Changes in lipid metabolism driven by steroid signalling modulate proteostasis in C. elegans.

Alzheimer's, Parkinson's and Huntington's diseases can be caused by mutations that enhance protein aggregation, but we still do not know enough about the molecular players of these pathways to develop treatments for these devastating diseases. Here, we screen for mutations that might enhance aggregation in Caenorhabditis elegans, to investigate the mechanisms that protect against dysregulated homeostasis. We report that the stomatin homologue UNC-1 activates neurohormonal signalling from the sulfotransferase SSU-1 in ASJ sensory/endocrine neurons. A putative hormone, produced in ASJ, targets the nuclear receptor NHR-1, which acts cell autonomously in the muscles to modulate polyglutamine repeat (polyQ) aggregation. A second nuclear receptor, DAF-12, functions oppositely to NHR-1 to maintain protein homeostasis. Transcriptomics analyses of unc-1 mutants revealed changes in the expression of genes involved in fat metabolism, suggesting that fat metabolism changes, controlled by neurohormonal signalling, contribute to protein homeostasis. Furthermore, the enzymes involved in the identified signalling pathway are potential targets for treating neurodegenerative diseases caused by disrupted protein homeostasis.

The diverse functions of the DEG/ENaC family: linking genetic and physiological insights.

The DEG/ENaC family of ion channels was defined based on the sequence similarity between degenerins (DEG) from the nematode Caenorhabditis elegans and subunits of the mammalian epithelial sodium channel (ENaC), and also includes a diverse array of non-voltage-gated cation channels from across animal phyla, including the mammalian acid-sensing ion channels (ASICs) and Drosophila pickpockets. ENaCs and ASICs have wide ranging medical importance; for example, ENaCs play an important role in respiratory and renal function, and ASICs in ischaemia and inflammatory pain, as well as being implicated in memory and learning. Electrophysiological approaches, both in vitro and in vivo, have played an essential role in establishing the physiological properties of this diverse family, identifying an array of modulators and implicating them in an extensive range of cellular functions, including mechanosensation, acid sensation and synaptic modulation. Likewise, genetic studies in both invertebrates and vertebrates have played an important role in linking our understanding of channel properties to function at the cellular and whole animal/behavioural level. Drawing together genetic and physiological evidence is essential to furthering our understanding of the precise cellular roles of DEG/ENaC channels, with the diversity among family members allowing comparative physiological studies to dissect the molecular basis of these diverse functions.

Physiological insight into the conserved properties of Caenorhabditis elegans acid-sensing degenerin/epithelial sodium channels.

Acid-sensing ion channels (ASICs) are members of the diverse family of degenerin/epithelial sodium channels (DEG/ENaCs). They perform a wide range of physiological roles in healthy organisms, including in gut function and synaptic transmission, but also play important roles in disease, as acidosis is a hallmark of painful inflammatory and ischaemic conditions. We performed a screen for acid sensitivity on all 30 subunits of the Caenorhabditis elegans DEG/ENaC family using two-electrode voltage clamp in Xenopus oocytes. We found two groups of acid-sensitive DEG/ENaCs characterised by being either inhibited or activated by increasing proton concentrations. Three of these acid-sensitive C. elegans DEG/ENaCs were activated by acidic pH, making them functionally similar to the vertebrate ASICs. We also identified three new members of the acid-inhibited DEG/ENaC group, giving a total of seven additional acid-sensitive channels. We observed sensitivity to the anti-hypertensive drug amiloride as well as modulation by the trace element zinc. Acid-sensitive DEG/ENaCs were found to be expressed in both neurons and non-neuronal tissue, highlighting the likely functional diversity of these channels. Our findings provide a framework to exploit the C. elegans channels as models to study the function of these acid-sensing channels in vivo, as well as to study them as potential targets for anti-helminthic drugs. KEY POINTS: Acidosis plays many roles in healthy physiology, including synaptic transmission and gut function, but is also a key feature of inflammatory pain, ischaemia and many other conditions. Cells monitor acidosis of their surroundings via pH-sensing channels, including the acid-sensing ion channels (ASICs). These are members of the degenerin/epithelial sodium channel (DEG/ENaC) family, along with, as the name suggests, vertebrate ENaCs and degenerins of the roundworm Caenorhabditis elegans. By screening all 30 C. elegans DEG/ENaCs for pH dependence, we describe, for the first time, three acid-activated members, as well as three additional acid-inhibited channels. We surveyed both groups for sensitivity to amiloride and zinc; like their mammalian counterparts, their currents can be blocked, enhanced or unaffected by these modulators. Likewise, they exhibit diverse ion selectivity. Our findings underline the diversity of acid-sensitive DEG/ENaCs across species and provide a comparative resource for better understanding the molecular basis of their function.

