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T Sharp - One of the best experts on this subject based on the ideXlab platform.
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affinity of pindolol Penbutolol and tertatolol for pre and postsynaptic serotonin 5 ht 1a receptors in human and rat brain
Journal of Neurochemistry, 2002Co-Authors: Me Castro, Paul Harrison, A Pazos, T SharpAbstract:There is considerable interest in the use of drugs that selectively block presynaptic (somatodendritic) serotonin 5-HT(1A) receptors for the adjunctive treatment of major depressive disorder. The 5-HT(1A)/beta-adrenoceptor ligands (+/-)-pindolol, (-)-tertatolol, and (-)-Penbutolol are currently under clinical investigation, and knowledge of their affinity at different populations of central 5-HT(1A) receptors is needed. Here we have determined the affinity of these drugs for presynaptic and postsynaptic 5-HT(1A) receptors in postmortem human and rat brain using receptor autoradiography and the selective 5-HT(1A) radioligand [(3)H]WAY-100635. The binding of [(3)H]WAY-100635 was specific and saturable and showed high affinity in the rat dorsal raphe nucleus and hippocampus (K(D) = 1.5-1.7 nM). In competition studies, the three compounds had nanomolar affinity and produced monophasic displacement of [(3)H]WAY-100635 binding in all regions of both species. (-)-Penbutolol and (-)-tertatolol had similar affinity for pre-and postsynaptic 5-HT(1A) receptors in both rat and human brain. However, in the human, but not the rat, the affinity of (+/-)-pindolol in dorsal raphe nucleus (K(i) = 8.9 +/- 1. 1 nM) was slightly but significantly higher than that in hippocampus (K(i) = 14.4 +/- 1.5 nM in CA1). In summary, our data show that (+/-)-pindolol, (-)-tertatolol, and (-)-Penbutolol are all high-affinity ligands at native human and rat 5-HT(1A) receptors. (-)-Penbutolol and (-)-tertatolol do not discriminate between the pre- and postsynaptic 5-HT(1A) sites tested in either species, but (+/-)-pindolol showed a slightly higher affinity for the presynaptic site in human brain. Further work is needed to establish whether the latter difference is clinically relevant.
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effects of tertatolol Penbutolol and pindolol in combination with paroxetine on presynaptic 5 ht function an in vivo microdialysis and electrophysiological study
British Journal of Pharmacology, 1999Co-Authors: Se Gartside, Em Clifford, Pj Cowen, T SharpAbstract:The antidepressant efficacy of selective serotonin reuptake inhibitors (SSRIs) might be enhanced by co-administration of 5-HT1A receptor antagonists. Thus, we have recently shown that the selective 5-HT1A receptor antagonist, WAY 100635, blocks the inhibitory effect of an SSRI on 5-HT cell firing, and enhances its ability to elevate extracellular 5-HT in the forebrain. Here we determined whether the β-adrenoceptor/5-HT1A receptor ligands (±)-pindolol, (−)-tertatolol and (−)-Penbutolol, interact with paroxetine in a similar manner. Both (−)-tertatolol (2.4 mg kg−1 i.v.) and (−)-Penbutolol (2.4 mg kg−1 i.v.) enhanced the effect of paroxetine (0.8 mg kg−1 i.v.) on extracellular 5-HT in the frontal cortex, whilst (±)-pindolol (4 mg kg−1 i.v.) did not. (−)-Tertatolol (2.4 mg kg−1 i.v.) alone caused a slight increase in 5-HT however, (−)-Penbutolol (2.4 mg kg−1 i.v.) alone had no effect. In electrophysiological studies (−)-tertatolol (2.4 mg kg−1 i.v.) alone had no effect on 5-HT cell firing but blocked the inhibitory effect of paroxetine. In contrast, (−)-Penbutolol (0.1–0.8 mg kg−1 i.v.) itself inhibited 5-HT cell firing, and this effect was reversed by WAY 100635 (0.1 mg kg−1 i.v.). We have recently shown that (±)-pindolol inhibits 5-HT cell firing via a WAY 100635-sensitive mechanism. Our data suggest that (−)-tertatolol enhances the effect of paroxetine on forebrain 5-HT via blockade of 5-HT1A autoreceptors which