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Presentación De Powerpoint P.269 THE AMPAKINE CX717 HAS A RAPID, BUT SHORT-LASTING ANTIDEPRESSANT-LIKE ACTIVITY IN THE RAT Marta Gordillo-Salas1, Jun Ren2, John Greer2 & Albert Adell1,3 1 Institute of Biomedicine & Biotechnology of Cantabria, IBBTEC (CSIC-UC), Santander, Spain. 2 University of Alberta, Department of Physiology, Edmonton, Canada. 3 CIBERSAM, Biomedical Research Networking Center Consortium, Mental Health, Santander, Spain. INTRODUCTION METHODS Major depressive disorder (MDD) is the most prevalent of psychiatric disorders. Currently available antidepressant drugs Animals: Male Sprague Dawley rats (Envigo) weighing 280 350g. increase the availability of certain neurotransmitters in the brain. Briefly, it has been proposed that increasing the activity – – Drug administration: CX717 (20 mg/kg) was dissolved in 33% 2-hydroxypropyl- -cyclodextrine (HPCD, Sigma-Aldrich) and of serotonin, noradrenaline and dopamine might help lessen depression and anxiety. However, these medications can β injected IP. This solution was further diluted to 300 µM in artificial CSF for intracortical infusion through dialysis probes take up to several weeks to be effective. In recent years, new approaches have emerged to treat MDD. Among them, implanted bilaterally in the medial prefrontal cortex (mPFC; AP: +3.2, ML: 0.5 and DV: -5.4). ketamine, scopolamine and deep brain stimulation (DBS) have exhibited fast and sustained therapeutic action. ± Forced swimming test (FST): Immobility, climbing and swimming were measured. Interestingly, these novel therapies require the stimulation of AMPA glutamate receptors to exert their antidepressant In vivo microdialysis: Extracellular levels of serotonin (5-HT), noradrenaline (NA), dopamine (DA) and glutamate (Glu) were effects. Consequently, it has been proposed that ampakines may be associated with mood enhancing properties. determined using an Alexys ® Analyzer (Antec, The Hetherlands). Western blotting: After the administration of 20 mg/kg of CX717, animals were killed by decapitation, their brains removed AIM OF THE STUDY from the skulls, and mPFCs dissected out on ice and rapidly stored at −80 °C. The sources and dilution of primary antibodies The aim of the present work was to investigate the antidepressant-like effects of the ampakine CX717 in the forced swim used were: rabbit anti-BDNF (1:250), rabbit anti-GluA1 (1:700), mouse anti-GFAP (1:1000), rabbit anti-EAAT1 (1:500) test (FST), which is one of the most commonly used assays for the study of depressive-like behavior in rodents. The changes Statistical analysis: Student t-test or two-way ANOVA followed by Newman-Keuls post-hoc test. Data expressed as mean ± SEM. in intracellular signaling pathways and cortical transmitter release over time were also examined. RESULTS T e s t T e s t + 1 T e s t + 7 5 0 5 0 5 0 4 0 4 0 4 0 * * 3 0 3 0 3 0 2 0 * 2 0 * 2 0 Counts/5 min Counts/5 min Counts/5 min * 1 0 1 0 1 0 0 0 0 IMMOBILITY CLIMBING SWIMMING IMMOBILITY CLIMBING SWIMMING IMMOBILITY CLIMBING SWIMMING The administration of 20 mg/kg CX717 elicits antidepressant-like effects (measured as reduction of immobility) that last up to 24 h (Test +1), but not seven days (Test +7) later. *P < 0.05, two-tailed Student’s t-test. Control - Left (7) Control - Left (6) 2 0 0 2 0 0 CX717 (300 µM) - Left (7) Vehicle (8) Vehicle (8) CX717 (300 µM) - Left (7) Control - Right (7) Control - Right (8) CX717 (20 mg/kg) (8) CX717 (20 mg/kg) (8) CX717 (300 µM) - Right (6) CX717 (300 µM) - Right (7) 1 5 0 1 5 0 8 0 0 0 2 5 0 2 0 0 6 0 0 0 1 0 0 1 0 0 1 5 0 * 4 0 0 0 1 0 0 * 5 0 D o p a m in e 5 0 2 0 0 0 * D o p a m in e Noradrenaline (% of baseline) (% of baseline) * 5 0 Noradrenaline (% of baseline) (% of baseline) 0 0 0 0 -1 0 1 2 -1 0 1 2 -1 0 