We believe that the GANE (glutamate amplifies noradrenergic effects) model makes a novel and vital contribution to understanding emotional modulation of attention and memory – specifically via its detailed description of the influence of glutamate on noradrenergic processes mediating the impact of emotional arousal on the fate of neutral items. However, Mather et al. do not address potential individual differences in such mechanisms, which may be linked to mood disorders and addiction.

In our BANE (biased attention via norepinephrine) model, we described effects of the locus coeruleus–norepinephrine system in enhancing attention and memory for stimuli that are salient because of associations with arousal (Markovic et al. Reference Markovic, Anderson and Todd2014). However, a key focus of the BANE model was individual differences in prioritization of affectively salient stimuli (Markovic et al. Reference Markovic, Anderson and Todd2014; Todd et al. Reference Todd, Cunningham, Anderson and Thompson2012). This emphasis on individual differences has been based in part on observations of human carriers of a common deletion variant in the ADRA2b gene, which codes for noradrenergic α_2B-autoreceptors (Small et al. Reference Small, Brown, Forbes and Liggett2001). The GANE model makes a valuable contribution in extending beyond the BANE model to incorporate the role of glutamatergic activity in enhancing effects of arousal on processing stimuli that are already high priority. However, the authors are somewhat dismissive of studies examining polymorphisms in genes coding for noradrenergic receptors and, specifically, of the notion that findings concerning the role of ADRA2b can be discussed in relation to the GANE model's hotspot mechanisms. They do so based partly on evidence that α_2B-receptors are unlikely to play an important role in GANE hotspots because the inhibitory role of α_2B-receptors is not as well established as for α_2A-receptors and because α_2B-receptors are poorly expressed in key regions mediating affective salience. We argue that the study of genetic influences on affective prioritization of salient stimuli can provide data relevant to some of the GANE model's claims, and that evidence against an inhibitory role of α_2B-receptors in key brain regions is not entirely straightforward.

First, we argue that genotyping studies have value, in general, for understanding mechanisms of stimulus prioritization because, along with pharmacologic manipulations (e.g., De Martino et al. Reference De Martino, Strange and Dolan2008; Strange et al. Reference Strange, Hurlemann and Dolan2003), they are among the few vehicles for examining effects of inhibitory versus excitatory noradrenergic processes in humans. Because the specificity of ligands for receptor subtypes is limited (Jasper et al. Reference Jasper, Lesnick, Chang, Yamanishi, Chang, Hsu, Daunt, Bonhaus and Eglen1998), genotyping studies can help specify the role of each subtype in patterns of brain activation and behavior. Of course, we acknowledge that it is important to use other methods, such as positron emission tomography and examination of mRNA activity, to help confirm the role of specific ADRA2a and ADRA2b polymorphisms in α₂ activity.

Second, it is important to consider potential individual differences in the activity of specific receptor subtypes in proposed hotspot processes and what the behavioral consequences might be. Genetic differences influencing such receptor function are one source of such differences, and can provide a valuable window into how GANE mechanisms can vary normally and go awry. For example, common variants in genes coding for both ADRA2b and ADRA2a receptors have been associated with neural and behavioral indices of enhanced attention and memory for affectively salient stimuli that characterize affective disorders as well as cognitive biases associated with addictive behaviors (de Quervain et al. Reference de Quervain, Kolassa, Ertl, Onyut, Neuner, Elbert and Papassotiropoulos2007; Havranek et al. Reference Havranek, Hulka, Tasiudi, Eisenegger, Vonmoos, Preller, Mossner, Baumgartner, Seifritz, Grunblattt and Quednow2015; Todd et al. Reference Todd, Müller, Lee, Robertson, Eaton, Freeman, Palombo, Levine and Anderson2013). Using genotyping to infer the role of each receptor subtype on such endophenotypes can help elucidate how patterns of inhibitory/excitatory activity proposed by GANE may contribute to variation in healthy populations and in psychopathology.