mediate paroxetine-induced inhibition of 5-HT cell firing. In comparison, the mechanisms by which (−)-Penbutolol enhances the effect of paroxetine on extracellular 5-HT is unclear, since (−)-Penbutolol itself appears to have agonist properties at the 5-HT1A autoreceptor. Indeed, the agonist action of (±)-pindolol at 5-HT1A autoreceptors probably explains its inability to enhance the effect of paroxetine on 5-HT in the frontal cortex. Overall, our data suggest that both (−)-tertatolol and (−)-Penbutolol are superior to (±)-pindolol in terms of enhancing the effect of an SSRI on extracellular 5-HT. Both (−)-tertatolol and (−)-Penbutolol are worthy of investigation for use as adjuncts to SSRIs in the treatment of major depression. Keywords: SSRI, antidepressant, paroxetine, β-adrenoceptor/5-HT1A receptor ligands, (±)-pindolol, (−)-tertatolol, (−)-Penbutolol, 5-HT cell firing, extracellular 5-HT Introduction Increasing 5-HT transmission in the forebrain is proposed to underlie the therapeutic action of many antidepressant drugs including selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and some tricyclic antidepressants (TCAs) (Delgado et al., 1990; Blier & de Montigny, 1994). However, indirect 5-HT autoreceptor activation by such drugs may actually hamper their therapeutic efficacy. Thus, current strategies aimed at improving antidepressant drug efficacy include the co-administration of 5-HT autoreceptor antagonists (Artigas et al., 1994; Blier & Bergeron, 1995). The rationale behind this strategy is the finding in animal studies that 5-HT1A autoreceptor antagonists prevent 5-HT reuptake inhibitors (both selective and non-selective), and MAOIs, from indirectly inhibiting 5-HT cell firing, via activation of 5-HT1A autoreceptors (Sheard et al., 1972; Scuvee-Moreau & Dresse, 1979; Chaput et al., 1986; Aghajanian et al., 1970; Gartside et al., 1995; 1997; Sharp et al., 1997a). Hence, the ability of SSRIs and MAOIs to elevate extracellular 5-HT in the forebrain can be enhanced by co-administration of a selective 5-HT1A receptor antagonist such as WAY 100635 (Gartside et al., 1995; Hjorth et al., 1996; Romero et al., 1996a; Sharp et al., 1997a). Although no selective 5-HT1A receptor antagonist drugs are presently available for use in humans, there are several non-selective β-blockers with high affinity for the 5-HT1A receptor (Middlemiss et al., 1977; see also Sanchez et al., 1996a), and these may be useful alternatives. Indeed, (±)-pindolol has already been used in combination with SSRIs, in a number of clinical studies. However, whilst early open trials found a markedly improved antidepressant effect of combined (±)-pindolol/SSRI treatment (Artigas et al., 1994; Blier & Bergeron, 1995), more recent double-blind placebo-controlled trials have produced mixed results (Berman et al., 1997; Moreno et al., 1997; Perez et al., 1997; Zanardi et al., 1997; for review see McAskill et al., 1998). Against this background, it is of note that emerging evidence indicates that (±)-pindolol has partial agonist properties at the 5-HT1A autoreceptor (Hjorth & Carlsson, 1986; Clifford et al., 1998; Newman-Tancredi et al., 1998). This feature may mean that (±)-pindolol would be of limited value as an adjunct to antidepressant therapy. In the present study, we have selected two further β-adrenoceptor antagonists, (−)-tertatolol, and (−)-Penbutolol, with reported antagonist properties at the 5-HT1A receptor (Hjorth & Sharp, 1993; Jolas et al., 1993; Prisco et al., 1993; Sanchez et al., 1996a,1996b), and compared them with (±)-pindolol in two respects; firstly, their ability to enhance the effect of an SSRI on extracellular 5-HT in the forebrain and secondly, their ability to block the inhibitory effect of an SSRI on 5-HT cell firing in the dorsal raphe nucleus (DRN). Some of these data have been presented in preliminary form to the British Pharmacological Society (Gartside et al., 1998).
