Alpha 2B adrenoceptor genotype moderates effect of reboxetine on negative emotional memory bias in healthy volunteers

Abstract

Evidence suggests that emotional memory plays a role in the pathophysiology of depression/anxiety disorders. Noradrenaline crucially modulates emotional memory. Genetic variants involved in noradrenergic signaling contribute to individual differences in emotional memory and vulnerability to psychopathology. A functional deletion polymorphism in the α-2B adrenoceptor gene (ADRA2B) has been linked to emotional memory and post-traumatic stress disorder. The noradrenaline reuptake inhibitor reboxetine attenuates enhanced memory for negative stimuli in healthy and depressed individuals. We examined whether the effect of reboxetine on emotional memory in healthy individuals would be moderated by ADRA2B genotype. ADRA2B deletion carriers demonstrated enhanced emotional memory for negative stimuli compared with deletion noncarriers, consistent with prior studies. Reboxetine attenuated enhanced memory for negative stimuli in deletion noncarriers but had no significant effect in deletion carriers. This is the first demonstration of genetic variation influencing antidepressant drug effects on emotional processing in healthy humans.

Figure 1.

Interaction between reboxetine and ADRA2B genotype influences post-treatment symptoms of irritability, anxiety, and dizziness. A, Significant decrease in post-treatment irritability in ADRA2B deletion carriers under placebo that was absent in nondeletion carriers. B, Significant decrease in anxiety in ADRA2B deletion carriers under placebo compared with reboxetine. C, Significant increase in dizziness in ADRA2B nondeletion carriers under reboxetine compared with placebo. *p < 0.05. **p < 0.01. ***p < 0.001. Bars indicate SEM.

Figure 2.

Effect of reboxetine on enhanced memory for negative pictures is dependent on ADRA2B genotype. Under reboxetine, EEM for negative pictures is attenuated with nondeletion carriers (N = 22) compared with under placebo (N = 30); however, there was no difference in EEM in deletion carriers under reboxetine (N = 33) compared with placebo (N = 29). **p < 0.01. Negative EEM Index = percentage increased recall of negative versus neutral pictures.

Figure 3.

Exploration of deletion variant dose-dependent effects of reboxetine on enhanced memory for negative pictures and gene dose-dependent effects. 0 indicates noncarriers (N = 52); 1, heterozygous carriers (N = 47); 3, homozygous carriers (N = 15). **p < 0.01. Negative EEM Index = percentage increased recall of negative versus neutral pictures.