Using microdialysis, receptor autoradiography and in situ hybridization, we examined the effects of fluoxetine alone or with WAY-100635 on: (a) extracellular 5-HT in frontal cortex; and (b) density and sensitivity of 5-HT 1A autoreceptors in rat brain. WAY-100635 (0.3 mg/kg, s.c.) doubled the increase in extracellular 5-HT produced by fluoxetine (3 mg/kg, i.p.) (SSRI) Selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs) are extensively used in the treatment of major depression. The increase in forebrain extracellular 5-HT elicited by SSRIs is limited by a negative feed-back involving raphe autoreceptors . The prevention of this inhibitory mechanism with 5-HT 1A receptor antagonists augments the neurochemical and behavioral effects of SSRIs (Gartside et al. 1995;Artigas et al. 1996;Hashimoto et al. 1997;Mitchell and Redfern 1997;Grignaschi et al. 1998;Trillat et al. 1998). At the clinical level, the ␤ -adrenoceptor/ 5-HT 1A receptor antagonist pindolol accelerates the antidepressant effects of SSRIs in open-label and placebocontrolled trials Blier and Bergeron 1995;Pérez et al. 1997;Zanardi et al. 1997Zanardi et al. , 1998Bordet et al. 1998). However, its effectiveness to potentiate antidepressant response in chronically ill or treatmentresistant patients is still controversial (Maes et al. 1996(Maes et al. , 1999Berman et al. 1997;Moreno et al. 1997;Pérez et al. 1999). Based on this rationale, selective 5-HT 1A receptor antagonists (for use with SSRIs; add-on strategy) and dual action compounds (5-HT reuptake inhibitor ϩ 5-HT 1A antagonist) are being developed for use in the treatment of major depression. The prolonged administration of SSRIs has been reported to desensitize raphe 5-HT 1A autoreceptors, as assessed by single unit recordings and brain microdialysis (Blier and de Montigny 1994;Invernizzi et al. 1994;Arborelius et al. 1995;Le Poul et al. 1995). This reduces the efficacy of the above negative feedback and increases extracellular 5-HT (Bel and Artigas 1993;Invernizzi et al. 1994;Rutter et al. 1994;Arborelius et al. 1996). Other studies, however, have failed to observe such effects even using large doses of SSRIs (Hjorth and Auerbach 1994a;Bosker et al. 1995;Invernizzi et al. 1995).To our knowledge, there are no published reports on the effects of prolonged treatments with combinations of SSRIs and 5-HT 1A receptor antagonists on these experimental paradigms, except in abstract form (Dawson et al. 1998). As with pindolol, future selective 5-HT 1A receptor antagonists would be administered for a limited period of time. Should prolonged blockade of 5-HT 1A receptor result in receptor sensitization, the withdrawal of the antagonist would increase the efficacy of the above negative feed-back and reduce the ability of the SSRI to increase extracellular 5-HT, thus increasing the possibility of a clinical relapse. Since this is crucial for the success of this therapeutic strategy, we examined the effects of two-week treatments with fluoxetine, WAY-100635 and their combination...

