Effects of chronic paroxetine treatment on dialysate serotonin in 5-HT1B receptor knockout mice

Abstract The role of serotonin (5-HT) 1B receptors in the mechanism of action of selective serotonin re-uptake inhibitors (SSRI) was studied by using intracerebral in vivo microdialysis in conscious, freely moving wild-type and 5-HT 1B receptor knockout (KO 5-HT 1B ) mice in order to compare the effects of chronic administration of paroxetine via osmotic minipumps (1 mg per kg per day for 14 days) on extracellular 5-HT levels ([5-HT]ext) in the medial prefrontal cortex and ventral hippocampus. Basal ext values in the medial prefrontal cortex and ventral hippocampus, 20 h after removing the minipump, were not altered by chronic paroxetine treatment in both genotypes. On day 15, in the ventral hippocampus, an acute paroxetine challenge (1 mg/kg i.p.) induced a larger increase in [5-HT]ext in saline-pretreated mutant than in wild-type mice. This difference between the two genotypes in the effect of the paroxetine challenge persisted following chronic paroxetine treatment. Conversely, in the medial prefrontal cortex, the paroxetine challenge increased [5-HT]ext similarly in saline-pretreated mice of both genotypes. Such a challenge produced a further increase in cortical [5-HT]ext compared with that in salinepretreated groups of both genotypes, but no differences were found between genotypes following chronic treatment. To avoid the interaction with raphe 5-HT 1A autoreceptors, 1 lM paroxetine was perfused locally through the dialysis probe implanted in the ventral hippocampus; similar increases in hippocampal [5-HT]ext were found in acutely or chronically treated wild-type mice. Systemic administration of the mixed 5-HT 1B/1D receptor antagonist GR 127935 (4 mg/kg) in chronically treated wildtype mice potentiated the effect of a paroxetine challenge dose on [5-HT]ext in the ventral hippocampus, whereas systemic administration of the selective 5-HT 1A receptor antagonist WAY 100635 did not. By using the zero net flux method of quantitative microdialysis in the medial prefrontal cortex and ventral hippocampus of wild-type and KO 5-HT 1B mice, we found that basal [5-HT]ext and the extraction fraction of 5-HT were similar in the medial prefrontal cortex and ventral hippocampus of both genotypes, suggesting that no compensatory response to the constitutive deletion of the 5-HT 1B receptor involving changes in 5-HT uptake capacity occurred in vivo. As steady-state brain concentrations of paroxetine at day 14 were similar in both genotypes, it is unlikely that differences in the effects of a paroxetine challenge on hippocampal [5-HT]ext are due to alterations of the drug's pharmacokinetic properties in mutants. These data suggest that there are differences between the ventral hippocampus and medial prefrontal cortex in activation of terminal 5-HT 1B autoreceptors and their role in regulating dialysate 5-HT levels. These presynaptic receptors retain their capacity to limit 5-HT release mainly in the ventral hippocampus following chronic paroxetine treatment in mice. Keywords: antidepressant drug, 5-hydroxytryptamine 1B autoreceptor, intracerebral microdialysis, knockout mice, paroxetine, selective serotonin re-uptake inhibitor

[Cervical screening: toward a new paradigm?]

International audienceOBJECTIVES: Analysis of the trials which compare the virologic testing (HPV testing) and the cytology in the cervical screening. MATERIAL AND METHODS: The MedLine database was consulted using the Keywords: "cervical screening", "pap smear", "liquid based cytology", "HPV testing", "adults", "adolescents", "cervical intraepithelial neoplasia (CIN)", "uterine cervix cancer". Articles were selected according their concern about the debate of the uterine cervix cancer screening in France. RESULTS: The HPV testing seems interesting allowing a decreasing delay in the diagnosis of CIN (more diagnosis of CIN2+ in the first round and less during the second one). But, when the two rounds are added, the number of CIN2+ are identical in the two arms (cytology and HPV testing) in all the trials (except the Italian NTCC trial). A negative HPV testing protects the women much longer than cytology can do: a delay of five years between two rounds seems ideal. The HPV testing alone increases the detection rate of cervical lesions, which could regress spontaneously and may induce an overtreatment, especially in the youngest population: a triage is necessary and the cytology appears to be the best way to select the candidates for colposcopy in case of positive HPV testing and cytology. The HPV infection presents some particularities in adolescent females: for this reason, the HPV testing should not be used in this special population. In vaccinated women, a consensus for the screening is necessary. CONCLUSION: The health care providers in France have to understand the characteristics of the HPV testing: its advantages compared to the cytologic screening are only evident in case of an organization of the screening in France and even in Europe