Targeting Stress Neuroadaptations for Addiction Treatment: A Commentary on Kaye et al. (2017).

372 KAYE ET AL. (2017—this issue) identify the importance of targeting stress for addiction treatment and how unpredictable stress plays a pivotal role in addiction etiology. They present an elegant model examining startle potentiation during unpredictable (vs. predictable) stressors in cued threat tasks to further elucidate the role of brain stress system neuroadaptations in addiction. Of note, modeling stress reactivity in addiction and, more broadly, examining neurobiological targets for stress-induced drug-motivated behaviors lend support to the seamless translation between preclinical and human research. Ultimately, the feasibility of both forward and back translation based on this program of research will likely lead to the development of novel treatments that are better able to target specific stress neurocircuitry to attenuate drug craving and self-administration and increase options to providers for the treatment of stress-precipitated substance use. The review by Kaye et al. (2017) should be particularly encouraging to the scientific community seeking to expand on the startle potentiation model and to examine or develop other models of addiction that tap into stress pathophysiology. Kaye and colleagues focus on the corticotrophinreleasing factor (CRF) and norepinephrine (NE) systems and the central extended amygdala (CeA). Indeed, there is an increasing amount of support for the role of the CRF and NE systems in addiction and stress-precipitated substance use (Back et al., 2010; Fox et al., 2012, 2014; McKee et al., 2015), particularly in rodent models of stress-induced reinstatement of drug seeking (Lê et al., 2011; Mantsch et al., 2016; Zislis et al., 2007). Unfortunately, there has been little translation of these findings to humans, and too few human laboratory studies have examined CRF or noradrenergic mechanisms underlying substance use. The pathophysiology of stress and neuroadaptations within brain stress systems is complex and expands beyond the CRF and NE systems and the CeA. Further investigation of other stress systems and stress-related neurocircuitry is also relevant and important in the etiology and treatment of addiction. Research remains limited on the role of urocortin, dynorphin, neuropeptide Y, hypocretins/orexin, and brain regions such as the striatum and prefrontal cortex (PFC) in COMMENTARY