Network control principles predict neuron function in the Caenorhabditis elegans connectome.

Recent studies on the controllability of complex systems offer a powerful mathematical framework to systematically explore the structure-function relationship in biological, social, and technological networks. Despite theoretical advances, we lack direct experimental proof of the validity of these widely used control principles. Here we fill this gap by applying a control framework to the connectome of the nematode Caenorhabditis elegans, allowing us to predict the involvement of each C. elegans neuron in locomotor behaviours. We predict that control of the muscles or motor neurons requires 12 neuronal classes, which include neuronal groups previously implicated in locomotion by laser ablation, as well as one previously uncharacterized neuron, PDB. We validate this prediction experimentally, finding that the ablation of PDB leads to a significant loss of dorsoventral polarity in large body bends. Importantly, control principles also allow us to investigate the involvement of individual neurons within each neuronal class. For example, we predict that, within the class of DD motor neurons, only three (DD04, DD05, or DD06) should affect locomotion when ablated individually. This prediction is also confirmed; single cell ablations of DD04 or DD05 specifically affect posterior body movements, whereas ablations of DD02 or DD03 do not. Our predictions are robust to deletions of weak connections, missing connections, and rewired connections in the current connectome, indicating the potential applicability of this analytical framework to larger and less well-characterized connectomes.

Social support and treatment utilization for posttraumatic stress disorder: Examining reciprocal relations among active duty service members.

Evidence-based treatments for posttraumatic stress disorder (PTSD) are underutilized by active duty service members in the United States. Social support may help service members overcome avoidance and facilitate treatment utilization. In turn, treatment utilization may improve social support. To evaluate these possibilities, the aim of the current study was to examine potential reciprocal associations between social support and treatment utilization among service members. Secondary analyses were conducted on a randomized controlled trial of 161 U.S. military service members with PTSD. Participants completed assessments of perceived social support and attendance at individual therapy sessions at baseline and 3- and 6-month follow-ups. To determine reciprocal relations between social support and treatment utilization, a Bayesian approach was used to estimate a random-intercept cross-lagged panel model with a two-part variable for treatment utilization (i.e., any therapy, and if so, dose). There were no between-person associations between average social support and treatment utilization. One prospective cross-lagged within-person association emerged as significant: social support at 3 months was negatively associated with any therapy use at 6 months; the model explained 26.1% of the variance in this observed variable. The findings revealed that low social support promoted subsequent treatment utilization, but such treatment did not lead to changes in social support. This suggests service members with PTSD may have been motivated to attend individual therapy in pursuit of social connection and support. Future research is needed to determine if reciprocal associations between various forms of social support and therapy utilization differ by treatment modality.

Scoping Review of Cannabis-Reduction Psychosocial Interventions and Reasons for Use among Young Adults with Psychosis.

Objective: No evidence-based intervention effectively reduces cannabis use in young adults with psychosis (YAP). To generate hypotheses about why, a scoping review was conducted to synthesize evidence about motivations for cannabis use and reduction/cessation for YAP and the psychosocial interventions trialed to identify possible gaps between motivations and interventive strategies. Methods: A systematic literature search was conducted in December, 2022. Reviews of titles and abstracts (N = 3,216) and full-texts (n = 136) resulted in 46 articles. Results: YAP use cannabis for pleasure, to reduce dysphoria, and for social and recreational reasons; motivations for cessation include insight about cannabis-psychosis interactions, incompatibility with goals and social roles, and support from social networks. Interventions with at least minimal evidence of efficacy include motivational interviewing, cognitive-behavioral strategies, and family skills training. Conclusions: Authors recommend additional research on mechanisms of change and motivational enhancement therapy, behavioral activation, and family-based skills interventions matched to YAP motivations for use/cessation.

Provider Intentions to Implement Cannabis Use Intervention in First Episode Psychosis Treatment.

