The ability to inhibit drinking is a significant challenge for recovering alcoholics, especially in the presence of alcohol-associated cues. Previous studies have demonstrated that the regulation of cue-guided alcohol seeking is mediated by the basolateral amygdala (BLA), nucleus accumbens (NAc), and medial prefrontal cortex (mPFC). However, given the high interconnectivity between these structures, it is unclear how mPFC projections to each subcortical structure, as well as projections between BLA and NAc, mediate alcohol-seeking behaviors. Here, we evaluate how cortico-striatal, cortico-amygdalar, and amygdalo-striatal projections control extinction and relapse in a rat model of alcohol seeking. Specifically, we used a combinatorial viral technique to express diphtheria toxin receptors in specific neuron populations based on their projection targets. We then used this strategy to create directionally selective ablations of three distinct pathways after acquisition of ethanol self-administration but before extinction and reinstatement. We demonstrate that ablation of mPFC neurons projecting to NAc, but not BLA, blocks cue-induced reinstatement of alcohol seeking and neither pathway is necessary for extinction of responding. Further, we show that ablating BLA neurons that project to NAc disrupts extinction of alcohol approach behaviors and attenuates reinstatement. Together, these data provide evidence that the mPFC¡NAc pathway is necessary for cueinduced reinstatement of alcohol seeking, expand our understanding of how the BLA¡NAc pathway regulates alcohol behavior, and introduce a new methodology for the manipulation of target-specific neural projections.

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Rationale Alcohol dependence is the third leading cause of preventable death in the USA. While single-agent pharmacotherapies have variable efficacy, medication combinations may produce additive effects by modulating multiple neural pathways. Objectives Here, we examined in animal models of ethanol consumption and relapse the combined effects of ondansetron (a serotonin-3 antagonist) and topiramate (a GABA/ glutamate modulator), two medications with demonstrated efficacy for treating alcohol dependence, hypothesizing that their combination would produce a more efficacious response. Methods The effects of acutely administered ondansetron (0–0.01 mg/kg) and topiramate (0–10 mg/kg) alone and in combination on ethanol consumption were examined in alcohol preferring (P) rats (N=20) and in rats from their background strain (Wistars, N=20) using a 24-h access free-choice paradigm. Next, we examined their ability to prevent an increase in ethanol consumption following a deprivation period (i.e., an animal model of relapse). Results Whether administered alone or combined with ondansetron, topiramate produced a similar modest but persistent reduction in ethanol consumption. However, an analysis of efficacy by drinking level revealed that the combination was superior to topiramate alone in heavy-drinking P rats, but was without effect in lighter-drinking P rats and Wistar rats. Both topiramate alone and the combination blocked the alcohol deprivation effect in both Wistar and P rats with the combination tending to produce a greater decrease than topiramate alone. Conclusions The combination of ondansetron and topiramate may be a promising treatment for preventing relapse and for treating alcohol dependence in heavy-, but not lighter-drinkers.

Synopsis Restoration of skeletal muscle mass and strength are critical to successful outcomes following orthopedic surgery. Blood flow restricted resistance exercise (BFR) has emerged as an attractive candidate to augment traditional low intensity physical rehabilitation exercise, and has yielded successful outcomes over a wide variety of applications. BFR is well tolerated and safe for the majority of individuals, though the post-surgical orthopedic patient has additional considerations due to their heightened risk for venous thromboembolism (VTE). While the pathogenesis of VTE is multifactorial and individual specific, it is commonly described as a combination of blood stasis, endothelial injury, and alterations in the constituents of the blood leading to hypercoagulability. The collective literature suggests that, given the pathogenic mechanisms of VTE, the finite use of a wide, partially occluding cuff during resistance exercise should be low risk and that the likelihood of BFR directly causing a VTE event is remote. Alternatively, it is plausible that BFR may enhance blood flow and promote fibrinolysis. Of greater concern would be the individual with preexisting asymptomatic VTE, which could be dislodged during BFR. Though, it is unknown if the direct risk associated with BFR is greater than the risk associated with traditional exercise alone. Presently, there are no universally agreed upon standards indicating which post-surgical orthopedic patients may perform BFR safely. While excluding all post-surgical orthopedic patients from performing BFR may be overly precautious, clinicians need to thoroughly screen for VTE signs and symptoms, be cognizant of each patient's risk factors, and use proper equipment and prescriptions methods prior to initiating BFR. J Orthop Sports Phys Ther, Epub 12 Sep 2018. doi:10.2519/jospt.2019.8375.