title: 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.
authors: Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: Elyse C
authors: EC
authors: Dankoski
authors: 1] Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: Kara L
authors: KL
authors: Agster
authors: Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: Megan E
authors: ME
authors: Fox
authors: 1] Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: Sheryl S
authors: SS
authors: Moy
authors: 1] Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [3] Center for Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: R Mark
authors: RM
authors: Wightman
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015283:Citalopram / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D055664:Electrochemical Techniques; D005106:Exploratory Behavior / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D012934:Social Isolation / Q000523:psychology*; D013997:Time Factors
chemical_list: D015283:Citalopram; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors