Pilot randomized clinical trial of the Teachable Moment Brief Intervention for hospitalized suicide attempt survivors.

OBJECTIVE: The aim of this study was to further evaluate the acceptability and feasibility of the Teachable Moment Brief Intervention (TMBI). METHOD: A single blind, pilot randomized controlled trial of the TMBI + care as usual (CAU) compared to CAU was conducted for patients who survived a recent suicide attempt that required medical inpatient hospitalization. The intervention was delivered on medical/surgical and inpatient psychiatry units in the medical center. Interviews were completed at baseline, 1, 3, and 12 months. RESULTS: Patients reported high ratings of satisfaction with the TMBI. Interventionists representing fields of Psychiatry, Social Work, and Counseling were able to deliver the intervention with fidelity to the treatment manual with equal adherence ratings. The TMBI patients were more likely to maintain a positive recovery trajectory on motivation and engagement in mental health services at 3 months. CONCLUSION: The TMBI provides an option for targeted intervention to health care providers as they engage patients admitted to an acute medical setting after a serious suicide attempt. This is the second pilot study demonstrating enhanced motivation in the post-hospitalization period.

Denial of Suicide Attempt Among Hospitalized Survivors of a Self-Inflicted Gunshot Wound.

OBJECTIVE: Evidence suggests that suicide attempts by self-inflicted gunshot wound (GSW) are underreported and may in turn affect disposition following hospitalization. This study aimed to evaluate the clinical characteristics and use of services among individuals who do not disclose suicidal intent following a self-inflicted GSW. METHODS: Electronic medical record data from 128 survivors of self-inflicted GSWs at a level 1 trauma center were analyzed to identify factors associated with nondisclosure of a suicide attempt to medical staff. RESULTS: Results indicated that 29% of patients denied that a self-inflicted GSW was a suicide attempt, and 43% of patients who denied suicidal intent were identified by the psychiatric consultation and liaison service as presenting under circumstances suspicious of a suicide attempt. Logistic regression analyses indicated that patients who denied having attempted suicide were 10.86 times more likely to be discharged to home than patients who disclosed suicidal intent. In a multiple regression model, no clinical or demographic characteristics were significantly associated with nondisclosure of suicide intent. CONCLUSIONS: Patients' nondisclosure of suicidal intent following a self-inflicted GSW may present a barrier to care for patients whose injuries are the result of a suicide attempt. Implications for reducing barriers to care for a high-risk population are discussed, including the impact of nondisclosure on future treatment and the potential utility of brief interventions for suicide risk reduction.

Yohimbine depresses excitatory transmission in BNST and impairs extinction of cocaine place preference through orexin-dependent, norepinephrine-independent processes.

The alpha2 adrenergic receptor (α(2)-AR) antagonist yohimbine is a widely used tool for the study of anxiogenesis and stress-induced drug-seeking behavior. We previously demonstrated that yohimbine paradoxically depresses excitatory transmission in the bed nucleus of the stria terminalis (BNST), a region critical to the integration of stress and reward pathways, and produces an impairment of extinction of cocaine-conditioned place preference (cocaine-CPP) independent of α(2)-AR signaling. Recent studies show yohimbine-induced drug-seeking behavior is attenuated by orexin receptor 1 (OX(1)R) antagonists. Moreover, yohimbine-induced cocaine-seeking behavior is BNST-dependent. Here, we investigated yohimbine-orexin interactions. Our results demonstrate yohimbine-induced depression of excitatory transmission in the BNST is unaffected by alpha1-AR and corticotropin-releasing factor receptor-1 (CRFR(1)) antagonists, but is (1) blocked by OxR antagonists and (2) absent in brain slices from orexin knockout mice. Although the actions of yohimbine were not mimicked by the norepinephrine transporter blocker reboxetine, they were by exogenously applied orexin A. We find that, as with yohimbine, orexin A depression of excitatory transmission in BNST is OX(1)R-dependent. Finally, we find these ex vivo effects are paralleled in vivo, as yohimbine-induced impairment of cocaine-CPP extinction is blocked by a systemically administered OX(1)R antagonist. These data highlight a new mechanism for orexin on excitatory anxiety circuits and demonstrate that some of the actions of yohimbine may be directly dependent upon orexin signaling and independent of norepinephrine and CRF in the BNST.

Subcellular localization of the antidepressant-sensitive norepinephrine transporter.

