| 1. |
- Hagsäter, S Melker, et al.
(författare)
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5-HT6 receptor antagonism reduces defecation in rat: A potential treatment strategy for irritable bowel syndrome with diarrhea
- 2019
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 864
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Tidskriftsartikel (refereegranskat)abstract
- © 2019 Elsevier B.V. Whereas the potential role of serotonin for the pathophysiology of irritable bowel syndrome (IBS) has since long been discussed, the possibility that 5-hydroxytryptamine 6 (5-HT6) receptors may serve as targets for the treatment of this condition has as yet not been explored. The aim of the current study was to assess to what extent defecation in rats is influenced by manipulation of 5-HT6 receptors. Reduced defecation following SB-399885 was observed in non-stressed animals assessed for 7 h after drug administration. While not impacting context-conditioned freezing, three 5-HT6 receptor antagonists (SB-399885, SB-271046 and SB-258585) also markedly reduced the number of faecal boli produced by rats exposed to context-conditioned fear. In contrast, a 5-HT6 receptor agonist, WAY-208466, influenced defecation neither in unstressed animals nor in rats experiencing conditioned fear stress. A clinical study on the possible effect of a 5-HT6 receptor antagonist in IBS with diarrhea appears warranted.
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| 2. |
- Hagsäter, S Melker, et al.
(författare)
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A Complex Impact of Systemically Administered 5-HT2A Receptor Ligands on Conditioned Fear
- 2021
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Ingår i: International Journal of Neuropsychopharmacology. - : Oxford University Press (OUP). - 1461-1457 .- 1469-5111. ; 24:9, s. 749-757
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Tidskriftsartikel (refereegranskat)abstract
- Background: Though drugs binding to serotonergic 5-HT2A receptors have long been claimed to influence human anxiety, it remains unclear if this receptor subtype is best described as anxiety promoting or anxiety dampening. Whereas conditioned fear expressed as freezing in rats is modified by application of 5-HT2A-acting drugs locally into different brain regions, reports on the effect of systemic administration of 5-HT2A receptor agonists and 5-HT2A antagonists or inverse agonists on this behavior remain sparse. Methods: We assessed the possible impact of systemic administration of 5-HT2A receptor agonists, 5-HT2A receptor inverse agonists, and a selective serotonin reuptake inhibitor (SSRI)-per se or in combination-on the freezing displayed by male rats when re-exposed to a conditioning chamber in which they received foot shocks 7 days earlier. Results: The 5-HT2A receptor agonists psilocybin and 25CN-NBOH induced a reduction in conditioned fear that was countered by pretreatment with 5-HT2A receptor inverse agonist MDL 100907. While both MDL 100907 and another 5-HT2A receptor inverse agonist, pimavanserin, failed to impact freezing per se, both compounds unmasked a robust fear-reducing effect of an SSRI, escitalopram, which by itself exerted no such effect. Conclusions: The results indicate that 5-HT2A receptor activation is not a prerequisite for normal conditioned freezing in rats but that this receptor subtype, when selectively over-activated prior to expression, exerts a marked fear-reducing influence. However, in the presence of an SSRI, the 5-HT2A receptor, on the contrary, appears to counter an anti-freezing effect of the enhanced extracellular serotonin levels following reuptake inhibition.
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| 3. |
- Hagsäter, S Melker, et al.
(författare)
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Selective serotonin reuptake inhibition increases noise burst-induced unconditioned and context-conditioned freezing.
- 2019
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Ingår i: Acta neuropsychiatrica. - : Cambridge University Press (CUP). - 1601-5215 .- 0924-2708. ; 31:1, s. 46-51
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Tidskriftsartikel (refereegranskat)abstract
- Whereas long-term administration of selective serotonin reuptake inhibitors (SSRIs) is effective for the treatment of anxiety disorders, acute administration of these drugs may exert a paradoxical anxiogenic effect. The aim of the present study was to explore the possible effect of an SSRI in situations of unconditioned or limited conditioned fear.Male Sprague Dawley rats were administered a single dose of an SSRI, escitalopram, before acquisition or expression of context conditioned fear, where noise bursts were used as the unconditioned stimulus. Freezing was assessed as a measure of unconditioned fear (=the acute response to noise bursts) or conditioned fear (=the response to the context), respectively.Noise bursts elicited an acute increase in freezing but no robust conditioned response 7 days after exposure. Administration of escitalopram before testing exacerbated the freezing response during presentation of the unconditioned stimulus and also unmasked a conditioned response; in contrast, administration of escitalopram prior to acquisition did not influence the conditioned response.The data suggest that freezing in rats exposed to a stimulus inducing relatively mild fear may be enhanced by acute pretreatment with an SSRI regardless of whether the freezing displayed by the animals is an acute unconditioned response to the stimulus in question or a conditioned response to the same stimulus.
