beck Depression Inventory, and higher ratings on the Drug, Alcohol, Family, and Medical scales of the ASI. At 9-month follow-up, AIDS risky behaviors as measured by the RAB were found to have decreased significantly. The degree of improvement was not associated with demographic variables but was predicted by higher intake problem severity and psychological symptomatology scale scores. While improvement in risky behavior was not related to type of treatment or duration of treatment, it was related to decreased substance use. The individuals whose risky behavior decreased were those whose substance use had decreased. Improvement, then required not only being in a treatment program, but also participation and involvement in the program. Treatment and not merely attendance would seem to be critical.

Therapist/patient race and sex matching: treatment retention and 9-month follow-up outcome.

AIMS: The current study was conducted to (a) replicate previous findings regarding the effect of patient/therapist race and sex-matching as this relates to the early dropout rate of substance abusers, and (b) to extend previous work by examining the impact of such matching on treatment retention and 9-month outcome. DESIGN: Patient and therapist characteristics were crossed in a 2 x 2 factorial design. Matching effects were then tested using retrospective data. PARTICIPANTS: Participants were 967 African-American cocaine-dependent people. SETTING: The study site was a university sponsored outpatient treatment facility located in an economically depressed section of a large Northeastern US city. MEASUREMENTS: Follow-up data were drawn from the Addiction Severity Index, the Risk for AIDS Behavior Inventory, and a questionnaire measuring post-discharge need for treatment, employment and education. Retention was defined as the number of days inclusive between the last date of service and the date of admission. FINDINGS: No significant differences in early dropout rates were found after initial contact with 10 different therapists. Matching therapist and patients with respect to gender and race did not decrease the premature dropout rate, but partial support for gender matching was noted. CONCLUSION: Matching therapist and substance abusing patients on gender and race may not be essential to improving retention and outcome.

A randomized controlled study of the effectiveness of intensive outpatient treatment for cocaine dependence.

OBJECTIVE: A randomized controlled study design was used to compare the effectiveness of intensive outpatient treatment with individual outpatient counseling and a combination of individual and group outpatient counseling for cocaine-dependent patients. METHODS: Volunteers for this study were recruited from among first admissions to an inner-city, public-sector outpatient substance abuse clinic. In-treatment, end-of-treatment, and nine-month follow-up assessments were compared for participants randomly assigned for 12 weeks to one of three treatment modalities--weekly individual outpatient counseling, weekly individual counseling plus one weekly group session, or a newly designed intensive group treatment program consisting of three hours of group treatment three days a week. RESULTS AND CONCLUSIONS: Patients who completed the intensive program showed significant improvement from intake to end-of-treatment scores on the Addiction Severity Index, the Beck Depression Inventory, and the Symptom Checklist. At nine-month follow-up, patients who had remained in treatment longer had fewer drug problems, a smaller proportion of positive urine drug screening tests, a better employment status, and fewer psychological problems compared with patients who left treatment earlier. Patients who remained in treatment were also more likely to be attending self-help meetings, continuing in outpatient treatment, or attending school. However, for the 447 patients randomly assigned to the three conditions, there were no significant differences between treatment modalities on any of the variables at nine-month follow-up. The new intensive treatment program was not shown to be superior to more traditional treatment programs.