Young adults with first episode psychosis use cannabis at high rates. In light of progressively tolerant attitudes toward cannabis, decreased perceptions of risk, and limited implementation of substance use modules within coordinated specialty care (CSC) programs, this study sought to describe factors contributing to CSC providers' intentions to implement motivational enhancement therapy (MET) for cannabis reduction. Two focus groups were conducted with CSC providers (n = 14), with questions guided by theory of planned behavior. Content and thematic analyses were conducted to identify salient themes associated with the theory. Participants generally indicated intentions to implement MET; limiting factors included concerns about clients' willingness to discuss cannabis use, perception of support for abstinence-only goals, and concerns about intervention mechanics such as computerized assessments. To reduce barriers limiting provider intention to implement MET, authors recommend training on assessment protocols, the merits of harm-reduction, and strategies for lower-risk cannabis use.Please confirm if the author names are presented accurately and in the correct sequence. Author 1 Given name: [Ryan] Last name [Petros]. Author 2 Given name: [Denise D.] Last name [Walker]. Author 3 Given name: [Adam] Last name [Davis]. Author 4 Given name: [Maria] Last name [Monroe-DeVita]. Also, kindly confirm the details in the metadata are correct.Confirmed!

Adapting narrative exposure therapy with a tribal community: A community-based approach.

OBJECTIVE: American Indian (AI) individuals are at increased risk for present-day trauma exposure and associated negative outcomes, as well as ongoing effects of intergenerational trauma exposure and adversity. However, few empirically supported treatments exist that are specifically tailored and/or tested with AI communities. This study describes the process of selecting, adapting, and implementing narrative exposure therapy (NET) with an AI community. METHODS: A community and academic partnership was formed and worked together to make culturally mindful changes to NET to best fit the needs of the community. The partnership incorporated community leaders/Elders (n = 7), providers (n = 11), and participants seeking treatment (n = 50) to implement an iterative process of adapting and implementing the adapted form of NET. RESULTS: Key adaptions included addressing historical and intergenerational trauma, greater protections for confidentiality in a small community, and incorporation of cultural customs and traditions. Overall, the adapted form of NET was favorably received by the participants, and the implementation appeared to be feasible, with improved retention over past trials of adapted trauma-focused treatments with this community and with highly positive satisfaction ratings and feedback. CONCLUSIONS: NET was shown to be an appropriate approach for this AI community and should be considered as a treatment option for other AI communities. Future work should consider strategies outlined in this adaption as well as following a similar process for working with AI communities to implement culturally appropriate interventions for trauma-related symptoms.

Neuropeptide-Driven Cross-Modal Plasticity following Sensory Loss in Caenorhabditis elegans.

Sensory loss induces cross-modal plasticity, often resulting in altered performance in remaining sensory modalities. Whereas much is known about the macroscopic mechanisms underlying cross-modal plasticity, only scant information exists about its cellular and molecular underpinnings. We found that Caenorhabditis elegans nematodes deprived of a sense of body touch exhibit various changes in behavior, associated with other unimpaired senses. We focused on one such behavioral alteration, enhanced odor sensation, and sought to reveal the neuronal and molecular mechanisms that translate mechanosensory loss into improved olfactory acuity. To this end, we analyzed in mechanosensory mutants food-dependent locomotion patterns that are associated with olfactory responses and found changes that are consistent with enhanced olfaction. The altered locomotion could be reversed in adults by optogenetic stimulation of the touch receptor (mechanosensory) neurons. Furthermore, we revealed that the enhanced odor response is related to a strengthening of inhibitory AWC→AIY synaptic transmission in the olfactory circuit. Consistently, inserting in this circuit an engineered electrical synapse that diminishes AWC inhibition of AIY counteracted the locomotion changes in touch-deficient mutants. We found that this cross-modal signaling between the mechanosensory and olfactory circuits is mediated by neuropeptides, one of which we identified as FLP-20. Our results indicate that under normal function, ongoing touch receptor neuron activation evokes FLP-20 release, suppressing synaptic communication and thus dampening odor sensation. In contrast, in the absence of mechanosensory input, FLP-20 signaling is reduced, synaptic suppression is released, and this enables enhanced olfactory acuity; these changes are long lasting and do not represent ongoing modulation, as revealed by optogenetic experiments. Our work adds to a growing literature on the roles of neuropeptides in cross-modal signaling, by showing how activity-dependent neuropeptide signaling leads to specific cross-modal plastic changes in neural circuit connectivity, enhancing sensory performance.

Neuropeptidergic Signaling and Active Feeding State Inhibit Nociception in Caenorhabditis elegans.

