Effect of a selective 5‐HT reuptake inhibitor in combination with 5‐HT1A and 5‐HT1B receptor antagonists on extracellular 5‐HT in rat frontal cortex in vivo

Sharp, Trevor; Umbers, Valerie; Gartside, Sarah E.

doi:10.1038/sj.bjp.0701235

Cited by 127 publications

(90 citation statements)

References 27 publications

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“…However, a small or no increase in 5-HT has been measured using microdialysis following acute SSRI administration (Sharp et al, 1997;Roberts et al, 1999;Dawson and Nguyen, 2000) questioning whether the acute anxiolytic effects are due to changes in 5-HT levels or whether other neurotransmitter systems play a role. It could be postulated that an overflow technique such as microdialysis simply lacks the sensitivity to measure small changes in 5-HT, and increases in synaptic 5-HT are sufficient to mediate the observed acute anxiolytic effect.…”

Section: Discussionmentioning

confidence: 99%

“…Preclinical microdialysis studies have demonstrated that the selective 5-HT 1B receptor antagonist SB-224289 augments the 5-HT increase seen with paroxetine, and that WAY100635 further potentiates this effect (Roberts et al, 1999). Another 5-HT 1B/D receptor antagonist, GR127935, also augments an SSRI effect in microdialysis (Rollema et al, 1996;Gobert et al, 1997) and potentiates the effects of an SSRI/5-HT 1A receptor antagonist combination (Sharp et al, 1997;Dawson and Nguyen, 2000). Therefore, 5-HT 1A/B/D receptor antagonism may play a beneficial role in the augmentation of the effects of SSRIs.…”

Section: Introductionmentioning

confidence: 99%

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SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

Starr

Price

Watson

et al. 2007

Neuropsychopharmacol

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Preclinically, the combination of an SSRI and 5-HT autoreceptor antagonist has been shown to reduce the time to onset of anxiolytic activity compared to an SSRI alone. In accordance with this, clinical data suggest the coadministration of an SSRI and (7) pindolol can decrease the time to onset of anxiolytic/antidepressant activity. Thus, the dual-acting novel SSRI and 5-HT 1A/B receptor antagonist, SB-649915-B, has been assessed in acute and chronic preclinical models of anxiolysis. SB-649915-B (0.1-1.0 mg/kg, i.p.) significantly reduced ultrasonic vocalization in male rat pups separated from their mothers (ED 50 of 0.17 mg/kg). In the marmoset human threat test SB-649915-B (3.0 and 10 mg/kg, s.c.) significantly reduced the number of postures with no effect on locomotion. In the rat high light social interaction (SI), SB-649915-B (1.0-7.5 mg/kg, t.i.d.) and paroxetine (3.0 mg/kg, once daily) were orally administered for 4, 7, and 21 days. Ex vivo inhibition of [ 3 H]5-HT uptake was also measured following SI. SB-649915-B and paroxetine had no effect on SI after 4 days. In contrast to paroxetine, SB-649915-B (1.0 and 3.0 mg/kg, p.o., t.i.d.) significantly (po0.05) increased SI time with no effect on locomotion, indicative of an anxiolytic-like profile on day 7. Anxiolysis was maintained after chronic (21 days) administration by which time paroxetine also increased SI significantly. 5-HT uptake was inhibited by SB-649915-B at all time points to a similar magnitude as that seen with paroxetine. In conclusion, SB-649915-B is acutely anxiolytic and reduces the latency to onset of anxiolytic behavior compared to paroxetine in the SI model.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

Starr

Price

Watson

et al. 2007

Neuropsychopharmacol

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“…Given that in functional assays (-)pindolol acts as an antagonist at the latter receptor (Schoeffter and Hoyer 1989), it is plausible that the latter property could account, at least in part, for the potentiating effect of (-)pindolol on the suppressant effect of venlafaxine on the firing activity of hippocampal neurons that was observed in the present study. Nonetheless, while in vivo microdialysis studies suggest that a 5-HT 1B antagonism may increase the output of 5-HT elicited by 5-HT reuptake inhibitors, there is evidence that this would only be so in the presence of normal firing of 5-HT neurons, i.e., in the presence of an adequate 5-HT 1A autoreceptor blockade (Hjorth 1993;Sharp et al 1997). The 5-HT 1A antagonism of (-)pindolol, thus, appears to be a sine qua non condition for its 5-HT 1B antagonistic property to be of functional relevance.…”

Section: Discussionmentioning

confidence: 99%

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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“…Since SSRIs produce a tonic elevation of serotonin levels in the extracellular space (Fuller, 1994;Malagié et al, 1995), their therapeutic effect is probably mediated, at least in part, by action at various levels of the serotonergic system, notably at serotonergic receptors (Barnes and Sharp, 1999). In particular, it has been proposed that the antidepressant effects of SSRIs would be related to desensitization of somatodendritic 5-HT 1A and terminal 5-HT 1B autoreceptors (Blier et al, 1987;Artigas et al, 1994Artigas et al, , 2001Pineyro and Blier, 1999), which is induced by and participates indirectly in the increase in 5-HT concentration in the extracellular space (Gartside et al, 1995(Gartside et al, , 1999Sharp et al, 1997;Trillat et al, 1998;Adell et al, 2001;Malagié et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

5-HT1A/1B Receptor-Mediated Effects of the Selective Serotonin Reuptake Inhibitor, Citalopram, on Sleep: Studies in 5-HT1A and 5-HT1B Knockout Mice

Monaca

Boutrel

Hen

et al. 2002

Neuropsychopharmacol

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Selective serotonin reuptake inhibitors (SSRIs) are extensively used for the treatment of depression. Aside from their antidepressant properties, they provoke a deficit in paradoxical sleep (PS) that is most probably mediated by the transporter blockade-induced increase in serotonin concentration in the extracellular space. Such an effect can be accounted for by the action of serotonin at various types of serotonergic receptors involved in PS regulation, among which the 5-HT 1A and 5-HT 1B types are the best candidates. According to this hypothesis, we examined the effects of citalopram, the most selective SSRI available to date, on sleep in the mouse after inactivation of 5-HT 1A or 5-HT 1B receptors, either by homologous recombination of their encoding genes, or pharmacological blockade with selective antagonists. For this purpose, sleep parameters of knockout mice that do not express these receptors and their wild-type counterparts were monitored during 8 h after injection of citalopram alone or in association with 5-HT 1A or 5-HT 1B receptor antagonists. Citalopram induced mainly a dose-dependent inhibition of PS during 2-6 h after injection, which was observed in wild-type and 5-HT 1B À/À mice, but not in 5-HT 1A À/À mutants. This PS inhibition was fully antagonized by pretreatment with the 5-HT 1A antagonist WAY 100635, but only partially with the 5-HT 1B antagonist GR 127935. These data indicate that the action of the SSRI citalopram on sleep in the mouse is essentially mediated by 5-HT 1A receptors. Such a mechanism of action provides further support to the clinical strategy of antidepressant augmentation by 5-HT 1A antagonists, because the latter would also counteract the direct sleep-inhibitory side-effects of SSRIs.

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Effect of a selective 5‐HT reuptake inhibitor in combination with 5‐HT_1A and 5‐HT_1B receptor antagonists on extracellular 5‐HT in rat frontal cortex in vivo

Cited by 127 publications

References 27 publications

SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

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

5-HT1A/1B Receptor-Mediated Effects of the Selective Serotonin Reuptake Inhibitor, Citalopram, on Sleep: Studies in 5-HT1A and 5-HT1B Knockout Mice

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