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| 4. |
- Hagsäter, S Melker, et al.
(författare)
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Serotonin depletion reduces both acquisition and expression of context-conditioned fear.
- 2021
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Ingår i: Acta neuropsychiatrica. - : Cambridge University Press (CUP). - 1601-5215 .- 0924-2708. ; 33:3, s. 148-155
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Tidskriftsartikel (refereegranskat)abstract
- Whereas numerous experimental and clinical studies suggest a complex involvement of serotonin in the regulation of anxiety, it remains to be clarified if the dominating impact of this transmitter is best described as anxiety-reducing or anxiety-promoting. The aim of this study was to assess the impact of serotonin depletion on acquisition, consolidation, and expression of conditioned fear.Male Sprague-Dawley rats were exposed to foot shocks as unconditioned stimulus and assessed with respect to freezing behaviour when re-subjected to context. Serotonin depletion was achieved by administration of a serotonin synthesis inhibitor, para-chlorophenylalanine (PCPA) (300mg/kg daily×3), (i) throughout the period from (and including) acquisition to (and including) expression, (ii) during acquisition but not expression, (iii) after acquisition only, and (iv) during expression only.The time spent freezing was significantly reduced in animals that were serotonin-depleted during the entire period from (and including) acquisition to (and including) expression, as well as in those being serotonin-depleted during either acquisition only or expression only. In contrast, PCPA administrated immediately after acquisition, that is during memory consolidation, did not impact the expression of conditioned fear.Intact serotonergic neurotransmission is important for both acquisition and expression of context-conditioned fear.
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| 5. |
- Hagsäter, S Melker
(författare)
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Serotonin in Fear and Anxiety
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- That the neurotransmitter serotonin (5-HT) has a central role in fear and anxiety is supported by numerous experimental and clinical studies. Arguably the most illustrative example is the effect of serotonergic-acting drugs, and in particular the selective serotonin reuptake inhibitors (SSRIs), in the treatment of anxiety disorders. Interestingly, long-term administration is required to induce a dampening effect on anxiety, while on the contrary acute administration can aggravate the symptoms in susceptible individuals. Freezing behaviour is a well-established measure of fear and anxiety, foremost assessed in studies performed on rodents. The bulk of the experiments presented in this thesis investigate the effect of pharmacological manipulations of the serotonin system on conditioned and unconditioned freezing behaviour. In paper I, the importance of an intact serotonergic neurotransmission in fear conditioning was explored. The serotonin system was compromised by administration of the serotonin-depleting agent para-chlorophenylalanine (PCPA). PCPA impaired both acquisition and expression of conditioned fear without imposing an effect on memory consolidation, supporting the notion that fear-induced release of serotonin primarily promotes rather than dampens fear conditioning. In paper II, the effects of 5-HT2A receptor agonism and antagonism alone and in combination with administration of an SSRI were investigated. The first main finding was that while administration of neither the 5-HT2A receptor antagonist MDL 100907 nor the 5-HT2A receptor inverse agonist pimavanserin consistently reduced expression of conditioned freezing, a marked reduction of fear was observed after administration of either drug combined with an SSRI. The second main finding was that administration of both a selective agonist for the 5-HT2A receptor and the psychedelic drug psilocybin reduced expression of conditioned freezing, an effect that was totally abolished by coadministration with MDL 100907. The experiments demonstrated that the 5-HT2A receptors have the ability to modulate fear expression in both directions, putatively involving 5-HT2A receptor populations in different areas of the brain. In paper III, the effects of chronic and acute administration of an SSRI were compared. Chronic administration but not acute administration induced a dampening effect on anxiety. Since these findings mirror the clinical situation, context-conditioned freezing could supposedly be applied in animal studies on the mechanism of action for the sluggish effects of SSRIs in anxiety disorders.In paper IV, the effect of acute administration of an SSRI was evaluated in a model of unconditioned fear. Acoustic noise bursts constituted the unconditioned stimulus. The SSRI increased the expression of unconditioned fear. Unconditioned models are tentatively related to panic disorder, the condition in which aggravation of anxiety after acute administration of an SSRI is most pronounced, suggesting that noise burst induced freezing presumably could be a useful tool in preclinical studies on the anxiety-provoking effects of SSRIs. In paper V, the effect of 5-HT6 receptor manipulations on gut motility was explored. It was found that 5-HT6 receptor antagonists reduced defecation in both stressed (fear conditioned) and non-stressed animals while an agonist for the same receptor was void of effect. This mechanism could putatively be utilized in the treatment of irritable bowel syndrome with diarrhea (IBS-D). In summary, the studies on rats presented in this thesis suggest that i) intact serotonergic transmission is required for both acquisition and expression of conditioned fear, ii) that the 5-HT2A receptor has an important role in modulating conditioned fear, iii) that chronic administration of an SSRI, in contrast to acute administration, reduces conditioned fear, iv) that acute administration of an SSRI increases unconditioned fear and v) that 5-HT6 receptor antagonism impairs gut motility.
