A different look at Doxycycline and CFS:
doxycycline inhibits LPS priming of NLRP3. doxycycline dose dependently inhibited the production of the cytokines IL-1β, IL-6, TNF-α, and IFN-γ and the chemokines MCP-1, MIP-1α, and MIP-1β by PBMC
https://pubmed.ncbi.nlm.nih.gov/34577552/
Serotonin binds to the 5HT2 and 5HT1A receptors in the motoneuron system. 5HT2 receptors are excitatory and appear to be the receptor that allows serotonin to be involved with promoting locomotion. When serotonin levels reach very high levels, a spillover effect will be seen, and serotonin will begin binding to 5HT1A receptors (which are known to be inhibitory) and will prevent motoneuron firing. (and orexin). Overexpression of serotonin 5HT1A receptor in the orexin neurons enhanced serotonergic inhibition and resulted in severe fragmentation of wakefulness, specifically early in the dark (active) period. Normalization of 5HT1A expression in the orexin neurons
in the presence of doxycycline (DOX) eliminated this fragmentation. These results suggest that serotonergic inhibition of orexin neurons may function as a negative feedback circuit early in the active period and could thereby contribute to the diurnal rhythms of sleep and wakefulness. Consistent with its likely role in promoting wakefulness, blockade of 5HT neuro-transmission through 5HT2A antagonists reduces wakefulness and enhances SWS.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738049/ (Consider that under inflammation, many cytokines induce IDO1 and therefore will shunt tryptophan away from serotonin.)
Wei, Glaser, and Deng (2014), through indirect measures with humans, found that serotonin release increases in concentration as the force of muscular contraction increases in exercise (addition of the inhibitory axonal binding site). No studies on humans have directly measured serotonin concentrations in the brain; however, 5HT1A receptors are known to exist in humans, and D’Amico et al. (2015) showed that motoneuron excitability in humans can be reduced via 5HT1A agonist drugs administration.
https://simplifaster.com/articles/central-fatigue-role-neurotransmitters-reduced-work-output