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in vivo microdialysis evidence for central serotonin1a and serotonin1b autoreceptor blocking properties of the beta adrenoceptor antagonist Penbutolol
Journal of Pharmacology and Experimental Therapeutics, 1993Co-Authors: S Hjorth, T SharpAbstract:Recently, we found that the beta 1/beta 2 adrenoceptor blocking agent (-)Penbutolol prevents behavioral and biochemical actions of the specific serotonin (5-HT)1A agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin. The putative 5-HT1 receptor antagonist profile of (-)Penbutolol was further explored in the present study, using in vivo microdialysis methods to assess its effects on central 5-HT release. (+)Penbutolol and (-)pindolol were included for comparison purposes. In contrast to (-)pindolol (8.0 mg/kg s.c.), administration of (-)Penbutolol (2.0 or 8.0 mg/kg s.c.) increased hippocampal 5-HT output. The (-)Penbutolol-induced 5-HT response was dose-related, stereoselective and Ca(++)-dependent. In addition, the 5-HT response to (-)Penbutolol was abolished by omitting the 5-HT reuptake blocker citalopram from the perfusion medium, suggesting the need for endogenous 5-HT tone. Local (-)Penbutolol (1 microM) perfusion increased the 5-HT output per se, and also blocked 5-HT release suppression caused by the 5-HT1B receptor agonist CP-93,129. Furthermore, (-)Penbutolol, but not its (+)antipode, prevented the decrease of 5-HT release induced by the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin. By comparison, the 5-HT1 receptor inactive beta adrenoceptor blockers metoprolol (beta 1) and ICI 118,551 (beta 2), given alone or in combination, did not increase 5-HT output and were ineffective in antagonizing the (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin response. The data indicate that (-)Penbutolol possesses 5-HT1A and 5-HT1B autoreceptor antagonist properties, and may be a useful tool in studies of central 5-HT receptor-mediated function.
Paul M. Grasby - One of the best experts on this subject based on the ideXlab platform.
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Drug action at the 5-HT1A receptor in vivo: autoreceptor and postsynaptic receptor occupancy examined with PET and [carbonyl-11C]WAY-100635
Nuclear medicine and biology, 2000Co-Authors: Eugenii A Rabiner, Roger N. Gunn, Martin R. Wilkins, Peter A. Sargent, Elizabeth Mocaer, Ewen Sedman, Philip J. Cowen, Paul M. GrasbyAbstract:Abstract Serotonin 1A (5-HT 1A ) receptors have been implicated in the pathophysiology and treatment of anxiety and depression and are a target for novel drug development. In this qualitative study, positron emission tomography (PET) and [ carbonyl - 11 C]WAY-100635 were used to assess 5-HT 1A autoreceptor and postsynaptic receptor occupancy in man in vivo by five different compounds with nanomolar affinity for this site. Occupancy by pindolol, Penbutolol, buspirone, EMD 68843, and S 15535 was compared to test-retest data from 10 healthy volunteers. All drugs, apart from buspirone, displayed occupancy at the 5-HT 1A receptor site. Pindolol demonstrated a preferential occupancy at the autoreceptor compared to the postsynaptic receptor over a plasma range of about 10–20 ng/mL. Differential occupancy may be an important component of novel drug action. The level of autoreceptor or postsynaptic occupancy needed to achieve significant physiological effects is not known, although it is of note that none of the drugs in this study achieved occupancies beyond 60%. Overall this study demonstrates the utility of PET in aiding novel drug development.
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Drug action at the 5-HT(1A) receptor in vivo: autoreceptor and postsynaptic receptor occupancy examined with PET and [carbonyl-(11)C]WAY-100635.
'Elsevier BV', 2000Co-Authors: Ea Rabiner, Pj Cowen, Rn Gunn, Pa Sargent, Wilkins Mr, Mocaer E, Sedman E, Paul M. GrasbyAbstract:Serotonin(1A) (5-HT(1A)) receptors have been implicated in the pathophysiology and treatment of anxiety and depression and are a target for novel drug development. In this qualitative study, positron emission tomography (PET) and [carbonyl-(11)C]WAY-100635 were used to assess 5-HT(1A) autoreceptor and postsynaptic receptor occupancy in man in vivo by five different compounds with nanomolar affinity for this site. Occupancy by pindolol, Penbutolol, buspirone, EMD 68843, and S 15535 was compared to test-retest data from 10 healthy volunteers. All drugs, apart from buspirone, displayed occupancy at the 5-HT(1A) receptor site. Pindolol demonstrated a preferential occupancy at the autoreceptor compared to the postsynaptic receptor over a plasma range of about 10-20 ng/mL. Differential occupancy may be an important component of novel drug action. The level of autoreceptor or postsynaptic occupancy needed to achieve significant physiological effects is not known, although it is of note that none of the drugs in this study achieved occupancies beyond 60%. Overall this study demonstrates the utility of PET in aiding novel drug development
Me Castro - One of the best experts on this subject based on the ideXlab platform.
