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Adrian Newmantancredi - One of the best experts on this subject based on the ideXlab platform.
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activity of serotonin 5 ht1a receptor biased Agonists in rat anxiolytic and antidepressant like properties
ACS Chemical Neuroscience, 2018Co-Authors: Magdalena Jastrzebskawiesek, Mark A Varney, Anna Partyka, Joanna Rychtyk, Marcin Kolaczkowski, Joanna śniecikowska, Anna Wesolowska, Adrian NewmantancrediAbstract:Although serotonin 5-HT1A receptors constitute attractive therapeutic targets, there is a lack of potential clinical candidates that have a high degree of selectivity and full agonist efficacy. Recently, novel 5-HT1A receptor "biased Agonists" F15599 (also known as NLX-101) and F13714 have been reported that exhibit distinctive properties for in vitro signaling, neurochemical, electrophysiological effects, and in brain imaging. The present study characterized their effects in rat models of anxiety (elevated plus-maze, EPM, and Vogel tests), in depressive-like behavior (forced swim test), and on the induction of the three serotonergic behaviors (forepaw treading, flat body posture, and lower lip retraction). The prototypical 5-HT1A receptor ligands (±)8-OH-DPAT and buspirone were tested as comparators. In the elevated plus-maze, F15599, F13714, and (±)8-OH-DPAT dose-dependently increased the amount and percentage of time spent in the open arms with minimal effective doses (MED) of 5 mg/kg p.o., 2.5 mg/kg p.o. and 1.25 mg/kg s.c., respectively. The effects of the three Agonists were abolished by pretreatment with the selective 5-HT1A receptor antagonist, WAY100635 (0.63 mg/kg s.c.). Buspirone did not show significant activity in the EPM. In contrast, in the Vogel test only buspirone was active, significantly increasing the number of licks and shocks accepted (active dose: 1.25 mg/kg s.c.). However, WAY100635 failed to reverse the effects of buspirone in this test, suggesting that they were not 5-HT1A receptor-mediated. In the forced swim test, F15599, F13714, and (±)8-OH-DPAT were potently active, abolishing immobility (MED: 0.63 mg/kg p.o., 0.63 mg/kg p.o. and 0.16 mg/kg s.c., respectively). Buspirone was not active. In measures of serotonergic behavior, F13714 and (±)8-OH-DPAT robustly elicited all three signs of serotonergic behaviors, whereas F15599 and buspirone elicited only lower-lip retraction. Taken together, these observations highlight the distinct profiles of activity of 5-HT1A Agonists and suggest that the novel biased agonist F15599 combines pronounced activity in a test of anxiety (elevated plus-maze) with potent antidepressant-like effects and low propensity to induce serotonergic behaviors. These data suggest that selective biased Agonists could constitute promising pharmacotherapeutics for mood disorders.
Wouter Koek - One of the best experts on this subject based on the ideXlab platform.
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pharmacological characterization of in vivo properties of putative mixed 5 ht 1a agonist 5 ht 2a 2c antagonist anxiolytics ii drug discrimination and behavioral observation studies in rats
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Mark S Kleven, Marie Bernadette Assie, Wouter KoekAbstract:To characterize their in vivo 5-hydroxytryptamine (5-HT)2A antagonist properties, the ability of the putative mixed 5-HT1A Agonists/5-HT(2A,2C) antAgonists (N-(29(4-(2-pyrimidinyl)-1-piperazinyl)ethyl)tricyclo(3.3.1.1(3,7) ) decane-1-carboxamide (WY-50,324), (2-(4-(4,4-bis(4-fluorophenyl)butyl)-1-piperazinyl)-3-pyridinecarboxy lic acid hydrochloride (FG5974), 9,10-didehydro-N-(2-propynyl)-6-methylergoline-8b-carboxamid e (LEK-8804) and trans-1,3,4,a5,10b-hexahydro10-methoxy-4-propyl-2H-(1)benzopyra nol[3,4-b]pyridine (CGS 18102A) to antagonize both head twitches and discriminative stimulus (DS) effects produced by (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) in rats were compared