Characterization of 5-hydroxytryptamine1A properties of flesinoxan: In Vivo electrophysiology and hypothermia study

Hadrava, Vratislav; Blier, Pierre; Dennis, Trevor; Ortemann, Catherine; Montigny, Claude de

doi:10.1016/0028-3908(95)00098-q

Cited by 55 publications

(39 citation statements)

References 31 publications

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“…Moreover, the fact that the intravenous administration of the 5-HT 1A agonists flesinoxan, 8-OH-DPAT and flibanserin suppresses the firing activity of dorsal hippocampus CA 3 pyramidal neurons (Hadrava et al 1995;Rueter et al 1998) corroborates this conclusion. The observation that a lesion of the 5-HT system with 5,7-DHT prevented the suppressant effect of paroxetine (Piñeyro et al 1994) as well as that of venlafaxine ( Figure 3C and 3D) on the firing activity of CA 3 pyramidal neurons, also provides strong credence to the idea that their suppressant effects result from in- creased levels of extracellular 5-HT subsequent to reuptake blockade.…”

Section: Discussionmentioning

confidence: 61%

Potentiation by (-)Pindolol of the Activation of Postsynaptic 5-HT1A Receptors Induced by Venlafaxine

Béı̈que

Blier

Montigny

et al. 2000

Neuropsychopharmacology

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The increase of extracellular 5-HT in brain terminal regions produced by the acute administration of 5-HT reuptake inhibitors (SSRI's) is hampered by the activation of somatodendritic 5-HT 1A autoreceptors in the raphe nuclei. The present in vivo electrophysiological studies were undertaken, in the rat, to assess the effects of the coadministration of venlafaxine, a dual 5-HT/NE reuptake inhibitor, and (-)pindolol on pre-and postsynaptic 5-HT 1A receptor function. The acute administration of venlafaxine and of the SSRI paroxetine (5 mg/kg, i.v.) induced a suppression of the firing activity of dorsal hippocampus CA 3 pyramidal neurons. This effect of venlafaxine was markedly potentiated by a pretreatment with (-)pindolol (15 mg/kg, i.p.) but not by the selective ␤ -adrenoceptor antagonist metoprolol (15 mg/kg, i.p .). That this effect of venlafaxine was mediated by an activation of postsynaptic 5-HT 1A receptors was suggested by its complete reversal by the 5-HT 1Aantagonist WAY 100635 (100 g/kg, i.v It is becoming increasingly clear that the therapeutic efficacy of antidepressant treatments such as selective serotonin reuptake inhibitors (SSRI's) finds its substrate in an enhanced serotonergic (5-HT) neurotransmission . At least in the rat, this occurs only in the midst of long-term administration of antidepressant treatments, which is necessary for the development of specific adaptative changes. Indeed, acute administration of SSRI's induces a reduction of firing activity of the 5-HT neurons of the raphe nuclei due to an increased activation of the somatodendritic 5-HT 1A autoreceptors, resulting from the increased extracellular 5-HT (de Montigny et al. 1981;Blier et al. 1984;Chaput et al. 1986;Hajós et al. 1995;Béïque et al. 1999). However, in the course of a long-term administration of SSRI's, 5-HT neurons recover their normal firing activity as a consequence of the desensitization of these autoreceptors . .). A short-term treatment with VLX (20 mg/kg/day ϫ 2 days) resulted in a ca. 90% suppression of the firing activity of 5-HT neurons in the dorsal raphe nucleus. This was prevented by the coadministration of (-)pindolol (15 mg/kg/day ϫ 2 days). Taken together, these results indicate that (-)pindolol potentiated the activation of postsynaptic 5-HTA way by which the action of the somatodendritic 5-HT 1A autoreceptors can be circumvented has been Activation of Postsynaptic 5-HT 1A Receptors 295 delineated by the electrophysiological observation that a 2-day administration of the mixed ␤ -adrenergic/5-HT 1A receptors antagonist (-)pindolol prevents the suppressant effects of paroxetine and of the 5-HT autoreceptor agonist LSD on the firing activity of dorsal raphe 5-HT (Romero et al. 1996). Although microdialysis studies cannot assess the postsynaptic impact, several such studies have corroborated the above by showing that the acute coadministration of (-)pindolol and an SSRI produces a greater elevation of extracellular levels of 5-HT in terminal regions than that achieved with the reuptake inhibitor alon...

