Biology subjects

Pinacho, R.

Publications and source records attributed to Pinacho, R..

3 recordsLinked to original sources

bioRxiv2023

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, 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 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 Fos expression in midbrain 5-HT 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 finds that SSRI discontinuation triggers a rebound activation of 5-HT neurons across a range of experiments. This effect is reminiscent of neural changes associated with various psychotropic drug withdrawal states, suggesting a common unifying mechanism.

neuroscience↗

bioRxiv2021

Effect of SSRI discontinuation on anxiety-like behaviours in mice

BackgroundAbrupt cessation of therapy with a selective serotonin reuptake inhibitor (SSRI) is associated with a discontinuation syndrome, typified by numerous disabling symptoms including anxiety. Surprisingly little is known of the behavioural effect of SSRI discontinuation in animals. AimHere, the effect of SSRI discontinuation on anxiety-like behaviour was systematically investigated in mice. MethodsExperiments were based on a 3-arm experimental design comprising saline, continued SSRI and discontinued SSRI. Mice were assessed 2 days after SSRI discontinuation over a 5 day period using the elevated plus maze (EPM) and other anxiety tests. ResultsAn exploratory experiment found cessation of paroxetine (12 days) was associated with decreased open arm exploration and reduced total distance travelled, in male but not female mice. Follow-up studies confirmed a discontinuation effect on the EPM in male mice after paroxetine (12 days) and also citalopram (12 days). Mice receiving continued paroxetine (but not citalopram) also showed decreased open arm exploration but this was dissociable from effects of discontinuation. The discontinuation response to paroxetine did not strengthen after 28 days treatment but was absent after 7 days treatment. A discontinuation response was not decernable in other anxiety and fear-learning tests applied 3-5 days after treatment cessation. Finally, discontinuation effects on the EPM were typically associated with decreased locomotion on the test. However, separate locomotor testing implicated anxiety-provoked behavioural inhibition rather than a general reduction in motor activity. ConclusionOverall, the current study provides evidence for a short-lasting behavioural discontinuation response to cessation of SSRI treatment in mice.

neuroscience↗

bioRxiv2020

CALCIUM-BINDING PROTEINS ARE ALTERED IN THE CEREBELLUM IN SCHIZOPHRENIA

Alterations in the cortico-cerebellar-thalamic-cortical circuit might underlie the diversity of symptoms in schizophrenia. However, molecular changes in cerebellar neuronal circuits, part of this network, have not yet been fully determined. Using LC-MS/MS, we screened altered candidates in pooled grey matter of cerebellum from schizophrenia subjects who committed suicide (n=4) and healthy individuals (n=4). Further validation by immunoblotting of three selected candidates was performed in two cohorts comprising schizophrenia (n=20), non-schizophrenia suicide (n=6) and healthy controls (n=21). We found 99 significantly altered proteins, 31 of them previously reported in other brain areas by proteomic studies. Transport function was the most enriched category, while cell communication was the most prevalent function. For validation, we selected the vacuolar proton pump subunit 1 (VPP1), from transport, and two EF-hand calcium-binding proteins, calmodulin and parvalbumin from cell communication. All candidates showed significant changes in schizophrenia (n=7) compared to controls (n=7). VPP1 was altered in the non-schizophrenia suicide group and increased levels of parvalbumin were linked to antipsychotics. Further validation in an independent cohort of non-suicidal chronic schizophrenia subjects (n=13) and non-psychiatric controls (n=14) showed that parvalbumin was increased while calmodulin was decrease in schizophrenia. Our findings provide evidence of an dysregulation of calcium-binding proteins in the cerebellum in schizophrenia, suggesting an impact on normal calcium-dependent synaptic functioning of cerebellar circuits. Our study also links VPP1 to suicide behaviours, suggesting a possible impairment in vesicle neurotransmitter refilling and release in these phenotypes.

neuroscience↗