BACKGROUND: Reuptake of synaptic norepinephrine (NE) via the antidepressant-sensitive NE transporter (NET) supports efficient noradrenergic signaling and presynaptic NE homeostasis. Limited, and somewhat contradictory, information currently describes the axonal transport and localization of NET in neurons. RESULTS: We elucidate NET localization in brain and superior cervical ganglion (SCG) neurons, aided by a new NET monoclonal antibody, subcellular immunoisolation techniques and quantitative immunofluorescence approaches. We present evidence that axonal NET extensively colocalizes with syntaxin 1A, and to a limited degree with SCAMP2 and synaptophysin. Intracellular NET in SCG axons and boutons also quantitatively segregates from the vesicular monoamine transporter 2 (VMAT2), findings corroborated by organelle isolation studies. At the surface of SCG boutons, NET resides in both lipid raft and non-lipid raft subdomains and colocalizes with syntaxin 1A. CONCLUSION: Our findings support the hypothesis that SCG NET is segregated prior to transport from the cell body from proteins comprising large dense core vesicles. Once localized to presynaptic boutons, NET does not recycle via VMAT2-positive, small dense core vesicles. Finally, once NET reaches presynaptic plasma membranes, the transporter localizes to syntaxin 1A-rich plasma membrane domains, with a portion found in cholera toxin-demarcated lipid rafts. Our findings indicate that activity-dependent insertion of NET into the SCG plasma membrane derives from vesicles distinct from those that deliver NE. Moreover, NET is localized in presynaptic membranes in a manner that can take advantage of regulatory processes targeting lipid raft subdomains.

Epitope-tagged receptor knock-in mice reveal that differential desensitization of alpha2-adrenergic responses is because of ligand-selective internalization.

Although ligand-selective regulation of G protein-coupled receptor-mediated signaling and trafficking are well documented, little is known about whether ligand-selective effects occur on endogenous receptors or whether such effects modify the signaling response in physiologically relevant cells. Using a gene targeting approach, we generated a knock-in mouse line, in which N-terminal hemagglutinin epitope-tagged alpha(2A)-adrenergic receptor (AR) expression was driven by the endogenous mouse alpha(2A)AR gene locus. Exploiting this mouse line, we evaluated alpha(2A)AR trafficking and alpha(2A)AR-mediated inhibition of Ca(2+) currents in native sympathetic neurons in response to clonidine and guanfacine, two drugs used for treatment of hypertension, attention deficit and hyperactivity disorder, and enhancement of analgesia through actions on the alpha(2A)AR subtype. We discovered a more rapid desensitization of Ca(2+) current suppression by clonidine than guanfacine, which paralleled a more marked receptor phosphorylation and endocytosis of alpha(2A)AR evoked by clonidine than by guanfacine. Clonidine-induced alpha(2A)AR desensitization, but not receptor phosphorylation, was attenuated by blockade of endocytosis with concanavalin A, indicating a critical role for internalization of alpha(2A)AR in desensitization to this ligand. Our data on endogenous receptor-mediated signaling and trafficking in native cells reveal not only differential regulation of G protein-coupled receptor endocytosis by different ligands, but also a differential contribution of receptor endocytosis to signaling desensitization. Taken together, our data suggest that these HA-alpha(2A)AR knock-in mice will serve as an important model in developing ligands to favor endocytosis or nonendocytosis of receptors, depending on the target cell and pathophysiology being addressed.

Yohimbine impairs extinction of cocaine-conditioned place preference in an alpha2-adrenergic receptor independent process.

Extinction, a form of learning that has the ability to reshape learned behavior based on new experiences, has been heavily studied utilizing fear learning paradigms. Mechanisms underlying extinction of positive-valence associations, such as drug self-administration and place preference, are poorly understood yet may have important relevance to addiction treatment. Data suggest a major role for the noradrenergic system in extinction of fear-based learning. Employing both pharmacological and genetic approaches, we investigated the role of the alpha(2)-adrenergic receptor (alpha(2)-AR) in extinction of cocaine-conditioned place preference (CPP) and glutamatergic transmission in the bed nucleus of the stria terminalis (BNST). We found that pre-extinction systemic treatment with the alpha(2)-AR antagonist yohimbine impaired cocaine CPP extinction in C57BL/6J mice, an effect that was not mimicked by the more selective alpha(2)-AR antagonist, atipamezole. Moreover, alpha(2A)-AR knockout mice exhibited similar cocaine CPP extinction and exacerbated extinction impairing effects of yohimbine. Using acute brain slices and electrophysiological approaches, we found that yohimbine produces a slowly evolving depression of glutamatergic transmission in the BNST that was not mimicked by atipamezole. Further, this action was extant in slices from alpha(2A)-AR knockout mice. Our data strongly suggest that extinction-modifying effects of yohimbine are unlikely to be due to actions at alpha(2A)-ARs.