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Context: Prognostic prediction models (PPMs) can help clinicians predict outcomes., Objective: To critically examine peer-reviewed PPMs predicting delayed recovery among pediatric patients with concussion., Data Sources: Ovid Medline, Embase, Ovid PsycInfo, Web of Science Core Collection, Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, Google Scholar., Study Selection: The study had to report a PPM for pediatric patients to be used within 28 days of injury to estimate risk of delayed recovery at 28 days to 1 year postinjury. Studies had to have at least 30 participants., Data Extraction: The Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies checklist was completed., Results: Six studies of 13 PPMs were included. These studies primarily reflected male patients in late childhood or early adolescence presenting to an emergency department meeting the Concussion in Sport Group concussion criteria. No study authors used the same outcome definition nor evaluated the clinical utility of a model. All studies demonstrated high risk of bias. Quality of evidence was best for the Predicting and Preventing Postconcussive Problems in Pediatrics (5P) clinical risk score., Limitations: No formal PPM Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) process exists., Conclusions: The 5P clinical risk score may be considered for clinical use. Rigorous external validations, particularly in other settings, are needed. The remaining PPMs require external validation. Lack of consensus regarding delayed recovery criteria limits these PPMs., (Copyright © 2024 by the American Academy of Pediatrics.)

Comparing self-reported symptom scores across time requires longitudinal measurement invariance (LMI), a psychometric property that means the measure is functioning identically across all time points. Despite its prominence as a measure of depression symptom severity in both research and health care, LMI has yet to be firmly established for the Patient Health Questionnaire-9 depression module (PHQ-9), particularly over the course of antidepressant pharmacotherapy. Accordingly, the objective of this study was to assess for LMI of the PHQ-9 during pharmacotherapy for major depressive disorder. This was a secondary analysis of data collected during a randomized controlled trial. A total of 1,944 veterans began antidepressant monotherapy and completed the PHQ-9 six times over 24 weeks of treatment. LMI was assessed using a series of four confirmatory factor analysis models that included all six time points, with estimated parameters increasingly constrained across models to test for different aspects of invariance. Root-mean-square error of approximation of the chi-square difference test values below 0.06 indicated the presence of LMI. Exploratory LMI analyses were also performed for separate sex, age, and race subgroups. Root-mean-square error of approximation of the chi-square difference test showed minimal change in model fits during invariance testing (≤ 0.06 for all steps), supporting full LMI for the PHQ-9. LMI was also supported for all tested veteran subgroups. As such, PHQ-9 sum scores can be compared across extended pharmacotherapy treatment durations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: Individuals with a history of moderate-severe traumatic brain injury (TBI) experience a significantly higher prevalence of insomnia compared to the general population. While individuals living with TBI have been shown to benefit from traditional insomnia interventions (e.g., face-to-face [F2F]), such as Cognitive Behavioral Therapy for Insomnia (CBTI), many barriers exist that limit access to F2F evidence-based treatments. Although computerized CBT-I (CCBT-I) is efficacious in terms of reducing insomnia symptoms, individuals with moderate-severe TBI may require support to engage in such treatment. Here we describe the rationale, design, and methods of a randomized controlled trial (RCT) assessing the efficacy of a guided CCBT-I program for reducing insomnia symptoms for participants with a history of moderate-severe TBI., Methods: This is an RCT of a guided CCBT-I intervention for individuals with a history of moderate-severe TBI and insomnia. The primary outcome is self-reported insomnia severity, pre- to post-intervention. Exploratory outcomes include changes in sleep misperception following CCBT-I and describing the nature of guidance needed by the Study Clinician during the intervention., Conclusion: This study represents an innovative approach to facilitating broader engagement with an evidence-based online treatment for insomnia among those with a history of moderate-severe TBI. Findings will provide evidence for the level and nature of support needed to implement guided CCBT-I. Should findings be positive, this study would provide support for a strategy by which to deliver guided CCBT-I to individuals with a history of moderate-severe TBI., Competing Interests: Declaration of competing interest Dr. Brenner reports grants from the VA, DOD, NIH, and the State of Colorado, editorial renumeration from Wolters Kluwer, and royalties from the American Psychological Association and Oxford University Press. In addition, she consults with sports leagues via her university affiliation. Dr. Forster reports grants from the VA, DOD and NIH., (Copyright © 2023. Published by Elsevier Inc.)

