Deep brain stimulation of the dorsal raphe induces anxiolytic and panicolytic-like effects and alters serotonin immunoreactivity.

Previously we showed that Deep Brain Stimulation (DBS) of the dorsal region (DRD) and of the lateral wings of the dorsal raphe (lwDR) respectively decreases anxiety and panic-like responses in the elevated T-maze (ETM). This study investigates neurobiological alterations which might respond for these behavioral effects. Male Wistar rats were submitted to high-frequency stimulation (100 µA, 100 Hz) of the DRD or of the lwDR for 1 h, and subsequently tested in the avoidance or escape tasks of the ETM. Since serotonin (5-HT) reuptake inhibitors are first line pharmacological treatment for anxiety disorders, we also tested the effects of chronic fluoxetine administration (10 mg/kg, IP, 21 days) on a separate group of rats. An open field was used for locomotor activity assessment. Additionally, we evaluated c-Fos immunoreactivity (Fos-ir) in serotonergic cells of the dorsal raphe (DR). Results showed that DBS of the DRD decreases avoidance reactions, an anxiolytic-like effect, without altering escape or locomotor activity. Both fluoxetine and DBS of the lwDR decreased escape responses in the ETM, a panicolytic-like effect, without altering avoidance measurements or locomotor activity. While DBS of the DRD decreased double immunostaining in the DRD, DBS of the lwDR increased Fos-ir and double immunostaining in the DRD and lwDR. Fluoxetine also increased double immunostaining in the lwDR and in the DRV but decreased it in the DRD. These results suggest that both the anxiolytic and panicolytic-like effects of DBS and fluoxetine are related to 5-HT modulation in different subnuclei of the DR.

Deep Brain Stimulation of the dorsal raphe abolishes serotonin 1A facilitation of AMPA receptor-mediated synaptic currents in the ventral hippocampus.

In a previous study we showed that Deep Brain Stimulation (DBS) of the rat dorsal subregion of the dorsal raphe (DRD), which sends serotonergic projections to forebrain areas, such as the ventral hippocampus, induces anxiolytic-like effects. The purpose of the present study was to investigate neurobiological alterations which might underline these behavioral effects. For that, we tested the influence of DBS upon the neuromodulatory action of serotonin on excitatory post-synaptic currents (EPSCs) in the ventral hippocampus. Male Wistar rats were submitted to high-frequency stimulation (100 µA, 100 Hz) of the DRD for 1 h during three consecutive days. On the third day, immediately after the DBS procedure, animals were euthanized. Slices of the ventral hippocampus were processed for whole cell patch clamp recordings of AMPA-receptor (AMPAR) mediated EPSCs in the CA1 area. As reported by others, we confirmed that in pre-weaning rats a high affinity 5-HT1A receptor agonist (8-OH-PIPAT, 0.5-5nM) inhibits EPSCs. However, in adult rats (non-operated or sham-operated), 8-OH-PIPAT (0.5-5 nM) increased EPSC amplitude, an effect blocked by the 5-HT1A antagonist WAY-100,635 (200 nM). Importantly, in adult rats exposed to DBS, the 5-HT1A agonist was devoid of effect. Taken together these results show that: 1) changes in 5-HT1A receptor-mediated hippocampal synaptic transmission occur with age; 2) these changes lead to a facilitatory effect of 5-HT1A receptors; 3) DBS blocks this serotonergic facilitatory action. These observations suggest that an alteration in serotonin modulation of limbic areas may underlie the psychotherapeutic effects of DBS.