piperidines and flesinoxan

This study investigates the mechanism of action of spadin, a putative fast-acting peptidic antidepressant (AD) and a functional blocker of the K(+) TREK-1 channel, in relation with the medial prefrontal cortex (mPFC)-dorsal raphé (DRN) serotonergic (5-HT) neurons connectivity. Spadin increased 5-HT neuron firing rate by 113%, an augmentation abolished after electrolytic lesion of the mPFC. Among the few receptor subtypes known to modulate TREK-1, the stimulation of 5-HT4 receptors and the blockade of mGluR2/3 ones both activated 5-HT impulse flow, effects also suppressed by mPFC lesion. The combination of spadin with the 5-HT4 agonist RS 67333 paradoxically reduced 5-HT firing, an effect reversed by acutely administering the 5-HT1A agonist flesinoxan. It also had a robust synergetic effect on the expression of Zif268 within the DRN. Together, these results strongly suggest that 5-HT neurons underwent a state of depolarization block, and that the mechanisms underlying the influences exerted by spadin and RS 67333 are additive and independent from each other. In contrast, the mGluR2/3 antagonist LY 341495 occluded the effect of spadin, showing that it likely depends on mPFC TREK-1 channels coupled to mGluR2/3 receptors. These in vivo electrophysiological data were confirmed by in vitro Ca(2+) cell imaging performed in cultured cortical neurons. Altogether, our results indicate that spadin, as a natural compound, constitutes a very good candidate to explore the "glutamatergic path" of fast-acting AD research. In addition, they provide the first evidence of 5-HT depolarization block, showing that the combination of 5-HT activators for strategies of AD augmentation should be performed with extreme caution.

Topics: Amino Acids; Aniline Compounds; Animals; Antidepressive Agents; Calcium; Dorsal Raphe Nucleus; Early Growth Response Protein 1; Excitatory Amino Acid Antagonists; Indoles; Male; Mice, Inbred C57BL; Mice, Knockout; Peptides; Piperazines; Piperidines; Potassium Channels, Tandem Pore Domain; Prefrontal Cortex; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Receptors, Serotonin, 5-HT4; Serotonergic Neurons; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Sulfonamides; Xanthenes

The therapeutic effect of current antidepressant drugs appears after several weeks of treatment and a significant number of patients do not respond to treatment. Here, we report the effects of the multi-modal antidepressant vortioxetine (Lu AA21004), a 5-HT(3) and 5-HT(7) receptor antagonist, 5-HT(1B) receptor partial agonist, 5-HT(1A) receptor agonist and 5-HT transporter (SERT) inhibitor, on rat 5-HT neurotransmission. Using in vivo electrophysiological recordings in the dorsal raphe nucleus of anaesthetized rats, we assessed the acute and subchronic effects of vortioxetine and/or the selective 5-HT(3) receptor agonist, SR57227 or the selective 5-HT(1A) receptor agonist flesinoxan, on 5-HT neuronal firing activity. Using ex-vivo autoradiography, we correlated SERT occupancy and presumed 5-HT firing activity. The selective serotonin reuptake inhibitor, fluoxetine, was used as comparator. Importantly, the recovery of 5-HT neuronal firing was achieved after 1 d with vortioxetine and 14 d with fluoxetine. SR57227 delayed this recovery. In contrast, vortioxetine failed to alter the reducing action of 3 d treatment of flesinoxan. Acute dosing of vortioxetine inhibited neuronal firing activity more potently than fluoxetine. SR57227 prevented the suppressant effect of vortioxetine, but not of fluoxetine. In contrast, flesinoxan failed to modify the suppressant effect of vortioxetine acutely administered. Differently to fluoxetine, vortioxetine suppressed neuronal firing without saturating occupancy at the SERT. Vortioxetine produced a markedly faster recovery of 5-HT neuronal firing than fluoxetine. This is at least partly due to 5-HT(3) receptor antagonism of vortioxetine in association with its reduced SERT occupancy.

Topics: Action Potentials; Animals; Antidepressive Agents; Autoradiography; Drug Administration Schedule; Drug Delivery Systems; Electrolytes; Male; Neurons; Piperazines; Piperidines; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin 5-HT3 Receptor Antagonists; Serotonin Plasma Membrane Transport Proteins; Serotonin Receptor Agonists; Sulfides; Time Factors; Vortioxetine

