Facilitation of Serotonin Signaling by SSRIs is Attenuated by Social Isolation

Abstract

Hypofunction of the serotonergic system is often associated with major depression and obsessive compulsive disorder (OCD). Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to treat these disorders, and require 3-6 weeks of chronic treatment before improvements in the symptoms are observed. SSRIs inhibit serotonin's transporter, and in doing so, increase extracellular serotonin concentrations. Thus, efficacy of SSRIs likely depends upon the brain's adaptive response to sustained increases in serotonin levels. Individual responsiveness to SSRI treatment may depend on a variety of factors that influence these changes, including ongoing stress. Social isolation is a passive, naturalistic form of chronic mild stress that can model depression in rodents. In this study, we examined how 20-day treatment with the SSRI citalopram (CIT) alters marble-burying (MB), open field behavior, and serotonin signaling in single- vs pair-housed animals. We used in vivo voltammetry to measure electrically evoked serotonin, comparing release rate, net overflow, and clearance. Pair-housed mice were significantly more responsive to CIT treatment, exhibiting reduced MB and facilitation of serotonin release that positively correlated with the frequency of electrical stimulation. These effects of CIT treatment were attenuated in single-housed mice. Notably, although CIT treatment enhanced serotonin release in pair-housed mice, it did not significantly alter uptake rate. In summary, we report that chronic SSRI treatment facilitates serotonin release in a frequency-dependent manner, and this effect is blocked by social isolation. These findings suggest that the efficacy of SSRIs in treating depression and OCD may depend on ongoing stressors during treatment.

Acute selective serotonin reuptake inhibitors regulate the dorsal raphe nucleus causing amplification of terminal serotonin release

“…SERT inhibition enhances serotonin release in a frequencydependent manner Next, we examined CIT's effects on neurotransmission dynamics. A duration of 30 min after CIT administration, [5-HT] max and t 1/2 had both increased relative to baseline, consistent with previous reports (Hashemi et al 2012;Dankoski et al 2014). Table S1 compares average preand post-CIT [5-HT] max , release rate, and t 1/2 values.…”

“…The amplification of serotonin release is frequency‐dependent, retaining information about the rate of stimulation, and is qualitatively similar to results observed in animals treated with SSRI for chronic periods (Dankoski et al . ). This similarity between acute and chronic responses to SSRIs complicates how we interpret the role of serotonin in the antidepressant response.…”

“…The dose of CIT used with i.p. injection was selected to be consistent with previously published studies (Hashemi et al 2009(Hashemi et al , 2011(Hashemi et al , 2012Dankoski et al 2014). In a few experiments, clearance was unaffected by CIT.…”

Molecular fMRI of Serotonin Transport

“…Corresponding 5HT removal velocities range from 0–20 nM/s. V eff values in the 10 −9 –10 −8 M/s range are consistent with kinetic measurements from SERT expressing cells (Blakely et al, 1991) and 5HT clearance rates recorded by in vivo voltammetry (Dankoski et al, 2014). …”

Electrochemical Analysis of Neurotransmitters

“…To overcome these challenges, researchers have identified several strategies involving anatomical positioning for norepinephrine and waveform/electrode modifications for serotonin. Subsequent work has successfully investigated the regulation of norepinephrine overflow in the bed nucleus of the stria terminalis (32, 33) and serotonin overflow in the substantia nigra pars reticulata (34, 35). …”