1D selective agonists – eletriptan and rizatriptan on pain reactions

P.1.g. Basic and clinical neuroscience − Neuropharmacology cavity in three stereotaxic coordinates. The coordinates were anterior-posterior (AP) −0.9 mm relative to the bregma, mediallateral +1.5 mm relative to the midline, and dorsal-ventral (DV) 4.0 mm relative to the skull surface. MDMA (30 and 100 mg) or dyes (fast green and fluorescence Dii) at an infusion rate of 0.2 ml/min for 10 min were delivered by direct intraventricular injection. Meanwhile, microdialysis cannulae were implanted for measuring 5-HT changes within the hypothalamus (AP −1.1, ML 0.9 and DV 9.0), frontal cortex (AP 3.3, ML 0.7 and DV 4.5), and nucleus raphe magnus (AP −12.0, ML 0.0 and DV 10.5). MDMA was also given by intraperitoneal injection at 2 mg/kg. In some cases, MDMA was reversely infused via microdialysis probes while 5-HT was determined with the same probes. Results: Intracerebroventricular injection of 30 mg and 100 mg MDMA caused an increase in hypothalamic 5-HT by 10-fold and 30-fold, respectively. This level was higher than the threshold to induce a toxidrome [3]. A similar increase was also found in raphe 5-HT. However, cortical 5-HT was only a 5−9 fold increase, a level below the threshold to induce a toxidrome. Moreover, microscopic images of the dyes (fast green and fluorescence Dii) injected into the lateral ventricular cavity revealed that the dyes were almost exclusively found within the ventricle cavity and nearby tissues. However, they were not found in the cortical regions such as the frontal cortex. Lastly, we tested whether the small effects on cortical 5HT were attributed to a lower response of cortical neurons to MDMA. We examined this hypothesis using reverse microdialysis. We found that 10mM and 30mM MDMA infused into the frontal cortex caused 20- and 40-fold, increases in 5HT respectively, which is similar to those in the hypothalamus and raphe. Conclusion: Contrary to the systemic effects of MDMA in humans, intracerebroventricular injection cannot homogenously deliver MDMA to all regions important for inducing the toxidrome. As a result, extracellular 5HT in the brain is generally below the threshold to induce the toxidrome. The failure of ICV delivery may be due to the cerebrospinal fluid (CSF)-brain and CSF-blood barriers that prohibit distribution of MDMA into the brain tissues, particularly to cortical regions. References [1] Molliver, M.E., O’Hearn, E., Battaglia, G. & De Souza, E.B. (1986). Direct intracerebral administration of MDA and MDMA does not produce serotonin neurotoxicity. Soc. Neurosci. Astr 12, 1234. [2] Monks, T.J., Jones, D.C., Bai, F. & Lau, S.S. (2004). The role of metabolism in 3,4-(+)-methylenedioxyamphetamine and 3,4-(+)methylenedioxymethamphetamine (ecstasy) toxicity. Ther Drug Monit 26, 132−6. [3] Zhang, G., Krishnamoorthy, S., Ma, Z., Vukovich, N.P., Huang, X. & Tao, R. (2009). Assessment of 5-hydroxytryptamine efflux in rat brain during a mild, moderate and severe serotonin-toxicity syndrome. Eur J Pharmacol 615, 66−75.

P.1.g.017 Assessment of cognitive impairments in a rat depression model using the touchscreen operant platform

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stress (CMS) has been shown to be a valid rodent model of depression as it induces anhedonia, one of the core symptoms of MDD. Anhedonia is defined as a loss of interest in activities that are usually perceived as pleasurable. Impaired cognition displays another symptom observed in depressed patients which has not been investigated in the CMS model, yet. Objectives: The overall goal was to optimize an animal model of depression which also enables the assessment of changes in cognitive functions in the course of a chronic mild stress (CMS) paradigm and following antidepressant drug treatment. The objectives were: (1) to investigate the eligibility of Long Evans (LE) rats exposed to the CMS paradigm as a model of depression, (2) to identify if the CMS paradigm impairs cognitive performance in LE rats, and (3) to determine if Wistar or LE rat strains are more suitable for cognitive assessment with the touchscreen operant platform 4) to assess procognitive effects of escitalopram in the CMS model. Methods: Sixteen LE rats were exposed to the CMS paradigm testing susceptibility of this strain towards stress exposure. The sucrose consumption test (SCT) was used as readout on the anhedonic-like state in rats exposed to CMS. Additionally, social interaction, y-maze, elevated plus-maze and open field were used for behavioral phenotyping of stressed vs. LE controls. Subsequently, stress exposed LE rats (N = 16) and controls (N = 12) as well as Wistar controls (N = 12) were tested in the Bussey-Saskida touchscreen operant platform. Pairwise discrimination including reversal task and retention were used to assess visual discrimination, stimulus-reward association learning, preservation and memory consolidation. Results: Preliminary data revealed a significant difference of cognitive performance in the touchscreen tasks between LE and Wistar control rats. In the CMS paradigm, LE rats proved to be equally susceptible to stress exposure as Wistar rats shown with the sucrose test. Conclusion: LE rats are more suitable for testing in the touchscreen operant platform by demonstrating a better performance level. Furthermore, rats of the LE strain react similar to the CMS paradigm as Wistar rats and seem therefore suitable for this stress model. Since no differences were found between LE stress and control groups, we cannot conclude that CMS affects cognitive function, such as cognitive flexibility, in this rather simple and non-hippocampus dependent task. This could be due to the fact that the LE CMS group was heterogeneous by consisting of anhedonic-like but also resilient and non-assignable rats. A comparison of a pure anhedonic-like group with a control group may lead to a clear difference in regard to cognitive performance in particular in more advanced touchscreen tasks. In summary, Long Evans rats are susceptible to the CMS paradigm and perform well in simple cognitive tasks and thus appear to be a good model for investigating cognitive function in depression.

