It is an over simplification

It is an over-simplification to consider limbic and frontal selective serotonin reuptake inhibitor regions entirely separately, as there is significant cross-talk between these areas through fronto-limbic connections. Just this year, Cullen et al. (2016) used fMRI to examine the effect of SSRIs, including fluoxetine, on fronto-limbic functional connectivity in depressed adolescents. They found that clinical response to treatment was associated with increased resting-state functional connectivity between amygdala and right frontal cortex, but decreased resting-state functional connectivity between amygdala and right precuneus and right posterior cingulate cortex. Overall, fMRI data reveals both similarities and differences in the ways that adolescent and adult brains respond to depression and to antidepressant treatments. In order to accurately interpret BOLD signal differences between healthy and depressed groups, medicated and non-medicated groups, and adolescent and adult groups, it is essential to know whether the BOLD signal is reflecting the same set of brain processes between the groups. To this end, we now investigate the ways in which fluoxetine treatment is likely to affect the relationship between neural activity, blood flow response and cellular metabolism (summarised in Fig. 1).
Antidepressants and neurovascular coupling
Antidepressants and brain energy use
Long-term effects of antidepressants taken during adolescence Anderson and Navalta (2004) put forward the hypothesis that, in adolescence, long-term effects of drugs may be delayed and only expressed once the vulnerable system reaches maturation (i.e adulthood). This phenomenon is referred to as neuronal imprinting and occurs when the effects of drug exposure outlast the drug itself. The use of SSRIs in development has been shown to have an effect on behaviour in adult mice and rats (Ansorge et al., 2004; Iniguez et al., 2010). Iniguez et al. (2010) found that adolescent male rats treated with fluoxetine for 15 consecutive days (postnatal days 35–49) displayed increased anxiety and decreased copulatory behaviour three weeks after treatment. Conversely, rats that were treated during adulthood (fluoxetine administered on postnatal days 65–79), did not show long-lasting increases in anxiety. Chronic fluoxetine treatment at different developmental stages also has different effects at the cellular level. In adult animals, fluoxetine treatment triggers either no change or a reduction in serotonin transporter expression (Lesch et al., 1993; Pineyro et al., 1994; Wegerer et al., 1999) whereas, in juvenile animals, fluoxetine treatment leads to a long-term increase in the expression of serotonin transporters in the frontal cortex (Wegerer et al., 1999). This result could reflect an increase in the density of serotonin transporters per synaptic terminal, or it could reflect an increase in the number of synaptic terminals themselves. The authors favour the latter theory, suggesting that fluoxetine treatment enhances the serotonin-triggered release of astrocytic growth factors, which in turn upregulate the growth of serotonergic nerve terminals, so long as the frontal cortex is still developing and relatively plastic. Other long-lasting cellular-level effects of fluoxetine treatment during adolescence include an increase in S100B, a glia-derived calcium-binding protein which may influence the development of serotonergic fibers (Bock et al., 2013) and, as discussed in Section 6, increased mitochondrial respiration (Da Silva et al., 2015; Braz et al., 2016). The functional brain response to serotonin of adolescent- versus adult-treated rats is less clear. An acutely administered high dose of fluoxetine suddenly increases serotonin levels in the brain, and this “serotonin challenge” leads to an increased BOLD signal in several regions of the rat brain. Compared to untreated rats, this BOLD response to serotonin challenge is smaller when rats had previously been chronically treated with fluoxetine during adulthood (Klomp et al., 2012; Bouet et al., 2012). Chronic treatment with fluoxetine during adolescence has been observed to either increase (Klomp et al., 2012) or decrease (Bouet et al., 2012) the BOLD response to serotonin challenge, compared to untreated rats.