@article{10902/32997,
year = {2024},
url = {https://hdl.handle.net/10902/32997},
abstract = {Cessation of therapy with a selective serotonin (5-HT) reuptake inhibitor (SSRI) is often associated with an early onset and disabling discontinuation syndrome, the mechanism of which is surprisingly little investigated. Here we determined the effect on 5-HT neurochemistry of discontinuation from the SSRI paroxetine. Paroxetine was administered repeatedly to mice (once daily, 12 days versus saline controls) and then either continued or discontinued for up to 5 days. Whereas brain tissue levels of 5-HT and/or its metabolite 5-HIAA tended to decrease during continuous paroxetine, levels increased above controls after discontinuation, notably in hippocampus. In microdialysis experiments continuous paroxetine elevated hippocampal extracellular 5-HT and this effect fell to saline control levels on discontinuation. However, depolarisation (high potassium)-evoked 5-HT release was reduced by continuous paroxetine but increased above controls post-discontinuation. Extracellular hippocampal 5-HIAA also decreased during continuous paroxetine and increased above controls post-discontinuation. Next, immunohistochemistry experiments found that paroxetine discontinuation increased c-Fos expression in midbrain 5-HT (TPH2 positive) neurons, adding further evidence for a hyperexcitable 5-HT system. The latter effect was recapitulated by 5-HT1A receptor antagonist administration although gene expression analysis could not confirm altered expression of 5-HT1A autoreceptors following paroxetine discontinuation. Finally, in behavioural experiments paroxetine discontinuation increased anxiety-like behaviour, which partially correlated in time with the measures of increased 5-HT function. In summary, this study reports evidence that, across a range of experiments, SSRI discontinuation triggers a rebound activation of 5-HT neurons. This effect is reminiscent of neural changes associated with various psychotropic drug withdrawal states, suggesting a common unifying mechanism.},
organization = {FUNDING: This work was supported by a Wellcome Trust PhD Studentship in Basic Science (HC; grant no. 219982/Z/19/Z), a studentship from the Oxford-MRC Doctoral Training Partnership (SG), and research support funds from the University of Oxford.},
publisher = {Nature Publishing Group},
publisher = {Neuropsychopharmacology, 2024,},
title = {Rebound activation of 5-HT neurons following SSRI discontinuation},
author = {Collins, Helen M. and Gullino, L. Sophie and Ozdemir, Dersu and Lazarenco, Caroline and Sudarikova, Yulia and Daly, Elizabeth and Pilar Cuéllar, María Fuencisla and Pinacho, Raquel and Bannerman, David M. and Sharp, Trevor},
}