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affinity of pindolol Penbutolol and tertatolol for pre and postsynaptic serotonin 5 ht 1a receptors in human and rat brain
Journal of Neurochemistry, 2002Co-Authors: Me Castro, Paul Harrison, A Pazos, T SharpAbstract:There is considerable interest in the use of drugs that selectively block presynaptic (somatodendritic) serotonin 5-HT(1A) receptors for the adjunctive treatment of major depressive disorder. The 5-HT(1A)/beta-adrenoceptor ligands (+/-)-pindolol, (-)-tertatolol, and (-)-Penbutolol are currently under clinical investigation, and knowledge of their affinity at different populations of central 5-HT(1A) receptors is needed. Here we have determined the affinity of these drugs for presynaptic and postsynaptic 5-HT(1A) receptors in postmortem human and rat brain using receptor autoradiography and the selective 5-HT(1A) radioligand [(3)H]WAY-100635. The binding of [(3)H]WAY-100635 was specific and saturable and showed high affinity in the rat dorsal raphe nucleus and hippocampus (K(D) = 1.5-1.7 nM). In competition studies, the three compounds had nanomolar affinity and produced monophasic displacement of [(3)H]WAY-100635 binding in all regions of both species. (-)-Penbutolol and (-)-tertatolol had similar affinity for pre-and postsynaptic 5-HT(1A) receptors in both rat and human brain. However, in the human, but not the rat, the affinity of (+/-)-pindolol in dorsal raphe nucleus (K(i) = 8.9 +/- 1. 1 nM) was slightly but significantly higher than that in hippocampus (K(i) = 14.4 +/- 1.5 nM in CA1). In summary, our data show that (+/-)-pindolol, (-)-tertatolol, and (-)-Penbutolol are all high-affinity ligands at native human and rat 5-HT(1A) receptors. (-)-Penbutolol and (-)-tertatolol do not discriminate between the pre- and postsynaptic 5-HT(1A) sites tested in either species, but (+/-)-pindolol showed a slightly higher affinity for the presynaptic site in human brain. Further work is needed to establish whether the latter difference is clinically relevant.
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beta-blocker binding to human 5-HT(1A) receptors in vivo and in vitro: implications for antidepressant therapy.
2000Co-Authors: Ea Rabiner, Pj Cowen, Rn Gunn, Me Castro, Pa Sargent, Mj Koepp, Jh Meyer, Cj Bench, Pj Harrison, Pazos AAbstract:A novel strategy for improving the treatment of depressive illness is augmentation of antidepressants with a 5-HT1(1A) autoreceptor antagonist. However, trials using the 5-HT1(1A)/beta-blocker pindolol are proving inconsistent. We report how positron emission tomography (PET) and in vitro autoradiography can inform trials of antidepressant augmentation. We show that in healthy volunteers, in vivo, pindolol (n = 10) and Penbutolol (n = 4), but not tertatolol (n = 4) occupy the human 5-HT(1A) receptors, at clinical doses. Pindolol, as well as the beta-blockers Penbutolol and tertatolol, has high affinity for human 5-HT(1A) receptors in post-mortem brain slices (n = 4). Pindolol shows preference for 5-HT(1A) autoreceptors versus the post-synaptic receptors both in vitro and in vivo. Our data reveal that pindolol doses used in antidepressant trials so far are suboptimal for significant occupancy at the 5-HT(1A) autoreceptor. Penbutolol or higher doses of pindolol are candidates for testing as antidepressant augmenting regimes in future clinical trials
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Affinity of (+/-)-pindolol, (-)-Penbutolol, and (-)-tertatolol for pre- and postsynaptic serotonin 5-HT(1A) receptors in human and rat brain.
