Journal Article

Rebound activation of 5-HT neurons following SSRI discontinuation

Pinacho, Raquel, Bannerman, David M., Gullino, L. Sophie, Collins, Helen M., Sudarikova, Yulia, Sharp, Trevor, Ozdemir, Dersu, Lazarenco, Caroline, Daly, Elizabeth, Pilar Cuéllar, Fuencisla

2024

Overview

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-HT 1A receptor antagonist administration although gene expression analysis could not confirm altered expression of 5-HT 1A 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.

• Publisher: Nature Publishing Group,Springer International Publishing
• Subject: Animals / Anxiety / Brain - drug effects / Brain - metabolism / c-Fos protein / Experiments / Gene expression / Hippocampus / Hippocampus - drug effects / Hippocampus - metabolism / Hydroxyindoleacetic Acid - metabolism / Immunohistochemistry / Male / Mesencephalon / Mice / Mice, Inbred C57BL / Microdialysis / Neurons / Neurons - drug effects / Neurons - metabolism / Paroxetine / Paroxetine - pharmacology / Receptor, Serotonin, 5-HT1A - drug effects / Receptor, Serotonin, 5-HT1A - metabolism / Selective Serotonin Reuptake Inhibitors - pharmacology / Serotonergic Neurons - drug effects / Serotonergic Neurons - metabolism / Serotonin - metabolism / Serotonin S1 receptors / Serotonin uptake inhibitors / Substance Withdrawal Syndrome - metabolism / Withdrawal