with those of the 5-HT2 antAgonists ketanserin and ritanserin, and the 5-HT1A Agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone. All of these compounds produced dose-related decreases in DOI-induced head twitches; however pretreatment with the 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide (WAY-100635) failed to alter the ability of ritanserin, ketanserin or CGS 18102A to attenuate DOI-induced head twitches. In contrast, WAY-100635 completely blocked the effects of 8-OH-DPAT, buspirone and WY-50,324, and partially blocked the effects of LEK-8804, demonstrating that 5-HT1A agonist properties are involved in the effects of all of the mixed compounds except CGS 18102A. In rats trained to discriminate DOI (0.63 mg/kg) from saline in a two-lever, FR10 drug discrimination paradigm, ketanserin, ritanserin and CGS 18102A blocked the DS effects of the training dose by more than 50%. In contrast, WY-50,324, FG5974, LEK-8804, buspirone and 8-OH-DPAT, up to doses that completely suppressed responding, failed to produce more than a 33% blockade of the DS effects of DOI. In vivo 5-HT1A agonist effects were demonstrated by the finding that relatively selective- and mixed-5-HT1A Agonists produced one or more elements of the "serotonin syndrome," i.e., flat-body posture, forepaw treading, or lower-lip retraction, and produced high levels of drug-lever selection in rats trained to discriminate 8-OH-DPAT (0.16 mg/kg) from saline. Because DOI-induced head twitches and DS effects are thought to be mediated by 5-HT2A receptors, the results demonstrate that the putative mixed compound, CGS 18102A has prominent 5-HT2A antagonist properties in vivo, whereas 5-HT2A antagonist effects of WY-50,324, FG5974 and LEK-8804 could not be clearly identified.
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effects of dopamine antAgonists in a two way active avoidance procedure in rats interactions with 8 oh dpat ritanserin and prazosin
Psychopharmacology, 1996Co-Authors: Eric Prinssen, Mark S Kleven, Wouter KoekAbstract:Using a conditioned avoidance procedure in rats, the present study examined the ability of 8-OH-DPAT, ritanserin, and prazosin to alter the effects of the dopamine antAgonists, raclopride and haloperidol, on avoidance- and on escape responding. The 5-HT1A agonist 8-OH-DPAT (0.16 mg/kg) significantly enhanced the inhibitory effects of both raclopride and haloperidol on the conditioned avoidance response and produced a small enhancement of the effects of haloperidol on escape failures. The α1-adrenoceptor antagonist prazosin (0.63 mg/kg) significantly enhanced the effects of raclopride on the conditioned avoidance response, but enhanced the effects of only a single dose of haloperidol; prazosin did not alter the effects of either dopamine antagonist on escape failures. The 5-HT2 antagonist ritanserin (0.16 mg/kg) failed significantly to alter the effects of the dopamine antAgonists examined here. These findings suggest that blockade of 5-HT2 receptors may not enhance the antipsychotic efficacy of D2-like antAgonists. Further, they confirm previous findings with respect to interactions between 5-HT1A Agonists and neuroleptics, and support the hypothesis that combined 5-HT1A agonist/D2-like antagonist properties may be of clinical importance.
Shenghai Zhang - One of the best experts on this subject based on the ideXlab platform.
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5-HT1A Receptor Agonist Promotes Retinal Ganglion Cell Function by Inhibiting OFF-Type Presynaptic Glutamatergic Activity in a Chronic Glaucoma Model