2000Co-Authors: Me Castro, Pj Harrison, Pazos A, Sharp TAbstract:There is considerable interest in the use of drugs that selectively block presynaptic (somatodendritic) serotonin 5-HT(1A) receptors for the adjunctive treatment of major depressive disorder. The 5-HT(1A)/beta-adrenoceptor ligands (+/-)-pindolol, (-)-tertatolol, and (-)-Penbutolol are currently under clinical investigation, and knowledge of their affinity at different populations of central 5-HT(1A) receptors is needed. Here we have determined the affinity of these drugs for presynaptic and postsynaptic 5-HT(1A) receptors in postmortem human and rat brain using receptor autoradiography and the selective 5-HT(1A) radioligand [(3)H]WAY-100635. The binding of [(3)H]WAY-100635 was specific and saturable and showed high affinity in the rat dorsal raphe nucleus and hippocampus (K(D) = 1.5-1.7 nM). In competition studies, the three compounds had nanomolar affinity and produced monophasic displacement of [(3)H]WAY-100635 binding in all regions of both species. (-)-Penbutolol and (-)-tertatolol had similar affinity for pre-and postsynaptic 5-HT(1A) receptors in both rat and human brain. However, in the human, but not the rat, the affinity of (+/-)-pindolol in dorsal raphe nucleus (K(i) = 8.9 +/- 1. 1 nM) was slightly but significantly higher than that in hippocampus (K(i) = 14.4 +/- 1.5 nM in CA1). In summary, our data show that (+/-)-pindolol, (-)-tertatolol, and (-)-Penbutolol are all high-affinity ligands at native human and rat 5-HT(1A) receptors. (-)-Penbutolol and (-)-tertatolol do not discriminate between the pre- and postsynaptic 5-HT(1A) sites tested in either species, but (+/-)-pindolol showed a slightly higher affinity for the presynaptic site in human brain. Further work is needed to establish whether the latter difference is clinically relevant
Sidney B. Auerbach - One of the best experts on this subject based on the ideXlab platform.
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autoreceptor antagonists enhance the effect of the reuptake inhibitor citalopram on extracellular 5 ht this effect persists after repeated citalopram treatment
Neuropharmacology, 1997Co-Authors: C Gundlah, S Hjorth, Sidney B. AuerbachAbstract:Abstract The effect of repeated administration of the reuptake inhibitor citalopram (10 mg/kg s.c., b.i.d. for 14 days) or saline on extracellular 5-hydroxytryptamine (5-HT) and autoreceptor sensitivity was assessed using microdialysis in the frontal cortex (FCx) and dorsal hippocampus (DH) of unanesthetized rats. Acute citalopram (5 mg/kg s.c.) challenge produced significant increases in DH and FCx 5-HT. The nonselective 5-HT1A/1B receptor antagonist (−)-Penbutolol (8 mg/kg s.c.), administered 2 hr after citalopram challenge, significantly enhanced 5-HT in FCx and DH of both the chronic citalopram and saline pretreatment groups. Administration of the selective 5-HT1A receptor antagonist WAY 100635 (0.3 mg/kg s.c.) after citalopram challenge significantly enhanced 5-HT in FCx but not DH of both pretreatment groups. This suggests that there may be differences between DH and FCx in regulation of 5-HT release. Nevertheless, these results provide evidence that 5-HT autoreceptors are still active in restraining 5-HT release even after repeated administration of an antidepressant drug. © 1997 Elsevier Science Ltd.