Food availability and nutritional status are important cues affecting behavioral states. Here we report that, in Caenorhabditis elegans, a cascade of dopamine and neuropeptide signaling acts to inhibit nociception in food-poor environments. In the absence of food, animals show decreased sensitivity and increased adaptation to soluble repellents sensed by the polymodal ASH nociceptors. The effects of food on adaptation are affected by dopamine and neuropeptide signaling; dopamine acts via the DOP-1 receptor to decrease adaptation on food, whereas the neuropeptide receptors NPR-1 and NPR-2 act to increase adaptation off food. NPR-1 and NPR-2 function cell autonomously in the ASH neurons to increase adaptation off food, whereas the DOP-1 receptor controls neuropeptide release from interneurons that modulate ASH activity indirectly. These results indicate that feeding state modulates nociception through the interaction of monoamine and neuropeptide signaling pathways.

Legalization of cannabis: Considerations for intervening with adolescent consumers.

Eight states and the District of Columbia have legalized the recreational use of cannabis for adults and more are expected to follow suit. After alcohol, cannabis is the most commonly used drug by adolescents. Consumption of this drug during this developmental period poses unique risks. Therefore, attention must be paid both to how legalization affects adolescents and how tailored interventions can effectively address their needs for assistance. This commentary offers considerations for how legalization might be crafted so as to benefit adolescents. It additionally focuses on how services might be designed to reach and intervene with teens who are questioning their use or are experiencing a cannabis use disorder and desire assistance in quitting.

The Relationship Between Marijuana and Conventional Cigarette Smoking Behavior from Early Adolescence to Adulthood.

Longitudinal analyses investigated (a) the co-occurrence of marijuana use and conventional cigarette smoking within time and (b) bidirectional associations between marijuana and conventional cigarette use in three developmental periods: adolescence, young adulthood, and adulthood. A cross-lag model was used to examine the bidirectional model of marijuana and conventional cigarette smoking frequency from ages 13 to 33 years. The bidirectional model accounted for gender, school-age economic disadvantage, childhood attention problems, and race. Marijuana use and conventional cigarette smoking were associated within time in decreasing magnitude and increased cigarette smoking predicted increased marijuana use during adolescence. A reciprocal relationship was found in the transition from young adulthood to adulthood, such that increased conventional cigarette smoking at age 24 years uniquely predicted increased marijuana use at age 27 years, and increased marijuana use at age 24 years uniquely predicted more frequent conventional cigarette smoking at age 27 years, even after accounting for other factors. The association between marijuana and cigarette smoking was found to developmentally vary in the current study. Results suggest that conventional cigarette smoking prevention efforts in adolescence and young adulthood could potentially lower the public health impact of both conventional cigarette smoking and marijuana use. Findings point to the importance of universal conventional cigarette smoking prevention efforts among adolescents as a way to decrease later marijuana use and suggest that a prevention effort focused on young adults as they transition to adulthood would lower the use of both cigarette and marijuana use.

Alcohol use disorder as a moderator of the relationship between posttraumatic stress disorder and suicidality among military personnel.

BACKGROUND: Alcohol use disorder (AUD), posttraumatic stress disorder (PTSD), and suicide are substantial public health concerns among military service members, yet the nature of their relationships is not well understood. Here, we tested the hypothesis that AUD moderates the relationship between PTSD symptom severity and suicidal ideation. METHODS: This secondary analysis uses data collected at baseline for a randomized clinical trial. The sample consists of 160 active-duty service members from three service branches (Army, Air Force, and Navy). All participants met diagnostic criteria for PTSD and were not engaged in evidence-based PTSD treatment at the time of enrollment. Zero-inflated Poisson generalized linear regression models were used to test the associations of PTSD and AUD symptom severity with the presence and severity of suicidal ideation. RESULTS: Findings suggest that AUD symptom severity moderates (i.e., amplifies) the relationship between PTSD symptoms and severity of suicidal ideation among military personnel with untreated PTSD. Among service members with mild or absent AUD, we found no significant association between PTSD symptoms and the severity of suicidal ideation. However, when AUD severity was average (i.e., sample mean) or high (mean + 1SD), PTSD symptoms were significantly positively associated with the severity of suicidal ideation. CONCLUSIONS: This study highlights the importance of assessing AUD and PTSD as a part of suicide risk evaluations of veterans. The results also provide strong support for the maintenance and further development in the military health system of treatment programs that simultaneously address AUD and PTSD comorbidity.

Testing a Brief Quitline Intervention for Tobacco Cannabis Co-Users: A Randomized Controlled Pilot Study.

