The ventral bed nucleus of the stria terminalis (vBNST) has been implicated in stress-induced cocaine use. Here we demonstrate that, in the vBNST, corticotropin releasing factor (CRF) is expressed in neurons that innervate the ventral tegmental area (VTA), a site where the CRF receptor antagonist antalarmin prevents the reinstatement of cocaine seeking by a stressor, intermittent footshock, following intravenous self-administration in rats. The vBNST receives dense noradrenergic innervation and expresses ␤ adrenergic receptors (ARs). Footshock-induced reinstatement was prevented by bilateral intra-vBNST injection of the ␤-2 AR antagonist, ICI-118,551, but not the ␤-1 AR antagonist, betaxolol. Moreover, bilateral intra-vBNST injection of the ␤-2 AR agonist, clenbuterol, but not the ␤-1 agonist, dobutamine, reinstated cocaine seeking, suggesting that activation of vBNST ␤-2 AR is both necessary for stress-induced reinstatement and sufficient to induce cocaine seeking. The contribution of a ␤-2 AR-regulated vBNST-to-VTA pathway that releases CRF was investigated using a disconnection approach. Injection of ICI-118,551 into the vBNST in one hemisphere and antalarmin into the VTA of the contralateral hemisphere prevented footshock-induced reinstatement, whereas ipsilateral manipulations failed to attenuate stressinduced cocaine seeking, suggesting that ␤-2 AR regulate vBNST efferents that release CRF into the VTA, activating CRF receptors, and promoting cocaine use. Last, reinstatement by clenbuterol delivered bilaterally into the vBNST was prevented by bilateral vBNST pretreatment with antalarmin, indicating that ␤-2 AR-mediated actions in the vBNST also require local CRF receptor activation. Understanding the processes through which stress induces cocaine seeking should guide the development of new treatments for addiction.

Traumatic brain injury (TBI) commonly results in cognitive and psychiatric problems. Cognitive impairments occur in approximately 30% of patients suffering from mild TBI (mTBI), and correlational evidence from clinical studies indicates that substance abuse may be increased following mTBI. However, understanding the lasting cognitive and psychiatric problems stemming from mTBI is difficult in clinical settings where pre-injury assessment may not be possible or accurate. Therefore, we used a previously characterized blast model of mTBI (bTBI) to examine cognitive- and addiction-related outcomes. We previously demonstrated that this model leads to bilateral damage of the medial prefrontal cortex (mPFC), a region critical for cognitive function and addiction. Rats were exposed to bTBI and tested in operant learning tasks several weeks after injury. bTBI rats made more errors during acquisition of a cue discrimination task compared to sham treated rats. Surprisingly, we observed no differences between groups in set shifting and delayed matching to sample, tasks known to require the mPFC. Separate rats performed cocaine self-administration. No group differences were found in intake or extinction, and only subtle differences were observed in drug-primed reinstatement 3–4 months after injury. These findings indicate that bTBI impairs acquisition of a visual discrimination task and that bTBI does not significantly increase the ability of cocaine exposure to trigger drug seeking.

The ability of stress to trigger cocaine seeking in humans and rodents is variable and is determined by the amount and pattern of prior drug use. This study examined the role of a corticotropin releasing factor (CRF)-regulated dopaminergic projection from the ventral tegmental area (VTA) to the prelimbic cortex in shock-induced cocaine seeking and its recruitment under self-administration conditions that establish relapse vulnerability. Male rats with a history of daily long-access (LgA; 14 ϫ 6 h/d) but not short-access (ShA; 14 ϫ 2 h/d) self-administration showed robust shock-induced cocaine seeking. This was associated with a heightened shock-induced prelimbic cortex Fos response and activation of cholera toxin b retro-labeled VTA neurons that project to the prelimbic cortex. Chemogenetic inhibition of this pathway using a dual virus intersectional hM4Di DREADD (designer receptor exclusively activated by designer drug) based approach prevented shock-induced cocaine seeking. Both shock-induced reinstatement and the prelimbic cortex Fos response were prevented by bilateral intra-VTA injections of the CRF receptor 1 (CRFR1) antagonist, antalarmin. Moreover, pharmacological disconnection of the CRF-regulated dopaminergic projection to the prelimbic cortex by injection of antalarmin into the VTA in one hemisphere and the D1 receptor antagonist, SCH23390, into the prelimbic cortex of the contralateral hemisphere prevented shockinduced cocaine seeking. Finally, LgA, but not ShA, cocaine self-administration resulted in increased VTA CRFR1 mRNA levels as measured using in situ hybridization. Altogether, these findings suggest that excessive cocaine use may establish susceptibility to stress-induced relapse by recruiting CRF regulation of a stressor-responsive mesocortical dopaminergic pathway.

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OBJECTIVEA recent retrospective study of severe traumatic brain injury (TBI) in pediatric patients showed similar outcomes in those with a Glasgow Coma Scale (GCS) score of 3 and those with a score of 4 and reported a favorable long-term outcome in 11.9% of patients. Using decision tree analysis, authors of that study provided criteria to identify patients with a potentially favorable outcome. The authors of the present study sought to validate the previously described decision tree and further inform understanding of the outcomes of children with a GCS score 3 or 4 by using data from multiple institutions and machine learning methods to identify important predictors of outcome.METHODSClinical, radiographic, and outcome data on pediatric TBI patients (age < 18 years) were prospectively collected as part of an institutional TBI registry. Patients with a GCS score of 3 or 4 were selected, and the previously published prediction model was evaluated using this data set. Next, a combined data set that included data from two institutions was used to create a new, more statistically robust model using binomial recursive partitioning to create a decision tree.RESULTSForty-five patients from the institutional TBI registry were included in the present study, as were 67 patients from the previously published data set, for a total of 112 patients in the combined analysis. The previously published prediction model for survival was externally validated and performed only modestly (AUC 0.68, 95% CI 0.47, 0.89). In the combined data set, pupillary response and age were the only predictors retained in the decision tree. Ninety-six percent of patients with bilaterally nonreactive pupils had a poor outcome. If the pupillary response was normal in at least one eye, the outcome subsequently depended on age: 72% of children between 5 months and 6 years old had a favorable outcome, whereas 100% of children younger than 5 months old and 77% of those older than 6 years had poor outcomes. The overall accuracy of the combined prediction model was 90.2% with a sensitivity of 68.4% and specificity of 93.6%.CONCLUSIONSA previously published survival model for severe TBI in children with a low GCS score was externally validated. With a larger data set, however, a simplified and more robust model was developed, and the variables most predictive of outcome were age and pupillary response.