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Section: Discussionmentioning

confidence: 61%

Potentiation by (-)Pindolol of the Activation of Postsynaptic 5-HT1A Receptors Induced by Venlafaxine

Béı̈que

Blier

Montigny

et al. 2000

Neuropsychopharmacology

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“…Flesinoxan penetrates the brain in rats, albeit much less efficiently than the prototypical 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT (Hadrava et al, 1995). This relatively poor penetration appears to arise because flesinoxan is a substrate for P-glycoprotein, a multidrug transporter, which actively effluxes it from the brain at the blood-brain barrier (van der Sandt et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Flesinoxan is particularly useful as a pharmacological probe as it does not have pharmacologically active metabolites, unlike the azapirone 5-HT 1A agonists such as buspirone which have the metabolite 1-PP (1-(2-pyrimidinyl)-piperazine), an a 2 -adrenoreceptor antagonist. In rats, flesinoxan suppresses firing activity in dorsal raphe serotonergic neurons and dorsal hippocampus pyramidal neurons, and crosses the blood-brain barrier, albeit relatively slowly (Hadrava et al, 1995). In man, 1 mg intravenous flesinoxan produces a 5-HT 1A agonist profile: it significantly elevates adrenocorticotropic hormone, cortisol, growth hormone, and prolactin while reducing temperature (Pitchot et al, 2002;Seletti et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Occupancy of Agonist Drugs at the 5-HT1A Receptor

Bantick

Rabiner

Hirani

et al. 2003

Neuropsychopharmacol

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Drugs acting on the 5-HT 1A receptor are used in the treatment of depression, generalized anxiety disorder, and schizophrenia. This study investigated 5-HT 1A receptor occupancy by the 5-HT 1A agonist drugs flesinoxan (a highly selective probe for the 5-HT 1A receptor) and ziprasidone (a novel atypical antipsychotic drug). Using a within-subject design, 14 healthy volunteers each received two positron emission tomography scans using the selective 5-HT 1A antagonist radiotracer [ 11 C]WAY-100635. One scan constituted a baseline, while the other followed either 1 mg flesinoxan or 40 mg ziprasidone orally. In addition, rats were pretreated with intravenous flesinoxan at doses ranging from 0.001 to 5 mg/kg then [ 11 C]WAY-100635 binding measured ex vivo. Cerebral cortical and hippocampal regions of interest, and cerebellar reference regions were sampled to estimate 5-HT 1A receptor occupancy (inferred from reductions in specific radioligand binding). In man, occupancy was not significant despite volunteers experiencing side effects consistent with central serotonergic activity. The mean cerebral cortex occupancy (71 SD) for flesinoxan was 8.7% (713%), and for ziprasidone 4.6% (717%). However, in rats, flesinoxan achieved significant and dose-related occupancy (17-57%) at 0.25 mg/kg and above. We conclude that 5-HT 1A receptor agonists produce detectable occupancy only at higher doses that would produce unacceptable levels of side effects in man, although lower doses are sufficient to produce pharmacological effects. The development of agonist radiotracers may increase the sensitivity of detecting agonist binding, as 5-HT 1A antagonists bind equally to low-and high-affinity receptor states, while agonists bind preferentially to the high-affinity state.

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“…; Basse-Tomusc and Rebec, 1986;Cox et al, 1993), or flesinoxan (21-108 mg/kg i.v. ; Gobert et al, 1995;Hadrava et al, 1995).…”

Section: -Ht and Dual Action Antidepressant L Romero Et Alunclassified

Modulation of Serotonergic Function in Rat Brain by VN2222, a Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist

Romero

Celada

Martı́n-Ruiz

et al. 2002

Neuropsychopharmacol

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VN2222(1-(benzo [b]thiophen-3-yl)-3-[4-(2-methoxiphenyl piperazin-1-yl]propan-1-ol) is a potential antidepressant with high affinity for the serotonin transporter and 5-HT 1A receptors. Locally applied, VN2222 enhanced the extracellular 5-hydroxytryptamine (5-HT) concentration (5-HT ext ) in rat striatum to 780% of baseline whereas its systemic administration (1-10 mg/kg s.c.) reduced 5-HT ext . In the presence of citalopram, 8-OH-DPAT or VN2222 applied in medial prefrontal cortex reduced 5-HT ext . Fluoxetine, VN2222, and 8-OH-DPAT suppressed the firing rate of dorsal raphe 5-HT neurons (ED 50 : 790, 14.9, and 0.8 mg/kg i.v., respectively). These effects were antagonized by WAY 100635. Administration of VN2222 for 2 weeks desensitized 5-HT 1A receptors as assessed by microdialysis and single-unit recordings (ED 50 values for 8-OH-DPAT were 0.45 and 2.34 mg/kg i.v. for controls and rats treated with 6 mg/kg day VN2222). These results show that VN2222 is a mixed 5-HT reuptake inhibitor/5-HT 1A agonist that markedly desensitizes 5-HT 1A autoreceptors. These properties suggest that it may be a clinically effective dual action antidepressant drug.

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Characterization of 5-hydroxytryptamine1A properties of flesinoxan: In Vivo electrophysiology and hypothermia study

Cited by 55 publications

References 31 publications

Potentiation by (-)Pindolol of the Activation of Postsynaptic 5-HT1A Receptors Induced by Venlafaxine

Potentiation by (-)Pindolol of the Activation of Postsynaptic 5-HT1A Receptors Induced by Venlafaxine

Occupancy of Agonist Drugs at the 5-HT1A Receptor

Modulation of Serotonergic Function in Rat Brain by VN2222, a Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist

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