Background The dynorphin (DYN)/κ-opioid receptor (KOR) system undergoes neuroadaptations following chronic alcohol exposure that promote excessive operant self-administration and negative affective-like states; however, the exact mechanisms are unknown. The present studies tested the hypothesis that an upregulated DYN/KOR system mediates excessive alcohol self-administration that occurs during withdrawal in alcohol-dependent rats by assessing DYN A peptide expression and KOR function, in combination with site-specific pharmacological manipulations. Methods Male Wistar rats were trained to self-administer alcohol using operant behavioral strategies and subjected to intermittent alcohol vapor- or air-exposure. Changes in self-administration were assessed by pharmacological challenges during acute withdrawal. In addition, 22-kHz ultrasonic vocalizations were utilized to measure negative affective-like states. Immunohistochemical techniques assessed DYN A peptide expression and [35S]GTPγS coupling assays were performed to assess KOR function. Results Alcohol-dependent rats displayed increased alcohol self-administration, negative affective-like behavior, DYN A-like immunoreactivity and KOR signaling in the amygdala compared to non-dependent controls. Site-specific infusions of a KOR antagonist selectively attenuated self-administration in dependent rats whereas, a MOR/DOR antagonist cocktail selectively reduced self-administration in non-dependent rats. A MOR antagonist/partial KOR agonist attenuated self-administration in both cohorts. Conclusion Increased DYN A and increased KOR signaling could set the stage for a `one-two punch' during withdrawal that drives excessive alcohol consumption in alcohol-dependence. Importantly, intra-CeA pharmacological challenges functionally confirmed a DYN/KOR system involvement in the escalated alcohol self-administration. Together, the DYN/KOR system is heavily dysregulated in alcohol dependence and contributes to the excessive alcohol consumption during withdrawal.

BackgroundProbiotics have generated intensive research interest in recent years as a novel mode of treatment for physical and mental illness. Nevertheless, the anxiolytic potential of probiotics remains unclear. The present systematic review and meta-analysis aimed to evaluate the clinical and preclinical (animal model) evidence regarding the effect of probiotic administration on anxiety.MethodsThe PubMed, PsycINFO, and Web of Science databases were reviewed for preclinical and clinical studies that met the defined inclusion and exclusion criteria. The effects of probiotics on anxiety-like behavior and symptoms of anxiety were analyzed by meta-analyses. Separate subgroup analyses were conducted on diseased versus healthy animals, specific preclinical probiotic species, and clinical versus healthy human samples.ResultsData were extracted from 22 preclinical studies (743 animals) and 14 clinical studies (1527 individuals). Overall, probiotics reduced anxiety-like behavior in animals (Hedges’ g = -0.47, 95% CI -0.77 –-0.16, p = 0.004). Subgroup analyses revealed a significant reduction only among diseased animals. Probiotic species-level analyses identified only Lactobacillus (L.) rhamnosus as an anxiolytic species, but these analyses were broadly under-powered. Probiotics did not significantly reduce symptoms of anxiety in humans (Hedges’ g = -0.12, 95% CI -0.29–0.05, p = 0.151), and did not differentially affect clinical and healthy human samples.ConclusionsWhile preclinical (animal) studies suggest that probiotics may help reduce anxiety, such findings have not yet translated to clinical research in humans, perhaps due to the dearth of extant research with clinically anxious populations. Further investigation of probiotic treatment for clinically relevant anxiety is warranted, particularly with respect to the probiotic species L. rhamnosus.