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systemic uptake inhibition decreases serotonin release via somatodendritic autoreceptor activation
Synapse, 1995Co-Authors: John J Rutter, Chrisana Gundlah, Sidney B. AuerbachAbstract:In vivo microdialysis was used to examine the effects of peripheral uptake inhibition on extracellular serotonin (5-HT). Previous results from this lab indicated that systemic fluoxetine caused a decrease in 5-HT when terminal uptake was inhibited by local infusion of the uptake blocker. We hypothesized that the decrease in 5-HT levels in the terminal region was due to an increase in 5-HT in the vicinity of the inhibitory somatodendritic autoreceptors in the dorsal raphe nucleus (DRN). To test this prediction, rats were implanted with probes in both the basal diencephalon (a nerve terminal region) and the DRN (the cell body region). Fluoxetine (10 mg/kg i.p.) increased extracellular 5-HT, in a depolarization-dependent manner, by approximately 140% in both areas. In a separate experiment, fluoxetine was infused into the diencephalon overnight to block nerve terminal uptake sites. This pretreatment caused an eight- to 10-fold increase in 5-HT levels. Subsequent systemic fluoxetine, sertraline, or paroxetine, produced a 50% decrease in extracellular 5-HT in the diencephalon, presumably due to activation of the 5-HT1A somatodendritic autoreceptors. Consistent with this hypothesis, systemic administration of the 5-HT1 antagonists spiperone, Penbutolol, or WAY100135 reversed the fluoxetine-induced decrease in 5-HT to approximately 85% of the pre-fluoxetine baseline levels. Likewise, pretreatment with Penbutolol, but not selective s-adrenergic antagonists, blocked the fluoxetine-induced decrease in release. These findings suggest that the ability of acute systemic 5-HT uptake inhibition to elevate nerve terminal 5-HT is limited by autoreceptor activation following elevation of 5-HT in the DRN. © 1995 Wiley-Liss, Inc.
Stephan Hjorth - One of the best experts on this subject based on the ideXlab platform.
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S 15535, a novel benzodioxopiperazine ligand of serotonin (5-HT) 1A receptors: II. Modulation of hippocampal serotonin release in relation to potential anxiolytic properties
1997Co-Authors: Mark J. Millan, Stephan Hjorth, Rosario Samanin, Rudy Schreiber, Robert Jaffard, Brigitte De Ladonchamps, Sylvie Veiga, Bertrand Goument, Jean-louis Peglion, Michael SpeddingAbstract:In these studies, we characterized the influence of the novel ben-zodioxopiperazine serotonin (5-HT)1A ligand, S 15535, on the re-lease of 5-HT in rat hippocampus and compared its potential anxiolytic properties with those of the 5-HT1A receptor partial agonist, buspirone, the 5-HT1A antagonist, WAY 100,635 and the benzodiazepine, diazepam (DZM). (Doses are in milligrams per kilogram s.c., unless otherwise specified.) S 15535 dose-depen-dently (0.3–3.0) reduced dialysate concentrations of 5-HT in the hippocampus of anesthetized rats. This action of S 15535 (3.0) was blocked by WAY 100,635 (0.3), (2)-Penbutolol (2.0) and (2)-tertatolol (8.0), antagonists at 5-HT1A autoreceptors. In rats, fear-induced ultrasonic vocalizations (USVs) were dose-dependently abolished by S 15535 (0.16–2.5 s.c. and 0.63–10.0 p.o.), an action mimicked by buspirone (0.02–2.5) and DZM (0.16–10.0). Further
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serotonin 5 ht1a autoreceptor blockade potentiates the ability of the 5 ht reuptake inhibitor citalopram to increase nerve terminal output of 5 ht in vivo a microdialysis study
Journal of Neurochemistry, 1993Co-Authors: Stephan HjorthAbstract:: The present study addressed the possibility that disinhibition of serotonin (5-HT) autoreceptor-mediated negative feedback might potentiate the elevation of nerve terminal 5-HT output induced by selective 5-HT reuptake blockade. To this end, rats were given citalopram and the 5-HT autoreceptor-blocking agents (S)-UH-301 (5-HT1A) and (-)-Penbutolol (5-HT1A/1B), and the effect on extracellular 5-HT in the ventral hippocampus was monitored by means of in vivo microdialysis. Citalopram (5 mg/kg, s.c.) approximately doubled the 5-HT output, a response that was markedly augmented by (S)-UH-301 (3 mg/kg, s.c.) and (-)-Penbutolol (8 mg/kg, s.c.) and by combined treatment with (S)-UH-301 (3 mg/kg, s.c.) plus (-)-Penbutolol (1 microM; via the dialysis perfusion medium), but not by (-)-Penbutolol (1 microM) alone. These findings provide evidence that 5-HT, in particular 5-HT1A, autoreceptor-mediated negative feedback mechanisms are pivotal in determining the nerve terminal 5-HT output level after 5-HT reuptake inhibition. These findings have important implications for the interplay between different processes controlling 5-HT transmission in vivo and might possibly offer a lead toward novel, therapeutically exploitable principles.