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Show 16 noradrenergic concentrations are elevated (Tsuda et al., 1989; Russell et al., 2000). These rats show a phenotype characterized by hyperactivity, impulsivity, and deficits in sustained attention (Sagvolden, 2000; Fox et al., 2008). Guanfacine administration improves all of these measures (Sagvolden, 2006). The SHR thus provides support for the hypothesis that cognitive impairments resulting from elevated noradrenergic signaling may be ameliorated by administration of guanfacine. A rich literature indicates that dysfunction of the prefrontal cortex critically contributes to the detrimental effects of acute stress on cognition (Arnsten, 2009; Arnsten and Jin, 2012). Guanfacine improves performance on tasks that require the prefrontal cortex, and this effect seems to be most pronounced during states of noradrenergic disruption. If stress-induced impairments in prefrontal-mediated decision making contribute to relapse, then guanfacine may be an effective therapy. Consistent with this possibility, guanfacine reverses stress-induced deficits in prefrontal cortex-dependent measure of working memory in healthy subjects (Shansky et al., 2009) and enhances activation of medial and lateral prefrontal cortex during exposure to stress in cocaine-dependent individuals (Fox et al., 2012). Guanfacine also decreases stressinduced reinstatement of ethanol seeking in rats (Le et al., 2011) and attenuates stress-induced nicotine craving in humans (Fox et al., 2012). Thus, guanfacine offers promise as a potential therapy to prevent stress-induced relapse. Prazosin. Prazosin is a centrally acting α1-adrenergic receptor antagonist that is often prescribed for posttraumatic stress disorder (PTSD), which is characterized in part by maladaptive stress responses (Raskind et al., 2003; Bernardy et al., 2012). Excessive noradrenergic activity contributes to symptoms of PTSD (Geracioti et al., 2001), and blockade of α1-adrenergic receptors with prazosin decreases acoustic startle response, aggression, and social withdrawal in a rodent model of PTSD (Olson et al., 2011). Given these effects of prazosin in both animals and humans with heightened noradrenergic activity, prazosin may offer therapeutic benefit in contexts characterized by high noradrenergic signaling, such as stress. Consistent with this possibility, stimulation of low-affinity α1 receptors is thought to contribute to stress-induced impairments in spatial working memory tasks (Arnsten et al., 1999 |
