Investigation of the behavioural and neurobiological effects of SSRI discontinuation in mice

Cessation of a selective serotonin reuptake inhibitor (SSRI) is associated with SSRI discontinuation syndrome, which includes symptoms such as anxiety and sleep disturbances. Symptoms typically appear within a week of stopping treatment, can be severe, and can last for several weeks or even months in some patients. The syndrome recently rose to prominence following a series of reviews finding that more than half of patients discontinuing SSRI treatment will experience symptoms. Yet, there have been few preclinical studies of the condition and its neurobiological basis is unknown. Thus, the aim of this thesis was to establish a model with which to investigate the behavioural and neurobiological effects of SSRI discontinuation in mice.
Behavioural studies found that two days after discontinuation from 12 days of treatment with the SSRI paroxetine, mice exhibited increased anxiety-like behaviour and behavioural inhibition on the elevated plus maze compared to saline-treated and continued paroxetine controls. These effects were short-lasting, having dissipated five days after discontinuation, and required at least 12 days of treatment before their emergence. They were evident in male but not female mice, and were also present, albeit to a lesser extent, following citalopram and venlafaxine discontinuation. Sleep and circadian rhythms were also assessed using continuous homecage monitoring, finding evidence of changes in sleep-wake activity for seven days after paroxetine cessation.
The 5-hydroxytryptamine (5-HT) system was then probed to investigate the neurobiological effects of SSRI discontinuation. Immunohistochemical experiments found evidence of a rebound increase in c-FOS immunoreactivity in 5-HT neurons in the dorsal raphe nucleus two and five days after paroxetine cessation, suggesting that discontinuation was associated with 5-HT neuron activation. Ex vivo analysis of regional brain tissue also found evidence of a rebound increase in 5 HT synthesis following paroxetine discontinuation. In vivo microdialysis experiments showed that while basal hippocampal extracellular 5-HT fell to saline control levels following discontinuation, depolarisation-evoked 5-HT release was increased. Gene expression analysis found evidence of a reduction in 5 HT1A autoreceptor expression in the raphe nuclei following paroxetine discontinuation. It was therefore hypothesised that paroxetine discontinuation was associated with a fall in extracellular 5-HT, which led to the disinhibition of 5-HT neurons and thus a rebound increase in their excitability. Nonetheless, the behavioural effects of SSRI cessation could not be induced in mice receiving continued paroxetine by experimentally manipulating the 5-HT system with 5 HT1A receptor ligands, suggesting that this approach could not be used to precipitate SSRI discontinuation.
In summary, these studies provide the first model of SSRI discontinuation syndrome in mice and offer novel insights into the effects of SSRI cessation on the 5-HT system. Further work is needed to determine if changes to 5-HT transmission are causal in the symptoms of SSRI discontinuation syndrome.

Keywords: Mice
Discontinuation
Anxiety
Paroxetine
SSRI
Advisor: Sharp, T
Bannerman, D
Pinacho Garcia, R