Background: Bright light therapy (BLT) is efficacious for seasonal and non-seasonal depression. However, the current state of BLT use in practice is unknown, impeding efforts to identify and address utilization gaps. This study's objective was to investigate BLT delivery in a nationwide U.S. healthcare system., Methods: This was a retrospective observational study of electronic medical records from all veterans who received outpatient mood disorder-related care in the Veterans Health Administration (VHA) from October 2008 through September 2020. BLT delivery was measured through the placement of light box consults., Results: Of the 3,442,826 veterans who received outpatient mood disorder care, only 57,908 (1.68 %) received a light box consult. Consults increased by 548.44 % (99.9 % credible interval: 467.36 %, 638.74 %) over the timeframe and displayed a robust yearly cycle that peaked on either December 21st or December 22nd. Past mental health treatment for a mood disorder was associated with a higher probability of a consult (relative risk = 4.79, 99.9 % CI: 4.21, 5.60). There was low representation related to veteran age, gender, race, and ethnicity., Limitations: No information on patients who declined light boxes or actual light box use following consult placement., Conclusions: Outpatient BLT delivery for mood disorders in the VHA remains low, despite significant growth over the past decade. It also displays a strong seasonal rhythm that peaks on the winter solstice, suggesting a limited focus on seasonal depression and a suboptimal reactive approach to changing sunlight. Overall, there exists ample opportunity for novel implementation efforts aimed at increasing utilization of BLT., Competing Interests: Declaration of competing interest The authors have no known conflicts of interest to disclose., (Published by Elsevier B.V.)

Background: Increasing evidence suggests that conditions with decreased morning and increased evening light exposure, including shift work, daylight-saving time, and eveningness, are associated with elevated mortality and suicide risk. Given that the alignment between the astronomical, biological, and social time varies across a time zone, with later-shifted daylight exposure in the western partition, we hypothesized that western time zone partitions would have higher suicide rates than eastern partitions., Methods: United States (U.S.) county-level suicide and demographic data, from 2010 to 2018, were obtained from a Centers for Disease Control database. Using longitude and latitude, counties were sorted into the western, middle, or eastern partition of their respective time zones, as well as the northern and southern halves of the U.S. Linear regressions were used to estimate the associations between suicide rates and time zone partitions, adjusting for gender, race, ethnicity, age group, and unemployment rates., Results: Data were available for 2872 counties. Across the U.S., western partitions had statistically significantly higher rates of suicide compared to eastern partitions and averaged up to two additional yearly deaths per 100,000 people (p < .001)., Limitations: Ecological design and limited adjustment for socioeconomic factors., Conclusions: To our knowledge, this is the first study of the relationship between longitude-based time zone partitions and suicide. The results were consistent with the hypothesized elevated suicide rates in the western partitions, and concordant with previous reports on cancer mortality and transportation fatalities. The next step is to retest the hypothesis with individual-level data, accounting for latitude, photoperiodic changes, daylight-saving time, geoclimatic variables, physical and mental health indicators, as well as socioeconomic adversity and protection., Competing Interests: Declaration of competing interest The authors have no known conflicts of interest to disclose., (Published by Elsevier B.V.)

Bright light therapy (BLT) is a promising non-pharmacological treatment for a range of psychiatric conditions. The goal of this review was to provide a comprehensive overview of the efficacy of BLT across mental and behavioral illnesses. Using systematic umbrella review methodology, we searched Ovid MEDLINE, Embase, PsycInfo, Web of Science, and Google Scholar for systematic reviews of randomized controlled trials (RCTs) evaluating BLT for any mental or behavioral illness from the date of inception until March 2021. Review quality was assessed using the AMSTAR 2 tool and summary efficacy data were extracted from recent reviews. Of 792 unique records, 67 systematic reviews were included which targeted a range of disorders related to mood, neurocognition, sleep, and eating. Recent meta-analyses targeting seasonal or non-seasonal depression found that BLT outperformed light-related control conditions. Reviews of other disorders identified few RCTs and generally did not support the efficacy of BLT for various outcomes. Overall, the extant literature supports the efficacy of BLT for seasonal and non-seasonal depression, although higher quality systematic reviews are needed to increase confidence in these findings. There was no specific funding for this review, and it was preregistered on Prospero (ID: CRD42021240751).