O. Wiborg1 ° , L. Martis1 , S. Krog1 , T. Tran1 , C. Brison1 , A. Møller1 1 Aarhus University, Clinical Medicine, Risskov N, Denmark

P.1.g.018 Study of the effects of serotonin 1B/1D selective agonists − eletriptan and rizatriptan on pain reactions

Background: Major depressive disorder (MDD) is one of the leading causes for disability worldwide. Therefore, development and verification of antidepressant treatment strategies are vital to optimize therapy for patients and, hence, well established and validated MDD animal models are crucial. Chronic mild

K. Saracheva1 ° , D. Getova1 1 Medical University, Pharmacology and Clinical Pharmacology, Plovdiv, Bulgaria Purpose: Serotonin (5-hydroxtryptamine, 5-HT) is an important molecule in pain processing and modulation. Whether 5-HT has

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an analgesic or hyperalgesic action depends on the cell type and type of receptor it acts on [1]. Triptans still represent the most specific pharmacological treatment for neurovascular headaches, such as migraine and cluster headache. Of key relevance to the mechanism of action of triptans in migraine is their agonist activity at serotonin 5-HT1B/1D/1F receptors [2,3]. Nowadays 2 generations of triptans are introduced in clinical practice such as eletriptan and rizatriptan. The present experimental study was designed with the aim to clarify whether the analgesic effect of triptans is specifically restricted to a migraine-like kind of pain or can be demonstrated also in other kinds of pain, compared with the effects of dihydroergotamine (DHE). Methods: Male Wistar rats were used (8 groups, n = 8) treated s.c. with: 1. Control (saline); 2. Metamizol 150 mg/kg; 3. Eletriptan 0.1 mg/kg; 4. Eletriptan 0.5 mg/kg; 5. Rizatriptan 0.4 mg/kg; 6. Rizatriptan 0.8 mg/kg; 7. DHE 0.05 mg/kg; 8. DHE 0.1 mg/kg. Three nociceptive tests were used: hot plate, tail flick and analgesimeter. Criterion for hot-plate and tail flick test was the latency of reaction to thermal stimulus in seconds, for analgesimeter was the paw pressure reaction. The statistic evaluation was done by ANOVA by calculating mean and SEM for each group. The comparison between groups was done. Results: In analgesimeter test the rats treated with eletriptan in dose 0.5 mg/kg showed significant increase of the paw reaction compared with “zero time” of the same group and the group treated with metamizol. The group treated with rizatriptan in dose 0.8 mg/kg increased significantly the paw reaction compared with the control group and the group treated with metamizol of the 60th minute. Both doses of DHE do not change this paw reaction. In hot-plate test the rats treated with eletriptan in dose 0.5 mg/kg increased significantly the latency reaction of 60th and 120th minute compared to the control group and the group treated with metamizol. DHE in the higher dose used increased significantly the latency of reactions on 60th, 120th and 180th minute compared to the control group and the group treated with metamizol. In tail flick test both triptans increased significantly the latency reaction of the 60th, 120th, and 180th minute compared to the control group of the same hour. DHE in both doses also increased significantly the latency of reaction on 60th, 120th and 180th minute. Conclusion: Our results suggest that local peripheral activation of 5HT1 receptors localized on sensory afferents leads to antinociception in the used test in rats. Hence, the use of subtype selective 5-HT1 receptor agonists and we make a conclusion that triptans possess some antinociceptive effect on the test used [4]. DHE via its selective venous constrictor effects probably exert antinociceptive effects in periphery by changing blood circulation in extremities. References [1] Claudia Sommer. Is Serotonin Hyperalgesic or Analgesic? Current Pain and Headache Reports 2006, 10: 101–106 [2] Alessandra Ottani, Eleonora Ferraris, Daniela Giuliani et al. Effect of sumatriptan in different models of pain in rats. European Journal of Pharmacology 497 (2004) 181–186. [3] Beatriz God´ınez-Chaparro, Francisco J. L´opez-Santill´an, Carlos F. Arg¨uelles et al. Role of 5-HT1B/1D receptors in the reduction of formalin-induced nociception and secondary allodynia/hyperalgesia produced by antimigraine drugs in rats. Life Sciences 92 (2013) 1046– 1054 [4] V. Granados Soto, C.F. Arg¨uelles, H.I. Rocha-Gonz´alez et al. The role of peripheral 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F serotonergic receptors in the reduction of nociception in rats. Neuroscience Volume 165, Issue 2, 20 January 2010, Pages 561–568