Background: Tobacco cannabis co-use is common and becoming more prevalent. Frequent and heavy users of cannabis may struggle to quit smoking. Quitlines offer free cessation treatment in the United States and 25% of quitline callers may also be cannabis users. The present paper describes a randomized pilot study of a tailored intervention for cannabis and cigarette co-users. The intervention combines the quitline smoking cessation treatment with a motivational enhancement therapy-based cannabis intervention. Methods: The randomized pilot study was conducted within four state-funded quitlines with quitline coaches as interventionists. 102 quitline callers who were cannabis and cigarette co-users were randomized to receive treatment as usual (TAU) or the new Quitline Check-Up (QLCU) intervention. Outcomes were collected 90 days post-randomization. Primary outcomes included feasibility and acceptability of delivering the QLCU in the quitline setting. Secondary outcomes included 7-day point prevalence tobacco abstinence, past 30-day cannabis use, and Cannabis Use Disorder Identification Test scores. Results: Study participants were heavy cannabis users, averaging 25 days of use in the past 30; nearly 70% used at a level considered hazardous. Fidelity ratings indicated coaches were successful at delivering the intervention. Treatment engagement was high for both groups (TAU m = 3.4 calls; QLCU m = 3.6 calls) as was treatment satisfaction. Intent-to-treat quit rates (with survey non-responders classified as smokers) were 28.6% for the TAU control group and 24.5% for the QLCU group (P = .45). Discussion: Hazardous cannabis use rates were high in this sample of tobacco cannabis co-users calling quitlines to quit smoking. The intervention for co-users was acceptable and feasible to deliver. No improvements in tobacco cessation outcomes were observed. Pragmatic intervention development within a real-world clinical setting can streamline the intervention development process. More research is needed on tobacco cannabis co-users and who can benefit from a tailored intervention. Registered: ClinicalTrials.gov NCT04737772, February 4, 2021.

Associations between serotonin transporter gene polymorphisms and heat pain perception in adults with chronic pain.

BACKGROUND: The triallelic serotonin transporter gene linked polymorphic region (5-HTTLPR) has been associated with alterations in thermal pain perception. The primary aim of this study was to investigate the associations between heat pain (HP) perception and the triallelic 5-HTTLPR in a large cohort of adults with chronic pain. METHODS: The cohort included 277 adults with chronic pain who met inclusion criteria, and were consecutively admitted to an outpatient pain rehabilitation program from March 2009 through March 2010. Individuals were genotyped for the triallelic 5-HTTLPR (including rs25531) and categorized as high, intermediate, or low expressors of the serotonin transporter. Standardized measures of HP perception were obtained using a validated quantitative sensory test method of levels. RESULTS: The distribution of the high, intermediate, and low expressing genotypes was 61 (22%), 149 (54%) and 67 (24%), respectively. The Hardy-Weinberg P-value was 0.204 which indicated no departure from equilibrium. A significant effect of genotype was observed for values of HP threshold (P = 0.029). Individual group comparisons showed that values of HP threshold were significantly greater in the intermediate compared to the high expressing group (P = 0.009) but not the low expressing group (P > 0.1). In a multiple variable linear regression model, the intermediate group (P = 0.034) and male sex (P = 0.021) were associated with significantly greater values of HP 0.5, but no significant genotype-by-sex interaction effect was observed. CONCLUSIONS: In this study that involved adults with chronic pain, the intermediate triallelic 5-HTTLPR expressing group, but not the low expressing group, was associated with greater HP thresholds compared to the high expressing group.

Association of the PDYN gene with alcohol dependence and the propensity to drink in negative emotional states.

Synthetic κ-opioid receptor (KOR) agonists induce dysphoric and pro-depressive effects and variations in the KOR (OPRK1) and prodynorphin (PDYN) genes have been shown to be associated with alcohol dependence. We genotyped 23 single nucleotide polymorphisms (SNPs) in the PDYN and OPRK1 genes in 816 alcohol-dependent subjects and investigated their association with: (1) negative craving measured by a subscale of the Inventory of Drug Taking Situations; (2) a self-reported history of depression; (3) the intensity of depressive symptoms measured by the Beck Depression Inventory-II. In addition, 13 of the 23 PDYN and OPRK1 SNPs, which were previously genotyped in a set of 1248 controls, were used to evaluate association with alcohol dependence. SNP and haplotype tests of association were performed. Analysis of a haplotype spanning the PDYN gene (rs6045784, rs910080, rs2235751, rs2281285) revealed significant association with alcohol dependence (p = 0.00079) and with negative craving (p = 0.0499). A candidate haplotype containing the PDYN rs2281285-rs1997794 SNPs that was previously associated with alcohol dependence was also associated with negative craving (p = 0.024) and alcohol dependence (p = 0.0008) in this study. A trend for association between depression severity and PDYN variation was detected. No associations of OPRK1 gene variation with alcohol dependence or other studied phenotypes were found. These findings support the hypothesis that sequence variation in the PDYN gene contributes to both alcohol dependence and the induction of negative craving in alcohol-dependent subjects.