Objective: Bayesian meta-analyses offer several advantages over traditional approaches, including improved accuracy when using a small number of studies and enhanced estimation of heterogeneity. However, psychological trauma research has yet to see widespread adoption of these statistical methods, potentially due to researchers' unfamiliarity with the processes involved. The purpose of this article is to provide a practical tutorial for conducting random-effects Bayesian meta-analyses., Method: Explanations and recommendations are provided for completing the primary steps of a Bayesian meta-analysis, ranging from model specification to interpretation of results. Furthermore, an illustrative example is used to demonstrate the application of each step. In the example, results are synthesized from six studies included in a previously published systematic review (Holliday et al., 2020), with a combined sample size of 21,244,109, examining the association between posttraumatic stress disorder and risk of suicide in veterans and military personnel., Results: The posterior distributions for each model estimate, such as the pooled effect size and the heterogeneity parameter, are discussed and interpreted with regard to the probability of increased suicide risk., Conclusions: Our hope is that this tutorial, along with the provided data and code, facilitate the use of Bayesian meta-analyses in the study of psychological trauma. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objective: Kibler et al. (2009) reported that hypertension was related to PTSD independent of depression. These two conditions have significant diagnostic overlap. The present study sought to conceptually replicate this work with a veteran sample, using Bayesian estimation to directly update past results, as well as examine symptom severity scores in relation to hypertension., Method: This was a secondary analysis of data obtained from the United States-Veteran Microbiome Project. Lifetime diagnoses of PTSD and major depressive disorder (MDD) were obtained from a structured clinical interview and hypertension diagnoses were extracted from electronic medical records. PTSD and depressive symptom severity were obtained from self-report measures. Logistic regressions with Bayesian estimation were used to estimate the associations between hypertension and (a) psychiatric diagnostic history and (b) symptom severity scores., Results: Compared with veterans without lifetime diagnoses of either disorder, the PTSD-only group was estimated to have a 29% increase in hypertension risk, and the PTSD + MDD group was estimated to have a 66% increase in hypertension risk. Additionally, higher levels of PTSD symptom severity were associated with a higher risk of hypertension., Conclusion: PTSD diagnosis and symptom severity are uniquely associated with hypertension, independent of MDD or depressive symptom severity. These results support previous findings that PTSD might be a modifiable risk factor for the prevention and treatment of hypertension. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: Physical exercise offers benefits for treating psychological disorders, particularly depression. Exercise is associated with reduction of posttraumatic stress disorder (PTSD) symptoms in civilians. Given the comorbidities and unique trauma experiences of the veteran population, the current work aims to estimate the effect of exercise on PTSD symptoms in veteran samples., Observations: A systematic review identified 6 single-arm studies and 3 randomized controlled trials (RCTs) using exercise as an interventional treatment among veteran samples with full or subsyndromal PTSD. Most single-arm studies used yoga-based interventions, whereas RCTs showed more variety and included yoga, aerobic activity, and resistance exercises. Data synthesis of study results revealed a medium standardized mean difference for the single-arm trials (Hedges g , -0.60, P = .03) and a small-to-medium standardized mean difference for the RCTs (Hedges g , -0.40, P = .06). Single-arm studies were all rated at serious risk of bias. Only 1 RCT was rated at high risk of bias, although the remaining RCTs showed some concern of elevated bias., Conclusions: There is preliminary evidence that exercise may be a useful treatment option for PTSD symptom reduction in veterans. Our review also highlights the need for additional high-quality randomized trials to confirm the benefits of exercise for PTSD symptom reduction in veterans., Competing Interests: Author disclosures The authors report no actual or potential conflicts of interest or outside sources of funding with regard to this article., (Copyright © 2022 Frontline Medical Communications Inc., Parsippany, NJ, USA.)

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., Competing Interests: The authors have declared that no competing interests exist.

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. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

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. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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.

Background: Probiotics 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., Methods: The 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., Results: Data 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., Conclusions: While 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., Competing Interests: The authors have declared that no competing interests exist.

