Rebound activation of 5-HT neurons following SSRI discontinuation
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 th...
| Main Authors: | , , , , , , , , , |
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| Formato: | Journal article |
| Idioma: | English |
| Publicado em: |
Springer Nature [academic journals on nature.com]
2024
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| _version_ | 1826313767765409792 |
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| author | Collins, HM Gullino, LS Ozdemir, D Lazarenco, C Sudarikova, Y Daly, E Pilar Cuéllar, F Pinacho, R Bannerman, DM Sharp, T |
| author_facet | Collins, HM Gullino, LS Ozdemir, D Lazarenco, C Sudarikova, Y Daly, E Pilar Cuéllar, F Pinacho, R Bannerman, DM Sharp, T |
| author_sort | Collins, HM |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-09-25T04:21:47Z |
| format | Journal article |
| id | oxford-uuid:3d0883c9-43ab-4cfe-9391-08b6e8e0f43b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:21:47Z |
| publishDate | 2024 |
| publisher | Springer Nature [academic journals on nature.com] |
| record_format | dspace |
| spelling | oxford-uuid:3d0883c9-43ab-4cfe-9391-08b6e8e0f43b2024-08-12T19:36:02ZRebound activation of 5-HT neurons following SSRI discontinuationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:3d0883c9-43ab-4cfe-9391-08b6e8e0f43bEnglishJisc Publications RouterSpringer Nature [academic journals on nature.com]2024Collins, HMGullino, LSOzdemir, DLazarenco, CSudarikova, YDaly, EPilar Cuéllar, FPinacho, RBannerman, DMSharp, TCessation 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. |
| spellingShingle | Collins, HM Gullino, LS Ozdemir, D Lazarenco, C Sudarikova, Y Daly, E Pilar Cuéllar, F Pinacho, R Bannerman, DM Sharp, T Rebound activation of 5-HT neurons following SSRI discontinuation |
| title | Rebound activation of 5-HT neurons following SSRI discontinuation |
| title_full | Rebound activation of 5-HT neurons following SSRI discontinuation |
| title_fullStr | Rebound activation of 5-HT neurons following SSRI discontinuation |
| title_full_unstemmed | Rebound activation of 5-HT neurons following SSRI discontinuation |
| title_short | Rebound activation of 5-HT neurons following SSRI discontinuation |
| title_sort | rebound activation of 5 ht neurons following ssri discontinuation |
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