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| 6. |
- Manneberg, Otto, 1981-, et al.
(författare)
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Spatial confinement of ultrasonic force fields in microfluidic chips
- 2009
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Ingår i: Ultrasonics. - : Elsevier BV. - 0041-624X .- 1874-9968. ; 49, s. 112-119
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Tidskriftsartikel (refereegranskat)abstract
- We demonstrate and investigate multiple localized ultrasonic manipulation functions in series in microfluidic chips. The manipulation functions are based on spatially separated and confined ultrasonic primary radiation force fields, obtained by local matching of the resonance condition of the microfluidic channel. The channel segments are remotely actuated by the use of frequency-specific external transducers with refracting wedges placed on top of the chips. The force field in each channel segment is characterized by the use of micrometer-resolution particle image velocimetry ( micro-PIV). The confinement of the ultrasonic fields during single-or dual-segment actuation, as well as the cross-talk between two adjacent. fields, is characterized and quantified. Our results show that the field confinement typically scales with the acoustic wavelength, and that the cross-talk is insignificant between adjacent. fields. The goal is to define design strategies for implementing several spatially separated ultrasonic manipulation functions in series for use in advanced particle or cell handling and processing applications. One such proof-of-concept application is demonstrated, where. flow-through-mode operation of a chip with. flow splitting elements is used for two-dimensional pre-alignment and addressable merging of particle tracks.
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| 7. |
- Näslund, Jakob, et al.
(författare)
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Differences in anxiety-like behavior within a batch of wistar rats are associated with differences in serotonergic transmission, enhanced by acute sri administration, and abolished by serotonin depletion
- 2015
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Ingår i: International Journal of Neuropsychopharmacology. - : Oxford University Press (OUP). - 1461-1457 .- 1469-5111. ; 18:8, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Background: The anxiety-reducing effect of long-term administration of serotonin reuptake inhibitors is usually seen only in subjects with anxiety disorders, and such patients are also abnormally inclined to experience a paradoxical anxietyenhancing effect of acute serotonin reuptake inhibition. These unique responses to serotonin reuptake inhibitors in anxietyprone subjects suggest, as do genetic association studies, that inter-individual differences in anxiety may be associated with differences in serotonergic transmission. Methods: The one-third of the animals within a batch of Wistar rats most inclined to spend time on open arms in the elevated plus maze were compared with the one-third most inclined to avoid them with respect to indices of brain serotonergic transmission and how their behavior was influenced by serotonin-modulating drugs. Results: "Anxious" rats displayed higher expression of the tryptophan hydroxylase-2 gene and higher levels of the tryptophan hydroxylase-2 protein in raphe and also higher levels of serotonin in amygdala. Supporting these differences to be important for the behavioral differences, serotonin depletion obtained by the tryptophan hydroxylase-2 inhibitor p-chlorophenylalanine eliminated them by reducing anxiety in "anxious" but not "non-anxious" rats. Acute administration of a serotonin reuptake inhibitor, paroxetine, exerted an anxiety-enhancing effect in "anxious" but not "non-anxious" rats, which was eliminated by long-term pretreatment with another serotonin reuptake inhibitor, escitalopram. Conclusions: Differences in an anxiogenic impact of serotonin, which is enhanced by acute serotonin reuptake inhibitor administration, may contribute to differences in anxiety-like behavior amongst Wistar rats..
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| 8. |
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| 9. |
- Pettersson, Robert, 1985, et al.
(författare)
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Serotonin depletion eliminates sex differences with respect to context-conditioned immobility in rat
- 2016
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Ingår i: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 233:8, s. 1513-1521
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that male rats display more anxiety-like behavior than females as assessed using the elevated plus maze and that serotonin depletion abolishes this difference by exerting an anxiolytic-like effect in males only. To compare male and female rats with respect to immobility and startle responses to sudden noise bursts after contextual fear conditioning and to explore to what extent any possible sex difference in this regard is influenced by serotonin depletion during testing (but not acquisition). In line with previous studies, males displayed more immobility following contextual conditioning induced by previous exposure to foot shocks than females. In males but not females, the immobility response was reduced by administration of the serotonin synthesis inhibitor para-chlorophenylalanine (PCPA) between shock exposure and testing, the consequence being that males and females no longer differed in this regard. Untreated males but not females displayed a negative correlation between fear-conditioned startle and immobility, suggesting that the latter behavior, when excessive, interferes with the former. In line with this assumption, the reduction in immobility following administration of PCPA in males coincided with an increase in startle that was not observed in females, hence revealing a sex difference in startle not seen in untreated controls. The greater display of context-conditioned immobility in males compared with females appears to be serotonin-dependent.
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