Repeated administration of the 5-HT1B receptor antagonist SB-224289 blocks the desensitisation of 5-HT1B autoreceptors induced by fluoxetine in rat frontal cortex

Shalom, G.; Gur, Eitan; Kar, Louis D. Van de; Newman, Morris

doi:10.1007/s00210-004-0958-x

Cited by 16 publications

(8 citation statements)

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“…This has been previously demonstrated in guinea pigs in both frontal cortex and dentate gyrus (Roberts et al 2000), and we demonstrate here that 21 days paroxetine treatment produced an augmented SSRI-induced effect in the rat frontal cortex (when compared to an acute administration). Chronic SSRI treatment has been demonstrated to produce a functional desensitization of 5-HT 1A (Chaput et al 1986;Blier et al 1987;Le Poul et al 1995; and also possibly 5-HT 1B receptors (Shalom et al 2004), although the data for the latter are contradictory (Gobbi et al 1997; for review on both receptors see Hjorth et al 2000). Thus, co-administration of 5-HT 1A/B receptor antagonists (either as separate molecules or as a single molecule such as SB-649915-B) prevents this need for desensitization (Hervas et al 2001;Dawson et al , 2002 and, thus, produces acute increases in forebrain 5-HT.…”

Section: Discussionmentioning

confidence: 98%

Simultaneous blockade of 5-HT1A/B receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT1A/B receptor antagonist/5-HT transport inhibitor SB-649915-B

et al. 2007

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Section: Discussionmentioning

confidence: 98%

Simultaneous blockade of 5-HT1A/B receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT1A/B receptor antagonist/5-HT transport inhibitor SB-649915-B

et al. 2007

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“…There is also evidence that 5-HT 1B receptor desensitization is seen following chronic SSRI treatment indicating that these receptors may play a part in mediating the effects seen with SSRIs (Blier and Bouchard, 1994;Newman et al, 2004;Shalom et al, 2004). 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).…”

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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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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“…This elevated level of 5-HT, in turn, stimulates 5-HT receptors to initiate a cascade of effects and relieve the symptoms of repetitive behaviors. However, the elevated 5-HT level also stimulates inhibitory autoreceptors (5-HT 1B/1D ) which by definition, regulate the release of 5-HT in an inhibitory manner and negatively affect the mode of action of SSRIs [5,6]. It is, thus, anticipated that coadministration of SSRIs with 5-HT 1B/1D receptor antagonists to be advantageous over SSRIs alone with respect to the magnitude of extracellular brain 5-HT levels produced [7][8][9].…”

Section: Background and Significancementioning

confidence: 99%

Selective Serotonin Reuptake Inhibitors (SSRIs) with Dual Functionality; Hybrid Anti-Autism Candidates

Ghoneim¹

2011

TOPROCJ

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Autism is a lifelong neurodevelopmental disorder significantly on the rise worldwide. Prevalence rate increased dramatically from 1 case/10000 in the early 90's to 1 case/110 in 2011. The diagnosis is characterized by three main domains: dysfunction in social interaction, communication impairment and repetitive behaviors. Selective Serotonin Reuptake Inhibitors (SSRIs) are currently the drug class of choice for treating autism symptoms. The major drawback of SSRIs is that they take several weeks to become therapeutically efficient. Co-administration of SSRIs with 5-HT 1B/1D receptor antagonists proved to be advantageous over SSRIs alone with respect to the magnitude of brain serotonin levels produced. The theory is that the acute blockade of 5-HT 1B/1D receptor would prevent the negative feedback these autoreceptors exert normally on serotonin release and hence enhance the efficiency of SSRIs (i.e. synergistic effect).We hypothesize to incorporate the dual pharmacophoric profile of serotonin reuptake inhibition and 5-HT 1B/1D antagonism in one single molecule carrying dual functionalities. A library of 12 virtual hybrids was successfully designed. The organic synthesis of two chosen hybrids was completed with full structure elucidation, including elemental analysis and proton-Nuclear Magnetic Resonance.The main outcome of the study is obtaining an unprecedented library of novel hybrid molecules combining serotonin reuptake inhibition with 5HT 1B/1D antagonism in one single molecule. In addition, establishing chemical synthesis and other foundation materials needed for further investigation (In vitro and in vivo pharmacological evaluation) towards our ultimate goal of developing new therapeutic line of autism, where no other lines of treatment have been consistently successful.

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Repeated administration of the 5-HT1B receptor antagonist SB-224289 blocks the desensitisation of 5-HT1B autoreceptors induced by fluoxetine in rat frontal cortex

Cited by 16 publications

References 31 publications

Simultaneous blockade of 5-HT1A/B receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT1A/B receptor antagonist/5-HT transport inhibitor SB-649915-B

Simultaneous blockade of 5-HT1A/B receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT1A/B receptor antagonist/5-HT transport inhibitor SB-649915-B

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

Selective Serotonin Reuptake Inhibitors (SSRIs) with Dual Functionality; Hybrid Anti-Autism Candidates

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