P.1.g.019 Antidepressant- and anxiolytic-like properties of S 47445, a novel positive allosteric modulator of AMPA type glutamate receptors S. Bretin1 ° , D. David2 , A. Diaz Martinez3 , A. Gardier2 , J.P. Guilloux2 , R. Linge Mendez3 , S. Maccari4 , J. Mairesse4 , I. Mendez David2 , M. Papp5 , A. Pazos Carro3 , E. Mocaer1 1 Institut de Recherches Internationales Servier, Pole Innovation Th´erapeutique Neuropsychiatrie, Suresnes cedex, France; 2 Universit´ e Paris-Sud − Facult´e de M´edecine, INSERM UMR-S 1178, Chatenay-Malabry, France; 3 University of Cantabria − Instituto de Biomedicina y Biotechnologia de Cantabria IBBTEC, Servicio de Estabulacion y Experimentacion Animal SEEA, Santander − Cantabria, Spain; 4 UMR CNRS/USTL 8576 Structural and Functional Glycobiology Unit − North University of Lille, Neural Plasticity team, Villeneuve d’Ascq, France; 5 Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland Purpose of the study: S 47445 is a potentiator of glutamate AMPA-type receptors, possessing procognitive, neurotrophic properties and enhancing synaptic plasticity [1−4]. In vivo S 47445 antidepressant and anxiolytic-like properties were studied in four different rodent models. Methods: – Adult male C57Bl/6NTac mice were treated for 8 weeks with corticosterone (CORT, 35 mg/ml) and received p.o. either S 47445 or fluoxetine during the last 34 days of corticosterone treatment. Animals were then tested in behavioural paradigms predictive of anxiolytic/antidepressant-like activity (the elevated plus maze (EPM), open field (OF), splash test (ST), forced swim test (FST) and fur coat state was monitored weekly. Hippocampal neurogenesis (proliferation survival and maturation) was assessed using immunohistochemistry. – Pregnant Sprague-Dawley rats were submitted to Prenatal Restraint Stress (PRS) procedure from day 11 of pregnancy until delivery and received i.p. S 47445 or fluoxetine for 4 weeks. Animals were then tested in the EPM, ST, FST and the darklight box test. – Male Wistar rats were submitted for 8 weeks to chronic mild stress (CMS) procedure and received either S 47445 p.o. or imipramine or venlafaxine for 5 weeks by i.p. The amount of sucrose intake was measured weekly. – C57/BL6J male mice were submitted to bilateral olfactory bulbectomy (OB) and received i.p. S 47445 or fluoxetine for 4 weeks with assessment of locomotor activity. Treatments were given at 0.3 (CORT and CMS only), 1, 3, 10 mg/kg for S 47445−11; fluoxetine at 18 mg/kg (CORT and OB) or 5 mg/kg (PRS); imipramine and venlafaxine at 10 mg/kg. Results: S 47445 reversed corticosterone-induced depressivelike state by increasing grooming duration at 3 and 10 mg/kg, reversing coat state’s deterioration at all tested doses and by decreasing the immobility duration in TST and FST at 3 and 10 mg/kg, respectively. Moreover, S 47445 at 1 mg/kg and 1, 3, 10 mg/kg significantly reversed the anxiety phenotype observed in OF and EPM, respectively. Similar effects were observed with fluoxetine for all these tests, except the absence of effect in coat state. S 47445 also demonstrated significant neurogenic effects on proliferation, survival and maturation of hippocampal newborn neurons mainly at 3 and 10 mg/kg. S 47445 reversed the PRS grooming decrease (1 and 10 mg/kg) and immobility duration in FST (1 mg/kg), the latency to visit