Epistasis between 5-HTTLPR and ADRA2B polymorphisms influences attentional bias for emotional information in healthy volunteers

Individual differences in emotional processing are likely to contribute to vulnerability and resilience to emotional disorders such as depression and anxiety. Genetic variation is known to contribute to these differences but they remain incompletely understood. The serotonin transporter (5-HTTLPR) and alpha(2B)-adrenergic autoreceptor (ADRA2B) insertion/deletion polymorphisms impact on two separate but interacting monaminergic signalling mechanisms that have been implicated in both emotional processing and emotional disorders. Recent studies suggest that the 5-HTTLPR s allele is associated with a negative attentional bias and an increased risk of emotional disorders. However, such complex behavioural traits are likely to exhibit polygenicity, including epistasis. This study examined the contribution of the 5-HTTLPR and ADRA2B insertion/deletion polymorphisms to attentional biases for aversive information in 94 healthy male volunteers and found evidence of a significant epistatic effect (p < 0.001). Specifically, in the presence of the 5-HTTLPR s allele, the attentional bias for aversive information was attenuated by possession of the ADRA2B deletion variant whereas in the absence of the s allele, the bias was enhanced. These data identify a cognitive mechanism linking genotype-dependent serotonergic and noradrenergic signalling that is likely to have implications for the development of cognitive markers for depression/anxiety as well as therapeutic drug effects and personalized approaches to treatment

Deletion variant of alpha2b-adrenergic receptor gene moderates the effect of COMT val(158)met polymorphism on episodic memory performance

The COMT val(158) variant has been associated with impaired cognitive function compared to the met(158) variant yet gene-gene interactions are not well described. In this study we demonstrate an interaction between this COMT polymorphism and a deletion variant of ADRA2B, the gene encoding the alpha2b-adrenergic receptor on episodic memory performance. Specifically, carriage of the ADRA2B deletion abolished the relative memory impairment in homozygous COMT val(158) carriers compared to met(158) carrier

Effects of amisulpride on emotional memory using a dual-process model in healthy male volunteers

Memory dysfunction occurs in a number of neuropsychiatric disorders. Therapeutic psychopharmacological agents may exacerbate such memory impairment. Detailed characterisation of drug-induced memory impairment is therefore important. We recently showed that the D2/D3 antagonist amisulpride quantitatively impairs emotional memory in a randomised placebo-controlled study of 33 healthy volunteers. Current evidence suggests that two qualitatively different processes (recollection and familiarity) contribute to recognition memory and can be investigated using a Dual-Process Signal Detection model. Using such a model, we found that amisulpride levels at encoding were significantly inversely correlated with recollection estimates for emotional but not neutral stimuli or familiarity estimates in healthy male volunteers. This suggests that dopamine antagonism at encoding preferentially impairs the recollection component of emotional memory, relative to the familiarity component. This was supported by receiver operating characteristic analysis. We also found a significantly increased false recognition rate, associated with significantly shorter reaction times for emotional but not neutral stimuli in the amisulpride group. These findings have important implications for our understanding of recognition memory processes, as well as the interpretation of neuropsychological findings in medicated patient

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

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

The role of dopamine in attentional and memory biases for emotional information

Abstract OBJECTIVE: Cognitive models suggest that biased processing of emotional information may play a role in the genesis and maintenance of psychotic symptoms. The role of dopamine and dopamine antagonists in the processing of such information remains unclear. The authors investigated the effect of a dopamine antagonist on perception of, and memory for, emotional information in healthy volunteers. METHOD: Thirty-three healthy male volunteers were randomly assigned to a single-blind intervention of either a single dose of the dopamine D(2)/D(3) antagonist amisulpride or placebo. An attentional blink task and an emotional memory task were then administered to assess the affective modulation of attention and memory, respectively. RESULTS: A significant interaction was observed between stimulus valence and drug on recognition memory accuracy; further contrasts revealed enhanced memory for aversive-arousing compared with neutral stimuli in the placebo but not the amisulpride group. No effect of amisulpride was observed on the perception of emotional stimuli. CONCLUSIONS: Amisulpride abolished the enhanced memory for emotionally arousing stimuli seen in the placebo group but had no effect on the perception of such stimuli. These results suggests that dopamine plays a significant role in biasing memory toward emotionally salient information and that dopamine antagonists may act by attenuating this bias