Frontiers Media S.A., 2019Co-Authors: Xujiao Zhou, Shenghai ZhangAbstract:Serotonin receptors are potential neuroprotective agents in degenerative diseases of the central nervous system. The protective effects of serotonin receptor (5-HT1A) Agonists on the survival and function of retinal ganglion cells (RGCs) by regulating the release of the presynaptic neurotransmitter γ-aminobutyric acid (GABA) were confirmed in our previous study of a chronic glaucoma rat model. However, the roles of excitatory amino acids and their interactions with the 5-HT1A receptor in glaucoma remain unknown. Here, we found that ocular hypertension increased glutamine synthetase (GS) and excitatory amino acid transporter 2 (EAAT2) expression in rat retinas. In addition, the high expression of GS and EAAT2 induced by glaucoma was downregulated by the 5-HT1A receptor agonist 8-OH-DPAT and the 5-HT1A receptor antagonist WAY-100635, respectively. Patch-clamp techniques were used to record glutamate receptor-mediated spontaneous and miniature glutamatergic excitatory post-synaptic currents (sEPSCs and mEPSCs) as well as L-glutamate-induced current in OFF-type and ON-type RGCs in rat retinal slices. Although there were no significant differences in the frequency and amplitude of sEPSC and mEPSC release between normal and glaucoma OFF- and ON-type RGCs, exogenous 8-OH-DPAT administration specifically reduced the frequency, but not the amplitude, of sEPSC and mEPSC release in glaucoma OFF-type rather than ON-type RGCs; these effects were completely blocked by WAY-100635. In summary, 8-OH-DPAT decreases and increases GS and EAAT2 expression of glaucomatous retina, respectively, while decreasing sEPSC and mEPSC frequency. In contrast, WAY-100635 increases and decreases GS and EAAT2 expression of glaucomatous retina, respectively, while increasing sEPSC and mEPSC frequency. The reduction of glutamatergic presynaptic transmission by 8-OH-DPAT deactivates RGCs at the neural network level and reduces the excitotoxic damage in the pathological process of chronic glaucoma
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Data_Sheet_1_5-HT1A Receptor Agonist Promotes Retinal Ganglion Cell Function by Inhibiting OFF-Type Presynaptic Glutamatergic Activity in a Chronic Glaucoma Model.docx
2019Co-Authors: Xujiao Zhou, Shenghai ZhangAbstract:Serotonin receptors are potential neuroprotective agents in degenerative diseases of the central nervous system. The protective effects of serotonin receptor (5-HT1A) Agonists on the survival and function of retinal ganglion cells (RGCs) by regulating the release of the presynaptic neurotransmitter γ-aminobutyric acid (GABA) were confirmed in our previous study of a chronic glaucoma rat model. However, the roles of excitatory amino acids and their interactions with the 5-HT1A receptor in glaucoma remain unknown. Here, we found that ocular hypertension increased glutamine synthetase (GS) and excitatory amino acid transporter 2 (EAAT2) expression in rat retinas. In addition, the high expression of GS and EAAT2 induced by glaucoma was downregulated by the 5-HT1A receptor agonist 8-OH-DPAT and the 5-HT1A receptor antagonist WAY-100635, respectively. Patch-clamp techniques were used to record glutamate receptor-mediated spontaneous and miniature glutamatergic excitatory post-synaptic currents (sEPSCs and mEPSCs) as well as L-glutamate-induced current in OFF-type and ON-type RGCs in rat retinal slices. Although there were no significant differences in the frequency and amplitude of sEPSC and mEPSC release between normal and glaucoma OFF- and ON-type RGCs, exogenous 8-OH-DPAT administration specifically reduced the frequency, but not the amplitude, of sEPSC and mEPSC release in glaucoma OFF-type rather than ON-type RGCs; these effects were completely blocked by WAY-100635. In summary, 8-OH-DPAT decreases and increases GS and EAAT2 expression of glaucomatous retina, respectively, while decreasing sEPSC and mEPSC frequency. In contrast, WAY-100635 increases and decreases GS and EAAT2 expression of glaucomatous retina, respectively, while increasing sEPSC and mEPSC frequency. The reduction of glutamatergic presynaptic transmission by 8-OH-DPAT deactivates RGCs at the neural network level and reduces the excitotoxic damage in the pathological process of chronic glaucoma.
Magdalena Jastrzebskawiesek - One of the best experts on this subject based on the ideXlab platform.
