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We investigated the modulatory effect of serotonin using acute tryptophan depletion (ATD) during a cognitive switching task involving visual\u2010spatial set shifting modified for a functional MRI environment. Ten healthy women over 55 years were tested on two separate occasions in this within\u2010group double\u2010blind sham\u2010controlled crossover study to compare behavioral and physiological brain functioning following ATD and following a (\u201cplacebo\u201d) sham depletion condition. ATD did not significantly affect task performance. It did modulate brain functional recruitment. During sham depletion women significantly activated the expected task\u2010relevant brain regions associated with the Switch task including prefrontal and anterior cingulate cortices. In contrast, following ATD participants activated posterior regions of brain more during switch than repeat trials. In addition to the main effects of depletion condition, a comparison of the ATD relative to the sham condition confirmed this anterior\u2010to\u2010posterior shift in activation. The posterior (increased) activation clusters significantly and negatively correlated with the reduced prefrontal activation clusters suggesting a compensation mechanism for reduced prefrontal activation during ATD. Thus, serotonin modulates an anterior\u2010to\u2010posterior shift of activation during cognitive switching in older adults. Neural adaptation to serotonin challenge during cognitive control may prove useful in determining cognitive vulnerability in older adults with a predisposition for serontonergic down\u2010regulation (e.g., in vascular or late life depression). 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