Psychotherapists risk making 2 types of errors with clients who struggle with addictive behaviors: failure to diagnose addictive behaviors and failure to effectively treat addictive behaviors. Given the high prevalence of addictive behaviors in clinical populations, therapists are in a unique position to assist individuals with these problems. It is assumed that therapists possess general diagnostic and treatment skills and yet many do not diagnose or do not treat addictive behaviors. Reasons for making these errors include prohibitive beliefs and limited knowledge about addictive behaviors. We offer specific recommendations to reduce these psychotherapy errors. These include: (a) more deliberate screening and diagnosis of addictive behaviors, (b) increased application of empirically supported addiction treatments, (c) required education and training in addictive behaviors, (d) modification of prohibitive attitudes about addressing addictive behaviors, and (e) increased attention paid to the addictive behaviors by professional psychotherapy organizations., (PsycINFO Database Record (c) 2016 APA, all rights reserved)

Background: The dynorphin (DYN)/kappa-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 pharmacologic 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 pharmacologic 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 [(35)S]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 with nondependent control rats. Site-specific infusions of a KOR antagonist selectively attenuated self-administration in dependent rats, whereas a mu-opioid receptor/delta-opioid receptor antagonist cocktail selectively reduced self-administration in nondependent rats. A mu-opioid receptor antagonist/partial KOR agonist attenuated self-administration in both cohorts., Conclusions: 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, intracentral nucleus of the amygdala pharmacologic 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., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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 alcohol and drug 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 8 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 alcohol exposure was extended to 4 weeks. Following 8 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.

Dopaminergic neurons in the substantia nigra pars compacta undergo apoptosis after transection of the medial forebrain bundle. We have assessed the temporal and sequential activities of microglia in these events by examining the complement-3 (OX-42), major histocompatibility complex class II antigen presentation (OX-6) and phagocytic activity (ED1), and correlating these indicators with dopaminergic neuronal loss. Microglia in the ipsilateral substantia nigra pars reticulata evinced activation morphology at 12 h postaxotomy. Phagocytic microglia apposed dying dopaminergic neurons in the pars compacta starting at 3 days postlesion; their number increased through 14 days and slowly decreased. Nuclear chromatin condensation and significant loss of tyrosine hydroxylase-positive dopaminergic neurons occurred around 7 days postlesion. In contrast to microglial expression of interleukin-1beta and inducible nitric oxide synthase at the axotomy site, nigral microglia were interleukin-1beta and inducible nitric oxide synthase-negative. Consistently, RNase protection assays showed that interleukin-1beta and inducible nitric oxide synthase transcripts in nigra were equivocal. The present data support the idea that phagocytosis of axotomized neurons by activated microglia is not limited to dead neurons but includes dying neurons probably without cytotoxic effects of inflammatory substances, such as interleukin-1beta or nitric oxide.

Agmatine, decarboxylated from arginine by arginine decarboxylase, is particularly prominent in the hypothalamus. The present study utilized the rat hypothalamo-neurohypophysial system to determine expression and "pre-synaptic" modulation of agmatine in the central nervous system (CNS). Under confocal-laser scanning, agmatine-like immunoreactivity (Agm-LI) was found enriched in arginine-vasopressin (AVP)-containing magnocellular neurons of the supraoptic nuclei (SON) and paraventricular nuclei (PVN). In addition, using electron microscopy, Agm-LI was found closely associated with large neurosecretory-like vesicles in neurohypophysial nerve terminals of posterior pituitary gland. Radioimmunoassay revealed that 10 and 30 microM agmatine concentration-dependently inhibited the depolarization-evoked AVP release from isolated neurohypophysial terminals. Using perforated patch-clamp, effects of agmatine on whole-terminal voltage-gated ion currents in the isolated neurohypophysial nerve terminals were examined. While it did not significantly affect either tetrodotoxin (TTX)-sensitive Na(+) or sustained Ca(2+)-activated K(+) channel currents, agmatine (1-40 microM) inhibited Ca(2+) channel currents in approximately 53% of the total nerve terminals investigated. The onset of inhibitory effect was immediate, and the inhibition was reversible and concentration-dependent with an IC(50)=4.6 microM. In the remaining (approximately 47%) neurohypophysial nerve terminals, only a higher (120 microM) concentration of agmatine could moderately inhibit Ca(2+) channel currents. The results suggest that: (1) endogenous agmatine is co-expressed in AVP-containing, hypothalamic magnocellular neurons of the SON/PVN and in neurohypophysial nerve terminals of posterior pituitary gland; (2) agmatine may serve as a physiological neuromodulator by regulating the voltage-gated Ca(2+) channel and, as a result, the release of AVP from neurohypophysial nerve terminals.