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activity of serotonin 5 ht1a receptor biased Agonists in rat anxiolytic and antidepressant like properties
ACS Chemical Neuroscience, 2018Co-Authors: Magdalena Jastrzebskawiesek, Mark A Varney, Anna Partyka, Joanna Rychtyk, Marcin Kolaczkowski, Joanna śniecikowska, Anna Wesolowska, Adrian NewmantancrediAbstract:Although serotonin 5-HT1A receptors constitute attractive therapeutic targets, there is a lack of potential clinical candidates that have a high degree of selectivity and full agonist efficacy. Recently, novel 5-HT1A receptor "biased Agonists" F15599 (also known as NLX-101) and F13714 have been reported that exhibit distinctive properties for in vitro signaling, neurochemical, electrophysiological effects, and in brain imaging. The present study characterized their effects in rat models of anxiety (elevated plus-maze, EPM, and Vogel tests), in depressive-like behavior (forced swim test), and on the induction of the three serotonergic behaviors (forepaw treading, flat body posture, and lower lip retraction). The prototypical 5-HT1A receptor ligands (±)8-OH-DPAT and buspirone were tested as comparators. In the elevated plus-maze, F15599, F13714, and (±)8-OH-DPAT dose-dependently increased the amount and percentage of time spent in the open arms with minimal effective doses (MED) of 5 mg/kg p.o., 2.5 mg/kg p.o. and 1.25 mg/kg s.c., respectively. The effects of the three Agonists were abolished by pretreatment with the selective 5-HT1A receptor antagonist, WAY100635 (0.63 mg/kg s.c.). Buspirone did not show significant activity in the EPM. In contrast, in the Vogel test only buspirone was active, significantly increasing the number of licks and shocks accepted (active dose: 1.25 mg/kg s.c.). However, WAY100635 failed to reverse the effects of buspirone in this test, suggesting that they were not 5-HT1A receptor-mediated. In the forced swim test, F15599, F13714, and (±)8-OH-DPAT were potently active, abolishing immobility (MED: 0.63 mg/kg p.o., 0.63 mg/kg p.o. and 0.16 mg/kg s.c., respectively). Buspirone was not active. In measures of serotonergic behavior, F13714 and (±)8-OH-DPAT robustly elicited all three signs of serotonergic behaviors, whereas F15599 and buspirone elicited only lower-lip retraction. Taken together, these observations highlight the distinct profiles of activity of 5-HT1A Agonists and suggest that the novel biased agonist F15599 combines pronounced activity in a test of anxiety (elevated plus-maze) with potent antidepressant-like effects and low propensity to induce serotonergic behaviors. These data suggest that selective biased Agonists could constitute promising pharmacotherapeutics for mood disorders.
E Meller - One of the best experts on this subject based on the ideXlab platform.
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lack of apparent receptor reserve at postsynaptic 5 hydroxytryptamine1a receptors negatively coupled to adenylyl cyclase activity in rat hippocampal membranes
Molecular Pharmacology, 1992Co-Authors: Frank D Yocca, L Iben, E MellerAbstract:Previous studies have demonstrated the existence of a large receptor reserve for Agonists at somatodendritic 5-hydroxytryptamine1A (5-HT1A) serotonin receptors in the raphe nuclei of the rat. 5-HT1A Agonists with anxiolytic properties (e.g., buspirone, gepirone, and ipsapirone) display full intrinsic activity at these receptors but are partial Agonists at postsynaptic 5-HT1A receptors, which suggests that the latter sites may be devoid of a receptor reserve. In the present studies, this was directly determined by examining the relationship between receptor occupancy and response at postsynaptic 5-HT1A receptors, in rat hippocampus, mediating the inhibition of forskolin-stimulated adenylyl cyclase activity, using the method of partial irreversible receptor inactivation. Rats were treated with vehicle or the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), and 24 hr later hippocampi were removed for saturation analysis of [3H]8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) binding to 5-HT1A receptors or for adenylyl cyclase assays. EEDQ (1 and 6 mg/kg) dose-dependently reduced the maximal number of [3H]8-OH-DPAT binding sites by 68.5 and 80%, respectively, without altering the Kd. Concentration-response curves were generated for inhibition of forskolin-stimulated adenylyl cyclase activity by 5-HT and the selective 5-HT1A agonist N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT). EEDQ treatment dose-dependently reduced the maximal inhibitory effect of 5-HT [percentage of inhibition: control, 23.6; EEDQ (1 mg/kg), 13.4; EEDQ (6 mg/kg), 8.9], without altering either the slope factor (1.01) or the EC50 (96.4 nM). Analogous results were obtained with DP-5-CT [percentage of maximal inhibition: control, 24.1; EEDQ (1 mg/kg), 15.2; EEDQ (6 mg/kg), 10.7), again without changes in slope factor (0.89) or EC50 (9.9 nM). Analysis of double-reciprocal plots of equieffective concentrations of agonist, followed by calculation of fractional receptor occupancy, revealed a linear relationship between receptor occupancy and response for both 5-HT and DP-5-CT (i.e., an absence of receptor reserve). The receptor specificity of the effect of EEDQ was demonstrated in two ways. First, it was shown that pretreatment of rats with the selective 5-HT1A partial agonist BMY 7378 (10 mg/kg) before EEDQ afforded substantial protection (about 75%) against loss of the inhibitory effect of DP-5-CT on forskolin-stimulated adenylyl cyclase activity. Second, EEDQ did not alter the inhibition of forskolin-stimulated adenylyl cyclase activity induced by the adenosine A1 receptor agonist phenylisopropyladenosine (PIA).(ABSTRACT TRUNCATED AT 400 WORDS)