Effect of sustained administration of the 5-HT1A receptor agonist flesinoxan on rat 5-HT neurotransmission

Haddjeri, Nasser; Ortemann, Catherine; Montigny, Claude de; Blier, Pierre

doi:10.1016/s0924-977x(99)00020-6

Cited by 30 publications

(11 citation statements)

References 42 publications

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“…The five-fold shift of the sensitivity of 5-HT 1A receptors produced by 6 mg/kg day VN2222 is greater than that produced by maximal doses of SSRIs and selective 5-HT 1A receptor agonists (Haddjeri et al, 1999;Le Poul et al, 1995, 1999 and suggests a very efficient desensitization of 5-HT 1A autoreceptors controlling serotonergic cell firing. Interestingly, the baseline firing rate of rats treated chronically with VN2222 was higher, although not significantly different from controls, which suggests that 5-HT neurons hadFat leastFrecovered their normal firing rate, in agreement with previous observations with other antidepressant drugs (Blier and de Montigny, 1994).…”

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

confidence: 85%

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

confidence: 85%

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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“…This contention receives further support from electrophysiological studies with the 5-HT 1A receptor agonist flesinoxan. Thus, tolerance develops to the flesinoxan-induced suppression of firing in serotonergic dorsal raphe neurons, but not to postsynaptic 5-HT 1A receptor mediated effects in the dorsal hippocampus (Haddjeri et al 1999). The present results suggest two possible reasons why hypothermia is not commonly observed in patients treated with SSRIs.…”

Section: Interactions Between 5-ht 1 Receptor Antagonists and Ssrismentioning

confidence: 96%

Involvement of 5-HT 1A and 5-HT 1B receptors for citalopram-induced hypothermia in the rat

Oerther

Ahlénius

2001

Psychopharmacology

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“…That said, much evidence suggests that chronic SSRI treatment does not affect postsynaptic 5-HT 1A receptor sensitivity (Dong et al, 1999;Le Poul et al, 2000;Li et al, 1997;Hensler, 2002). Indeed, as chronic administration of direct 5-HT 1A receptor agonists has been shown not to alter 5-HT 1A receptor sensitivity in CA3 (Dong et al, 1997;Haddjeri et al, 1999), one can conclude that these receptors are unresponsive to agonist-induced downregulation or desensitization. Thus, although the combined treatment with fluoxetine and Org 34850 causes a marked increase in extracellular 5-HT (Johnson et al, 2007), we would predict that this would not alter 5-HT 1A receptor sensitivity.…”

Section: Postsynaptic 5-ht 1a Receptorsmentioning

confidence: 99%

Glucocorticoid Receptor Antagonism Augments Fluoxetine-Induced Downregulation of the 5-HT Transporter

Johnson

Ingram

Grant³

et al. 2008

Neuropsychopharmacol

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The effects of combined treatment with a glucocorticoid receptor (GR) antagonist, Org 34850, and a selective serotonin reuptake inhibitor (SSRI), fluoxetine, were investigated on pre-and postsynaptic aspects of 5-HT neurotransmission. Rats were treated for 14 days with Org 34850 (15 mg per kg per day subcutaneously), fluoxetine (10 mg per kg per day intraperitoneally), or a combination of both drugs.[3 H]-citalopram binding (an index of 5-HT transporter (5-HTT) expression) was only slightly affected by Org 34850 alone: decreased in cortex and midbrain and increased in hippocampus. In contrast, chronic fluoxetine markedly decreased 5-HTT levels in all regions. Importantly, this decrease was significantly enhanced by combined Org 34850/fluoxetine treatment. There were no changes in the expression of 5-HTT mRNA, suggesting these effects were not due to changes in gene transcription. Expression of tryptophan hydroxylase mRNA and both 5-HT 1A autoreceptor mRNA and protein (assessed using [3 H]-8-OH-DPAT binding) were unchanged by any treatment. The expression of postsynaptic 5-HT 1A receptor protein in the forebrain was unaltered by fluoxetine, Org 34850 or the combined Org 34850/fluoxetine treatment. This downregulation of 5-HTT by fluoxetine and its enhancement by Org 34850 can explain our recent observation that GR antagonists augment the SSRI-induced increase in extracellular 5-HT. In addition, these data suggest that the augmentation of forebrain 5-HT does not result in downregulation of forebrain 5-HT 1A receptor expression. Given the importance of 5-HT 1A receptor-mediated transmission in the forebrain to the antidepressant response, these data indicate that co-administration of GR antagonists may be effective in augmenting the antidepressant response to SSRI treatment.

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Effect of sustained administration of the 5-HT1A receptor agonist flesinoxan on rat 5-HT neurotransmission

Cited by 30 publications

References 42 publications

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

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

Involvement of 5-HT 1A and 5-HT 1B receptors for citalopram-induced hypothermia in the rat

Glucocorticoid Receptor Antagonism Augments Fluoxetine-Induced Downregulation of the 5-HT Transporter

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