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1 Using brain microdialysis, we compared the relative role of 5-hydroxytryptamine (5-HT; serotonin) blockade and somatodendritic 5-HT 1A and/or terminal 5-HT 1B autoreceptor activation in the control of 5-HT output. 2 Fluoxetine (10 mg kg 71 i.p.) doubled the 5-HT output in frontal cortex and dorsal hippocampus. The 5-HT 1A receptor antagonist WAY 100635, (0.3 mg kg 71 s.c.) potentiated the eect of¯uoxetine only in frontal cortex (to *500 % of baseline). 3 Methiothepin (10 mg kg 71 s.c.) further enhanced the 5-HT rise induced by¯uoxetine+WAY 100635, to 835+179% in frontal cortex and 456+24% in dorsal hippocampus. Locally applied, methiothepin potentiated the¯uoxetine-induced 5-HT rise more in the former area. 4 The selective 5-HT 1B receptor antagonist SB-224289 (4 mg kg 71 i.p.) enhanced the eect of uoxetine (10 mg kg 71 i.p.) in both areas. As with methiothepin, SB-224289 (4 mg kg 71 i.p.) further enhanced the 5-HT increase produced by¯uoxetine+WAY 100635 more in frontal cortex (613+134%) than in dorsal hippocampus (353+59%). 5 Locally applied,¯uoxetine (10 ± 300 mM; EC 50 =28 ± 29 mM) and citalopram (1 ± 30 mM; EC 50 =1.0 ± 1.4 mM) increased the 5-HT output two to three times more in frontal cortex than in dorsal hippocampus. 6 These data suggest that the comparable 5-HT increase produced by systemic¯uoxetine in frontal cortex and dorsal hippocampus results from a greater eect of reuptake blockade in frontal cortex that is oset by a greater autoreceptor-mediated inhibition of 5-HT release. As a result, 5-HT autoreceptor antagonists preferentially potentiate the eect of¯uoxetine in frontal cortex.

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VN2222(1-(benzo [b]thiophen-3-yl)-3-[4-(2-methoxiphenyl piperazin-1-yl]propan-1-ol) is a potential antidepressant with high affinity for the serotonin transporter and 5-HT 1A receptors. Locally applied, VN2222 enhanced the extracellular 5-hydroxytryptamine (5-HT) concentration (5-HT ext ) in rat striatum to 780% of baseline whereas its systemic administration (1-10 mg/kg s.c.) reduced 5-HT ext . In the presence of citalopram, 8-OH-DPAT or VN2222 applied in medial prefrontal cortex reduced 5-HT ext . Fluoxetine, VN2222, and 8-OH-DPAT suppressed the firing rate of dorsal raphe 5-HT neurons (ED 50 : 790, 14.9, and 0.8 mg/kg i.v., respectively). These effects were antagonized by WAY 100635. Administration of VN2222 for 2 weeks desensitized 5-HT 1A receptors as assessed by microdialysis and single-unit recordings (ED 50 values for 8-OH-DPAT were 0.45 and 2.34 mg/kg i.v. for controls and rats treated with 6 mg/kg day VN2222). These results show that VN2222 is a mixed 5-HT reuptake inhibitor/5-HT 1A agonist that markedly desensitizes 5-HT 1A autoreceptors. These properties suggest that it may be a clinically effective dual action antidepressant drug.

INTRODUCTION In localized oesophageal cancer (EC), a correct clinical tumor staging is essential in order to offer an optimal treatment, although often challenging. The aim of this work is to assess the accuracy of the diagnostic tests by comparing them with the pathological staging. MATERIAL AND METHODS Retrospective observational study of patients who underwent oesophagectomy for cancer in a referral hospital between January 2003 and September 2019. Those patients who received neoadjuvant treatment were excluded in order to avoid bias from dowstaging effects. The preoperative stage cT and cN as well as the combination of both (cTNM) were compared with the pathological stage of the surgical specimen (pT, pN, pTNM), considered the gold standard. Computed tomography (CT) and endoscopic ultrasound (EUS) were evaluated for cT and cN, while Positron emission tomography (PET/CT) only for cN. Furthermore, the pT stage was correlated with the tumor length described in the oesophagogram (EG). RESULTS Among the 63 patients included, the clinical staging was correct in 16 cases (global accuracy 25.4%), it was overstaged in 21 (33.2%) and understaged in 26 (41.3%). For cT staging, the accuracy of EUS was higher than that of CT (46.6% and 34.9% respectively), specially for early stages. EG tumor length correlated with pT stage (p < 0.05). For cN staging, PET/CT had the highest sensitivity (50.0%) and NPV (75.0%). CONCLUSIONS Despite the multiple diagnostic tools used, the global accuracy of clinical staging in localized EC is still a challenge, with the therapeutic and prognostic implications that this entails.

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