Desensitization of somatodendritic 5-HT(1A) receptors is involved in the mechanism of action of several antidepressants, but the rapidity of this effect and the amount of agonist stimulation needed are unclear. We evaluated the capacity of the high-efficacy 5-HT(1A) agonist, F13714 (3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone) and of the partial agonist, flesinoxan, to desensitize somatodendritic 5-HT(1A) receptors involved in the control of 5-HT release.. Intracerebral microdialysis in the hippocampus of freely moving rats was used to examine the acute and chronic effects of the two compounds (administered by osmotic pumps for 3, 7 or 14 days) on extracellular 5-HT levels, measured by HPLC with electrochemical detection.. When given acutely, F13714, flesinoxan and the low-efficacy 5-HT(1A) agonist, buspirone, dose-dependently decreased extracellular 5-HT concentrations (ED(50) values: 0.04, 0.77 and 5.6 mg kg(-1), respectively). The selective 5-HT(1A) antagonist WAY100635 inhibited the effects of the three compounds. F13714 (2.5 mg kg(-1) per day for 3, 7 or 14 days and 0.63 mg kg(-1) for 7 days) significantly attenuated the inhibition of 5-HT release induced by buspirone (10 mg kg(-1)). In contrast, flesinoxan (10 mg kg(-1) per day) failed to alter the response to buspirone at any of the treatment durations.. Rat somatodendritic 5-HT(1A) receptors controlling hippocampal 5-HT release were rapidly desensitized by chronic activation with a high-efficacy 5-HT(1A) agonist, but not by chronic activation with a partial agonist. Thus, rapid 5-HT(1A) autoreceptor desensitization by high-efficacy agonists may accelerate the onset of the therapeutic effects of antidepressants.

Topics: Aminopyridines; Animals; Buspirone; Hippocampus; Male; Microdialysis; Piperazines; Piperidines; Protein Binding; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists

The serotonergic system is involved in the modulation of prepulse inhibition (PPI) and habituation of startle, which are deficient in schizophrenia patients. PPI is the reduction in startle amplitude that occurs when a weak "prepulse" precedes a startling stimulus by 30-500 msec. The roles of 5-HT(1A) and 5-HT(1B) receptors in modulating PPI and habituation were examined using wild-type (WT), 5-HT(1A) knockout (1AKO), and 5-HT(1B) knockout (1BKO) mice. The 5-HT(1A/1B) agonist RU24969 reduced PPI and habituation in WT and 1AKO, but not 1BKO mice, whereas the 5-HT(1A) agonist 8-OH-DPAT increased PPI in WT and 1BKO, but not in 1AKO mice. Similarly, the selective 5-HT(1B) agonist anpirtoline reduced PPI in WT, but not in 1BKO mice. In experiments using intact 129Sv mice, the 5-HT(1A) agonist flesinoxan increased PPI while anpirtoline decreased PPI and habituation. Findings suggest that 5-HT(1B) receptor activation decreases PPI and habituation, and 5-HT(1A) receptor activation increases PPI in mice.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Brain; Female; Habituation, Psychophysiologic; Indoles; Mice; Mice, Knockout; Neural Inhibition; Piperazines; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Reflex, Startle; Serotonin Receptor Agonists

The cardiovascular response to flesinoxan and 8-OH-DPAT (8-hydroxy-2-(di-N-propylamino)tetralin), 5-HT1A receptor agonists, has been investigated in anaesthetized Wistar rats and spontaneously hypertensive rats (SHR) and in conscious SHR. Flesinoxan and 8-OH-DPAT potently lowered blood pressure and heart rate in these models. In conscious SHR, atropine reversed the bradycardia induced by flesinoxan partially and that induced by 8-OH-DPAT completely. In pithed rats with vasopressin-raised blood pressure, neither flesinoxan nor 8-OH-DPAT lowered blood pressure or heart rate. Intracisternal administration of either flesinoxan or 8-OH-DPAT was less efficacious than intravenous administration. The cardiovascular responses to flesinoxan and 8-OH-DPAT in the anaesthetized Wistar were inhibited by the putative 5-HT1A antagonists methiothepin, buspirone, spiroxatrine and 8-MeO-C1EPAT (8-methoxy-2-(N-2-cholroethyl-N-n-propylamino)tetralin). 8-MeO-C1EPAT appeared to be the most suitable antagonist in this model. The 5-HT1C, antagonist ritanserin or the 5-HT3 antagonist GR 38032F had no effect on the responses to flesinoxan or 8-OH-DPAT. In conscious SHR however, 8-MeO-C1EPAT did not antagonize these cardiovascular responses. This study confirms the involvement of central 5-HT1A receptors in the cardiovascular effects of flesinoxan and 8-OH-DPAT.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Anesthesia; Animals; Antihypertensive Agents; Atropine; Blood Pressure; Decerebrate State; Heart Rate; Hemodynamics; Imidazoles; In Vitro Techniques; Male; Naphthalenes; Ondansetron; Piperazines; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Receptors, Serotonin; Ritanserin; Serotonin Antagonists; Tetrahydronaphthalenes