Deep brain stimulation and fluoxetine exert different long-term changes in the serotonergic system

Both selective serotonin reuptake inhibitors (SSRIs) and ventromedial prefrontal cortex (vmPFC) deep brain stimulation (DBS) modulate serotonergic activity. We compared the acute (1 day) and long-term (12 days) effects of vmPFC stimulation and fluoxetine on serotonin (5-HT) release and receptor expression in rats. Samples to measure serotonin levels were collected from the hippocampus using microdialysis. Serotonin transporter (SERT), 5-HT_1A and 5-HT_1B mRNA were measured using in situ hybridization. [³H]8-OH-DPAT and [¹²⁵I]cyanopindolol autoradiography were used to measure 5-HT_1A and 5-HT_1B binding. Our results show that after fluoxetine injections serotonin levels were approximately 150% higher than at baseline. Twelve days later, pre-injection 5-HT extracellular concentration was substantially higher than on day 1. In contrast, serotonin levels following DBS were only 50% higher than at baseline. While pre-stimulation 5-HT on day 12 was significantly higher than on treatment day 1, no stimulation-induced 5-HT peak was recorded. SERT expression in the dorsal raphe was increased after acute fluoxetine and decreased following a single day of DBS. Neither fluoxetine nor DBS administered acutely substantially changed 5-HT_1A or 5-HT_1B binding. Chronic fluoxetine treatment, however, was associated with a decrease in [³H]8-OH-DPAT prefrontal cortex and hippocampus expression. In contrast, chronic DBS induced a significant increase in [¹²⁵I]cyanopindolol binding in the prefrontal cortex, globus pallidus, substantia nigra and raphe nuclei. mRNA expression of 5-HT_1A and 5-HT_1B in raphe nuclei was not altered by either treatment. These results suggest that fluoxetine and DBS modulate activity of the serotonergic system but likely exert their effects through different mechanisms.