I neat new study that draws a direct parallel between PUFA-driven inflammation, serotonin and depression. As the study demonstrated, high levels of the PUFA arachidonic acid (AA) are highly correlated with lower density (expression) of the serotonin transported (SERT, 5-HTT), and the relationship is actually causative in both directions (AA<->serotonin). This results in increased serotonin availability/buildup since the primary role of SERT/5-HTT is to deactivate serotonin, using sodium as a co-factor.
https://en.wikipedia.org/wiki/Serotonin_transporter
“…The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene.[5] SERT is a type of monoamine transporter protein that transports serotonin from the synaptic cleft back to the presynaptic neuron.[6] This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it in a sodium-dependent manner. This protein is the target of many antidepressant medications of the SSRI and tricyclic antidepressant classes.[7]”
What’s even worse, the study demonstrates that serotonin and AA form a positive feedback cycle with the increased serotonin due to AA inhibiting SERT/5-HTT resulting in activation of the enzyme Phospholipase A2 (PLA2) that synthesizes AA from linoleic acid, which then results in stronger SERT/5-HTT inhbition and even higher serotonin availability. While the study tries to dance carefully around the role of serotonin in depression and states that “conflicting” results have been seen in other studies, it readily admits that AA is a known inducer of depression in animal models. Well, if AA is a highly inflammatory depressant and forms a positive feedback cycle with serotonin then I don’t see how serotonin could possibly be an anti-depressant…Another immediate takeaway from the study is that SSRI drugs are highly pro-inflammatory since they activate the AA<->serotonin cycle by inhibiting SERT/5-HTT (which is their primary mechanism of action). All in all, another great reason to avoid PUFA and eat plenty of salt (to taste).
https://www.sciencedirect.com/science/article/abs/pii/S0165032718330751
“…The relative peripheral levels of PUFA species are associated with neuropsychiatric illnesses, with elevated AA in proportion to DHA and EPA in MDD (Lin et al., 2010) and suicide risk (Huan et al., 2004; Lewis et al., 2011; Sublette et al., 2006). AA is particularly implicated in bipolar disorder, both postmortem (Kim et al., 2009) and in translational studies showing that multiple mood stabilizing medications downregulate AA metabolism (Rapoport, 2014).”
“…We have previously reported lower 5-HTT binding (BPP), using positron emission tomography (PET) and [11C]McN5652, in unmedicated MDD (Parsey et al., 2006a) and bipolar depressed (Oquendo et al., 2007a) groups compared with healthy controls. [11C]…We have reported lower [11C]DASB binding (VT/fP) in MDD patients with a history of suicide attempt (Miller et al., 2013), and lower binding potentials (BPF, BPP, and BPND, using a suboptimal reference region) in bipolar depression (Miller et al., 2016), considering a priori regions of interest (ROIs), although VT/fP did not differ in that study. ”
“…Separate models testing effects of DHA, EPA, and AA revealed no effects of DHA nor EPA on [11C]DASB binding potential (data not shown). However, AA had an effect on BPP (F = 9.14; df=1,19; p = 0.006) across regions, and given graphical evidence of a nonlinear relationship between AA level and BPP (Fig. 1A), we found that an added quadratic term was significant (F = 9.62; df=1,19; p = 0.006; also see Fig. 4, path a). The resulting inverted U-shaped relationship demonstrates that for most of the concentration range of AA, higher BPP correlated with lower AA levels. Exploratory analyses of PUFA effects on BPND and BPF (see Fig. 1B and C) similarly found that AA, but not DHA or EPA, demonstrated a comparable effect on BPND (F = 7.40; df=1,19; p = 0.014) while controlling for region, but had no statistically significant effect on BPF (F = 0.51; df=1,19; p = 0.484).”
“…Specifically, 5-HT2A/2C stimulates activation of cytosolic phospholipase A2 (cPLA2) (Berg et al., 1998; Qu et al., 2005; Garcia and Kim, 1997; Felder et al., 1990), triggering the release of unesterified AA from membrane phospholipids. Some of the released AA is recycled back into the membrane, a process that is stimulated by 5-HT1A receptors (Strosznajder et al., 1996). Remaining unesterified AA can decrease 5-HTT in certain brain regions (du Bois et al., 2006).”
“…Drs. Sublette, Mann and colleagues including Gregory Sullivan, M.D., a 2004 BBRF Young Investigator, discovered in their study that only one of the PUFAs they measured—AA, or arachidonic acid—had a potential impact on the availability of SERTs across the six brain areas that were imaged via PET scan. Specifically, they found that greater SERT availability in neurons correlated with lower AA levels in subjects, as measured in their plasma prior to the scans. This result led the team to hypothesize that AA may affect the severity of depression through its impact on the availability of SERTs in the brain. The nature of the observed correlation was complex, with extreme levels of AA affecting both SERTs and depression severity differently than moderate AA levels.”