Rationale Once dependent on alcohol or opioids, negative affect may accompany withdrawal. Dependent individuals are hypothesized to “self-medicate” in order to cope with withdrawal, which promotes escalated drug or alcohol use. Objectives The current study aimed to develop a reliable animal model to assess symptoms that occur during spontaneous alcohol and opioid withdrawal. Methods Dependence was induced using intermittent alcohol exposure or pulsatile heroin delivery and assessed for the presence of withdrawal symptoms during acute withdrawal by measuring somatic signs, behavior in the forced swim test (FST) and air-puff induced 22-kHz ultrasonic vocalizations (USVs). Additional animals subjected to eight weeks of alcohol vapor exposure were evaluated for altered somatic signs, operant alcohol self-administration and 22-kHz USV production, as well as performance in the elevated plus-maze (EPM). Results During spontaneous withdrawal from pulsatile heroin or intermittent alcohol vapor, animals displayed increased somatic withdrawal signs, FST immobility and 22-kHz USV production, but did not show any behavioral change in the EPM unless the duration of exposure was extended to four weeks. Following eight weeks of alcohol vapor exposure, animals displayed somatic withdrawal signs, escalated alcohol self-administration and increased 22-kHz USVs. Conclusions These paradigms provide consistent methods to evaluate the behavioral ramifications, and neurobiological substrates, of alcohol and opioid dependence during spontaneous withdrawal. As immobility in the FST and percent open-arm time in the EPM were dissociable, with 22-kHz USVs paralleling immobility in the FST, assessment of air-puff induced 22-kHz USVs could provide an ethologically-valid alternative to the FST.

Evidence from recent animal studies suggest that minocycline, a broad-spectrum antibiotic capable of regulating immune processes, may possess antidepressant properties. These studies, however, have yet to be comprehensively reviewed. Accordingly, this systematic review and meta-analysis summarizes the extant literature examining the effect of minocycline on depressive-like behavior in rodent models. PubMed, PsycINFO, and Web of Science databases were systematically searched for articles that met prespecified inclusion and exclusion criteria, and standardized mean differences (SMDs) were calculated for each continuous measure of depressive-like behavior. The overall effect of minocycline on depressive-like behavior was estimated using robust variance estimation meta-analysis. Separate subgroup analyses were conducted on diseased vs healthy animal models, different rodent species, and immobility-based vs anhedonia-based measures of depressive-like behavior. A total of 22 preclinical studies (816 animals) were included. Overall, minocycline reduced depressive-like behavior in rodents (SMD = −1.07, 95% CI −1.41–−0.74, p < 0.001). Subgroup analyses revealed that minocycline reduced depressive-like behavior in diseased, but not healthy, animal models. Finally, minocycline was found to reduce both immobility-based and anhedonia-based outcomes. These findings suggest that minocycline may be an effective treatment of core depressive symptoms, and that further investigation of minocycline treatment for clinically relevant depression in humans is warranted.

Added sugars are ubiquitous in contemporary Western diets. Although excessive sugar consumption is now robustly associated with an array of adverse health consequences, comparatively little research has thus far addressed its impact on the risk of mental illness. But ample evidence suggests that high-dose sugar intake can perturb numerous metabolic, inflammatory, and neurobiological processes. Many such effects are of particular relevance to the onset and maintenance of depressive illness, among them: systemic inflammation, gut microbiota disruption, perturbed dopaminergic reward signaling, insulin resistance, oxidative stress, and the generation of toxic advanced glycation end-products (AGEs). Accordingly, we hypothesize that added dietary sugars carry the potential to increase vulnerability to major depressive disorder, particularly at high levels of consumption. The present paper: (a) summarizes the existing experimental and epidemiological research regarding sugar consumption and depression vulnerability; (b) examines the impact of sugar ingestion on known depressogenic physiological processes; and (c) outlines the clinical and theoretical implications of the apparent sugar-depression link. We conclude that the extant literature supports the hypothesized depressogenic impact of added dietary sugars, and propose that an improved understanding of the effects of sugar on body and mind may aid in the development of novel therapeutic and preventative measures for depression.

The Beck Anxiety Inventory (BAI) is widely used within the Veterans Health Administration (VHA), both as an assessment tool and as a part of measurement-based care practices. However, there is preliminary evidence that the BAI may perform uniquely in veteran samples, emphasizing the need for a comprehensive investigation of the BAI in this population. The present study compared the normative data reported by Beck and Steer (1993) to secondary data generated by a nationwide sample of U.S. military veterans receiving treatment through the VHA. Secondary data, including initial BAI scores, demographic characteristics, treatment location, and diagnoses originally recorded during the course of usual VHA care over a 5-year period for 57,088 individual veterans, were extracted through the VA Informatics and Computing Infrastructure. BAI scores were compared across samples and various veteran subgroups. Exploratory and confirmatory factor analyses were also conducted. Results revealed that the BAI performed similarly across veteran and normative samples. Male and older veterans were found to have lower BAI scores than their respective counterparts. Factor analyses indicated that a three-factor model best fit the veteran data. Additionally, a cut score of 18 best differentiated between veterans with and without anxiety and related disorders. This study helps support the use of the BAI as a reliable and valid instrument for assessing anxiety symptoms in veterans. Additional research is recommended to better guide BAI interpretation across age groups and sexes/genders.