Reaching soldiers with untreated substance use disorder: lessons learned in the development of a marketing campaign for the Warrior Check-Up study.

The Warrior Check-Up, a confidential telephone-delivered intervention, is designed to reach active-duty soldiers with untreated substance-use disorder at a large U.S. military base. This paper describes the development and successful implementation of the study's marketing strategies at the recruitment period's midpoint (2010-2012). Qualitative analyses of focus groups (n = 26) and survey responses (n = 278) describe the process of campaign design. Measures of demographics, media exposure, post-traumatic stress, anxiety and depression gathered from callers (n = 172) are used in quantitative analysis assessing the campaign's success in reaching this population. Implications, limitations, and suggestions for future research are discussed. Department of Defense provided study funding.

The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein.

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by dilation of collecting ducts and by biliary dysgenesis and is an important cause of renal- and liver-related morbidity and mortality. Genetic analysis of a rat with recessive polycystic kidney disease revealed an orthologous relationship between the rat locus and the ARPKD region in humans; a candidate gene was identified. A mutation was characterized in the rat and screening the 66 coding exons of the human ortholog (PKHD1) in 14 probands with ARPKD revealed 6 truncating and 12 missense mutations; 8 of the affected individuals were compound heterozygotes. The PKHD1 transcript, approximately 16 kb long, is expressed in adult and fetal kidney, liver and pancreas and is predicted to encode a large novel protein, fibrocystin, with multiple copies of a domain shared with plexins and transcription factors. Fibrocystin may be a receptor protein that acts in collecting-duct and biliary differentiation.

A Self-Determination Model of Childhood Exposure, Perceived Prevalence, Justification, and Perpetration of Intimate Partner Violence.

The present research was designed to evaluate self-determination theory as a framework for integrating factors associated with intimate partner violence (IPV) perpetration. The proposed model suggests that childhood exposure to parental violence may influence global motivational orientations which, in turn result in greater cognitive biases (overestimating the prevalence of IPV and justification of IPV) which, in turn, contribute to an individual's decision to use abusive behavior. Participants included 124 men who had engaged in abusive behavior toward an intimate partner. Results provided reasonable support for the proposed model and stronger support for a revised model suggesting that controlled orientation, rather than autonomy orientation, appears to play a stronger role in the association between childhood exposure to parental violence and cognitive biases associated with abusive behavior.

Improving voluntary engagement for posttraumatic stress disorder treatment among active-duty service members using motivational enhancement therapy.

OBJECTIVE: Posttraumatic stress disorder (PTSD) prevalence in the military is high and effective treatments are underutilized. Motivational enhancement therapy (MET) "check-ups" are brief interventions to elicit treatment uptake for those who are nontreatment seeking. The aim of the current study was to test the efficacy of a novel MET intervention designed to promote treatment engagement among active-duty U.S. military personnel with untreated PTSD. METHOD: One hundred and sixty-one active-duty service members who met the criteria for PTSD were randomized to MET or treatment as usual (TAU, treatment resource and referral). MET participants (n = 82) received up to three 30-90 min telephone sessions. TAU participants (n = 79) were mailed PTSD resources and referrals. Follow-up assessments were conducted 6-week, 3- and 6-month postbaseline. RESULTS: Mixed effect model results indicated treatment uptake significantly increased over time but there were no significant differences between conditions or interactions. PTSD symptom severity significantly decreased for both conditions. There was also a significant three-way interaction with baseline readiness-to-change confidence. Those low in baseline readiness-to-change saw more favorable effects of MET (relative to TAU) at 6-month follow-up. CONCLUSIONS: Results suggest both MET and high-quality referral options have promise as a means of increasing evidence-based treatment uptake and decreasing PTSD for service members with PTSD. MET may be particularly useful for individuals with low confidence in their ability to address PTSD. Given the individual and societal costs of PTSD, there is a need for interventions facilitating treatment uptake. (PsycInfo Database Record (c) 2023 APA, all rights reserved).