Studies of the ADRA2b deletion variant can serve precisely that function. Convergent evidence is highly consistent with the view that ADRA2b deletion carriers have reduced inhibitory autoreceptor function. In vivo, consequences of carrying the ADRA2b deletion variant (found in ~50% of the populations we have studied) are similar to those of the α₂-antagonist yohimbine (de Quervain et al. Reference de Quervain, Kolassa, Ertl, Onyut, Neuner, Elbert and Papassotiropoulos2007). This claim is supported by the reliability and robustness of effects of enhanced emotional biases in attention and memory, increased amygdala and ventromedial prefrontal activation for arousing stimuli, and differences in amygdala gray matter volume associated with carrying the deletion variant (de Quervain et al. Reference de Quervain, Kolassa, Ertl, Onyut, Neuner, Elbert and Papassotiropoulos2007; Ehlers et al. Reference Ehlers, Palombo, Mueller, Levine, Anderson and Todd2015; Rasch et al. Reference Rasch, Spalek, Buholzer, Luechinger, Boesiger, Papassotiropoulos and Quervain2009; Todd et al. Reference Todd, Müller, Lee, Robertson, Eaton, Freeman, Palombo, Levine and Anderson2013; Reference Todd, Muller, Palombo, Robertson, Eaton, Freeman, Levine and Anderson2014; Reference Todd, Ehlers, Muller, Robertson, Palombo, Freeman, Levine and Anderson2015). According to the GANE model, affectively salient stimuli are one category of prioritized stimulus whose encoding is enhanced by arousal. Here, the enhanced affective prioritization we have observed in deletion carriers could lead to intensified positive feedback loops at hotspots, although possibly only when stimuli are prioritized because of their pre-existing associations with arousal. Further, because outside of the lab there are likely to be a range of motivationally relevant goals, behavior of deletion carriers may be driven by affective or visual salience over more “top-down” goals relative to non-carriers.

Finally, with regard to the authors' claims that it is α_2B-autoreceptors that carry the full burden of inhibitory function in the brain, we suggest that the picture is somewhat more complicated. There is evidence that, in addition to its pre-synaptic inhibitory function, α_2A is the most commonly observed postsynaptic receptor in the prefrontal cortex (Arnsten et al. Reference Arnsten, Steere and Hunt1996; U'Prichard et al. Reference U'Prichard, Bechtel, Rouot and Snyder1979). Indeed, some evidence suggests that increased post-synaptic α_2A activity in the PFC may be associated with enhanced rather than reduced noradrenergic transmission (Ramos et al. Reference Ramos, Stark, Verduzco, van Dyck and Arnsten2006). Moreover, brain regions mediating heightened emotional sensitivity in deletion carriers show relatively high levels of ADRA2b expression (Hawrylycz et al. Reference Hawrylycz, Lein, Guillozet-Bongaarts, Shen, Ng, Miller, van de Lagemaat, Smith, Ebbert, Riley, Abajian, Beckmann, Bernard, Bertagnolli, Boe, Cartagena, Chakravarty, Chapin, Chong, Dalley, Daly, Dang, Datta, Dee, Dolbeare, Faber, Feng, Fowler, Goldy, Gregor, Haradon, Haynor, Hohmann, Horvath, Howard, Jeromin, Jochim, Kinnunen, Lau, Lazarz, Lee, Lemon, Li, Li, Morris, Overly, Parker, Parry, Reding, Royall, Schulkin, Sequeira, Slaughterbeck, Smith, Sodt, Sunkin, Swanson, Vawter, Williams, Wohnoutka, Zielke, Geschwind, Hof, Smith, Koch, Grant and Jones2012: Allen Human Brain Atlas: http://human.brain-map.org). Animal research points further toward the importance of α_2B-receptors in emotional processing (Moriceau & Sullivan Reference Moriceau and Sullivan2004). This challenges the notion of a straightforward role for α_2A-receptors as the only mediators of inhibitory activity suggested by the GANE model.

In summary, although we acknowledge that effects of the deletion variant may be mediated by factors other than proposed GANE hotspot mechanisms, the growing body of research on polymorphisms influencing both a α_2A- and α_2B-receptors poses both questions and challenges for the GANE model.