The selective 5-HT6 receptor antagonist SLV has putative cognitive- and social interaction enhancing properties in rodent models of cognitive impairment.

In the present study, our aim was to investigate whether the novel highly selective 5-hydroxytryptamine6 (5-HT6) receptor antagonist SLV can ameliorate impairments in cognition and social interaction with potential relevance for both schizophrenia and Alzheimer's disease (AD). SLV sub-chronically - treated Wistar rats reared in isolation showed significantly enhanced prepulse inhibition (PPI) and object recognition performance when compared to vehicle - treated rats. In the isolated rats, also a significant reduction in expression of hippocampal neural cell adhesion molecule polysialylation (NCAM-PSA) was found which was ameliorated following treatment with SLV (30mg/kg). The social engagement deficit in rats exposed in utero (on gestational day 12.5) to valproic acid (VPA) was reversed by treatment with SLV (30mg/kg). SLV (20 and 30mg/kg, p.o.) fully reversed MK-801 - induced deficits in the ORT and also scopolamine - induced deficits in both the Object Recognition Task (ORT) and Object Location Task (OLT) in Wistar rats. In addition, a combination of sub-optimal doses of SLV and donepezil attenuated scopolamine-induced ORT deficits. Furthermore, SLV (10mg/kg, p.o.) reversed spontaneous alternation deficits in the T-maze induced by MK-801 administration in Swiss mice and in aged C57Bl/6J mice. SLV additionally improved T-Maze spatial learning and passive avoidance learning in Sprague-Dawley rats with amyoid-beta (Aß) injections into the hippocampus. In contrast, no benefits were found with SLV or the tested reference compounds (donepezil and RVT-101) on cognitive performance of 12months old Tg2576 mice. Also, in the social recognition task, an absence of cognitive enhancing properties was observed with SLV on "normal forgetting" in Wistar rats. Finally, analysis of spontaneous inhibitory postsynaptic currents (sIPSCs) frequency recorded from pyramidal cells revealed a reduction in the presence of 1µM of SLV. In conclusion, SLV was investigated in several rodent animal models and found to be effective at a least effective dose (LED) of 20mg/kg and 10mg/kg (p.o.) in the rat and the mouse, respectively.

In vivo/ex vivo and behavioural study on central effects of 5-HT1B/1D and 5-HT1A antagonists in guinea pigs.

Serotonin 5-HT1A and 5-HT1B/1D receptors control serotonin (5-HT) release and are targets for the pharmacological treatment of psychiatric disorders. We investigated effects of the 5-HT1B/1D antagonist GR127935, the 5-HT1A antagonist WAY 100635 and a combination of both in guinea pigs on the behaviour in the forced swimming test and on extracellular 5-HT in the hippocampus and the prefrontal cortex using in vivo microdialysis. Tissue content of 5-HT, 5-HIAA and 5-HT turnover (ratio 5-HIAA/5-HT) were determined in a sample containing i) the median and dorsal raphe nuclei, ii) the frontal cortex, or iii) the ventral hippocampus ex vivo. BEHAVIOUR: Administration of WAY 100635 (0.3-3.0 mg/kg, i.p.) or GR127935 (1.0-10.0 mg/kg, i.p.) or the combination of both delayed immobility in the forced swim test. MICRODIALYSIS: Systemic administration of WAY 100635 (1 mg/kg i.p.), perfusion with GR127935 (10 microM perfused into the frontal cortex) in the medial prefrontal cortex or the combination of both treatments had no significant effect on extracellular 5-HT. 5-HT TISSUE CONTENT AND 5-HT TURNOVER IN THE TISSUE: Compared to controls, WAY 100635, GR127935 and the combination thereof, decreased cortical 5-HT (-30%), increased 5-HIAA and consequently 5-HT turnover in the cortex threefold and the raphe nuclei twofold. WAY 100635 decreased 5-HT in the hippocampus (-40%), too. WAY 100635 and GR127935 and their combination increased hippocampal 5-HIAA and 5-HT turnover twofold, compared to controls. The results suggest that both 5-HT1 antagonists have subtle effects on 5-HT function under resting conditions; combined treatment has no superior effects compared to solitary treatment.

Amplitude dependency of regional chest wall resistance and elastance at normal breathing frequencies.

Current methods for measurement of chest wall properties assume that resistance (R) and elastance (E) are independent of the volume breathed. In six healthy subjects relaxed at functional residual capacity, we measured total and regional R and E of the chest wall within the range of normal breathing frequencies (0.2 to 0.6 Hz) and tidal volumes (250 to 750 ml), using volume forcing at the mouth as previously described. With these methods, esophageal and gastric pressures are compared with surface displacements measured with inductance plethysmographic belts to calculate R and E of rib cage and diaphragm-abdomen "pathways." Rib cage R and E were 25 to 30% higher than that of the total chest wall at each frequency and volume, whereas diaphragm-abdomen R and E were at least five times higher. R of the chest wall and each of the pathways decreased by about 70% with increasing frequency and by about 30% with increasing tidal volume. E of the chest wall and each of the pathways also decreased by about 30% with increasing tidal volume but was independent of frequency in this range. These results are consistent with nonlinear, viscoplastic models presented elsewhere. We conclude that: (1) despite the great structural differences between the rib cage and diaphragm-abdomen, each exhibits nonlinear behavior similar to that of the total chest wall; (2) chest wall R and E depend importantly on frequency and tidal volume.