GR-113808

Working memory deficits commonly occur in Parkinson's disease. 5-hydroxytryptamine₄ (5-HT₄) receptors are widely distributed in the prelimbic cortex (PrL) and involved in cognition. Here we tested the effects of activation and blockade of PrL 5-HT₄ receptors on working memories by T-maze rewarded alternation and Morris water maze tests in rats with unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle. The lesion induced working memory deficits, decreased dopamine levels in the limbic-related brain regions, changed normalized δ, high θ, α, β, low and high γ power of the PrL, and upregulated expression of PrL 5-HT₄ receptor. Intra-PrL injection of 5-HT₄ receptor agonist BIMU8 or antagonist GR113808 did not impact working memories in sham rats, but improved working memory deficits in the lesioned rats. Intra-PrL injection of BIMU8 or GR113808 had no effect on monoamine levels in the limbic-related brain regions or normalized low and high γ power of the PrL in sham rats. However, in the lesioned rats, intra-PrL injection of BIMU8 significantly increased dopamine and 5-HT levels in the medial prefrontal cortex, amygdala and dorsal hippocampus, while intra-PrL injection of GR113808 significantly increased dopamine levels in these brain regions and increased normalized low and high γ power of the PrL. These results suggest that 6-OHDA lesion in rats induces working memory deficits, while activation or blockade of PrL 5-HT₄ receptors improves the deficits in the lesioned rats, which possibly due to the changes of monoamine levels in the limbic-related brain regions and network activity of neurons in the PrL.

Perturbations of intestinal serotonergic neurotransmission seem to be involved in bowel dysmotility associated with irritable bowel syndrome (IBS) with diarrhea. Oral administration of probiotics is an emerging strategy to improve IBS symptoms, possibly via influencing local serotonin metabolism and neurotransmission. In the present study, we evaluated the effects of the yeast Saccharomyces boulardii CNCM I-745 (S. boulardii) on intestinal motility and serotonergic receptors.

Isolated rat ileum was contracted in a cumulative concentration way by serotonin (5-HT), various 5-HT agonists or by acetylcholine to determine their effective concentration 50% (EC₅₀). Single concentrations of S. boulardii or 5-HT antagonists were added before agonists to identify the receptors targeted by S. boulardii.

The serotonin antagonists 5-HT_1A WAY100635, 5-HT_2A ketanserin and 5-HT₄ GR113808 inhibited 5-HT-induced contractions in a concentration-dependent manner. S. boulardii between 0.05 and 1.5 mg/mL increased the EC₅₀ value of 5-HT suggesting an inhibitory effect against serotonin-induced contraction. Ileum contractions induced by the serotonin agonist 5-HT₁ carboxamidotryptamine or by the serotonin agonist 5-HT₂ alpha-methyl-5-HT were significantly reduced by S. boulardii at 1.5 mg/mL. The yeast did not affect acetylcholine-induced ileum contraction.

S. boulardii CNCM I-745 possesses relaxant properties on the rat ileum involving the inhibition of 5-HT and more specifically 5-HT_1A and 5-HT_2A/2B/2C receptor-induced contractions. These data suggest that the attenuation of 5-HT-induced ileal contractions by S. boulardii represents a probable mechanism of action sustaining its efficacy in patients affected by IBS with diarrhea.