Variability in serotonin (5-HT) function is associated with individual differences in normal mood and temperament, as well as psychiatric illnesses, all of which are influenced by amygdala function. This study evaluated the acute effects of 5-HT reuptake blockade on amygdala function using pharmacological functional MRI.
Eight healthy men completed a double-blind balanced crossover study with the selective 5-HT reuptake inhibitor, citalopram (20 mg infused over 30 min), and normal saline. Amygdala reactivity in response to novel facial expressions was assessed on three successive scans, once before drug/placebo infusion, once early in the infusion, and once at the end of infusion. Acute citalopram administration resulted in concentration-dependent increases in human amygdala reactivity to salient stimuli.
The current pattern of 5-HT-mediated amygdala reactivity may represent an important pathway through which SSRIs achieve an antidepressant effect. Intriguingly, our data may also reveal a mechanism contributing to clinical observations of extreme agitation, restlessness, and suicidal ideation in some individuals during acute SSRI treatment.
Developing a comprehensive model of how 5-HT modulates human amygdala reactivity supporting behavioral and physiological arousal will be instrumental for our understanding of basic neurobehavioral processes, their dysfunction in psychiatric illnesses, and their contribution to mechanism of treatment response.
The amygdala is an evolutionarily conserved deep brain structure uniquely capable of mediating both simple reflexive and more complex adaptive behavioral and physiologic responses to environmental challenge. Moreover, variability in the functional dynamics of the amygdala has been associated with a broad range of individual differences in normal mood and temperament, as well as pathological emotional states such as depression. Accordingly, identifying the mechanisms regulating amygdala function and, in turn, mediating the emergence of such inter-individual variability is a major focus of neurobiological, psychological, pharmacological, and genetic research.
Converging evidence from these and other disciplines has highlighted the importance of serotonin (5-HT) in the modulation of amygdala function and related behavioral processes. Available data from animal studies indicate that relative increases in amygdala 5-HT result in potentiation of amygdala activation and associated behavioral phenomenon, such as fear conditioning (Burghardt et al, 2004, 2007; Forster et al, 2006).
In humans, recent in vivo neuroimaging studies have revealed that decreased capacity for either 5-HT reuptake (Rhodes et al, 2007) or negative feedback autoregulation (Fisher et al, 2006) result in relatively increased amygdala reactivity.
In addition, human functional genetic polymorphisms resulting in relatively increased 5-HT signaling are similarly associated with increased amygdala reactivity (Hariri et al, 2002; Heinz et al, 2005; Meyer-Lindenberg et al, 2006).