1 2 -1 0 1 2 T im e (h ) T im e (h ) T im e (h ) T im e (h ) Control - Left (5) Control - Left (5) 2 0 0 CX717 (300 µM) - Left (8) CX717 (300 µM) - Left (5) Vehicle (7) 2 0 0 3 0 0 Control - Right (8) 2 0 0 Control - Right (7) Vehicle (7) CX717 (300 µM) - Right (7) CX717 (20 mg/kg) (6) CX717 (300 µM) - Right (7) 1 5 0 CX717 (20 mg/kg) (9) 1 5 0 1 5 0 2 0 0 1 0 0 1 0 0 1 0 0 * 1 0 0 * G lu ta m a te 5 0 (% of baseline) 5 0 G lu ta m a te 5 0 5-HT (% of baseline)0 0 (% of baseline) -1 0 1 2 -1 0 1 2 5-HT (% of0 baseline) 0 T im e (h ) T im e (h ) -1 0 1 2 -1 0 1 2 T im e (h ) T im e (h ) The local infusion of 300 µM CX717 bilaterally in the mPFC (black bar) increases the extracellular concentration of monoamines without altering that of glutamate. *P < 0.05, Newman-Keul’s test after significant repeated measures The administration of 20 mg/kg CX717 does not alter extracellular concentrations of monoamines and glutamate. ANOVA. BDNF p 1 1 G lu A 1 G F A P EAAT1 2 0 0 2 0 0 2 0 0 2 0 0 2 0 0 * * * * 1 5 0 1 5 0 * 1 5 0 1 5 0 * 1 5 0 * * 1 0 0 1 0 0 1 0 0 1 0 0 1 0 0 % C h a n g e % C h a n g e % C h a n g e % C h a n g e % C h a n g e 5 0 5 0 5 0 5 0 5 0 (normalized to control) (normalized to control) (normalized to control) (normalized to control) 0 0 0 (normalized to0 control) 0 1 7 1 h v e h 2 h v e h 6 h v e h 1 h v e h 2 h v e h 6 h v e h 1 h v e h 2 h v e h 6 h v e h 1 h C X 7 1 7 2 h C X 7 1 7 6 h C X 7 1 7 1 h C X 7 1 7 2 h C X 7 1 7 6 h C X 7 1 7 1 h v e h 2 h v e h 6 h v e h 1 h v e h 2 h v e h 6 h v e h 1 h C X 7 1 7 2 h C X 7 1 7 6 h C X 7 1 7 3 0 m in v e h 3 0 m in v e h 3 0 m in v e h 1 h C X 7 1 7 2 h C X 7 1 7 6 h C X 7 1 7 1 h C X 7 1 7 2 h C X 7 1 7 6 h C X 7 30 min CX717 30 min CX717 3 0 m in v e h 3 0 m in v e h 30 min CX717 30 min CX717 30 min CX717 The intraperitoneal administration of 20 mg/kg CX717 elicits rapid increases of BDNF The IP administration of 20 mg/kg CX717 The intraperitoneal administration of 20 mg/kg CX717 elicits more delayed increases of the glia markers GFAP and EAAT1 in the mPFC. *P < 0.05, two-tailed t-test. and p11 in the mPFC. *P < 0.05, two-tailed Student’s t-test. does not change the protein level of GluA1 Student’s in the mPFC. C o n tro l V e h + S h a m C o n tro l V e h + D B S V e h + S h a m * T e s t CX717 + Sham V e h + (S )-AMPA CONCLUSIONS CX717 + DBS T e s t CX717 + Sham 6 0 * C X 7 1 7 + (S )-AMPA * 6 0 * * * * * ▪ CX717 has a rapid, but short-lasting, antidepressant-like activity. 4 0 * * * 4 0 * * * * ** * * ▪ CX717 does not potentiate the antidepressant response of DBS or intra-cortical * 2 0 2 0 Counts/5 min infusion of (S)-AMPA, most likely because the effects of such treatments are Counts/5 min already maximal. 0 0 IMMOBILITY CLIMBING SWIMMING IMMOBILITY CLIMBING SWIMMING ▪ The increase in prefrontal monoamines caused by CX717 is only observed after T e s t + 1 Test +1 local infusion of the drug in the mPFC. It is possible that a sustained 6 0 6 0 * * * ** * administration of the drug is needed to alter prefrontal monoamine release. ** 4 0 4 0 ▪ The rapid antidepressant-like effects of CX717 are likely caused by a fast release * * ** of BDNF and synthesis of p11. 2 0 2 0 Counts/5 min Counts/5 min ▪ A delayed increase in glial markers (GFAP and EAAT1) might also contribute to 0 0 IMMOBILITY CLIMBING SWIMMING IMMOBILITY CLIMBING SWIMMING these effects. * T e s t + 7 Test +7 6 0 * 6 0 * * Funding: Supported by the Instituto de Salud Carlos III, Subdirección General del Evaluación y Fomento de la 4 0 * 4 0 * * * Investigación (FIS Grant PI16/00217) that was co-funded by the European Regional Development Fund A way to build * * Europe. Funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud 2 0 2 0 Counts/5 min Carlos III is also acknowledged.
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