Importance Understanding the extent to which population-level suicide risk screening facilities follow-up and engagement in mental health treatment is important as engaging at-risk individuals in treatment is critical to reducing suicidal behaviors. Objective To evaluate mental health follow-up and treatment engagement in the Veterans Health Administration (VHA) following administration of the Columbia-Suicide Severity Rating Scale (C-SSRS) screen, a component of the VHA’s universal suicide risk screening program. Design This cross-sectional study used data from VA’s Corporate Data Warehouse. Settings 140 VHA Medical Centers. Participants Patients who completed the C-SSRS screen in ambulatory care between October 1, 2018—September 30, 2020. Exposure Standardized suicide risk screening. Main outcomes and measures Mental health follow-up (one or more visits within 30 days of C-SSRS screening) and treatment engagement (two or more visits within 90 days of C-SSRS screening) were examined. Results 97,224 Veterans in Fiscal Year 2019 (FY19) (mean age 51.4 years; 86.8% male; 64.8% white, 22.4% African-American) and 58,693 Veterans in FY20 (mean age 49.6 years; 85.5% male; 63.4% white, 21.9% African-American) received the C-SSRS screen. Across FYs, a positive C-SSRS screen was associated with increased probability of mental health follow-up and treatment engagement. Patients who were not seen in mental health in the year prior to screening had the greatest increase in probability of mental health follow-up and engagement following a positive screen (P<0.001). For FY19, a positive C-SSRS screen in non-mental health connected patients was associated with an increased probability of follow-up from 49.8% to 79.5% (relative risk = 1.60) and engagement from 39.5% to 63.6% (relative risk = 1.61). For mental health-connected patients, a positive C-SSRS screen was associated with a smaller increase in probability of follow-up from 75.8% to 87.6% (relative risk = 1.16) and engagement from 63.3% to 76.4% (relative risk = 1.21). Results for FY20 were similar. Conclusions and relevance Identification of suicide risk through population-level screening was associated with increased mental health follow-up and engagement, particularly for non-mental health connected patients. Findings support the use of a standardized, comprehensive suicide risk screening program for managing elevated suicide risk in a large healthcare system.

The Beck Depression Inventory-II (BDI-II) is used within the Veterans Health Administration (VHA) to measure depression symptom severity. This naturalistic study aimed to examine VHA-specific BDI-II use and establish normative data and psychometric properties. Initial BDI-II data for 152,260 individual veterans were extracted from preexisting medical records using the VA Informatics and Computing Infrastructure. BDI-II scores were compared against Beck, Steer, and Brown (1996)’s original sample, as well as across veteran subgroups. Exploratory and confirmatory factor analyses were also conducted. Similar to Beck et al.’s (1996) sample, the BDI-II was most frequently administered in outpatient psychiatric VHA settings, although it was also used in inpatient and medical settings. Veterans scored significantly higher on the BDI-II than the original comparison groups. This was true across diagnostic categories. The largest discrepancy was seen between nondepressed veterans and corresponding patients from the original sample (Cohen’s d = 1.34). Older veterans endorsed less severe levels of depression symptomatology. Additionally, a 2-factor model similar to Beck et al.’s (1996) original solution provided the best fit to the data. Veterans reported higher levels of somatic-affective symptoms than cognitive symptoms. Although potentially useful, the BDI-II requires further investigation in veterans. Standard cut scores are not recommended for use in this population when evaluating severity of depression. A cut score of 27 or higher best differentiated between veterans with and without mood disorders in the current sample. Treatment providers should also consider using BDI-II factor scores, rather than the total score, to measure depressive symptom change.