Thesis (doctoral)--Lund University, 1995. / Added t.p. with thesis statement inserted.

In 1985, Mendelson and Gorzalka proposed the dual role hypothesis of serotonergic modulation of lordosis behaviour. In this hypothesis it was proposed that serotonergic activity can either inhibit or facilitate lordosis behaviour. Specifically it was suggested that the lordosis-inhibiting effects of serotonin are mediated by activity at 5-HT₁ receptors, whereas lordosis-facilitating effects of serotonin are mediated by activity at 5-HT₂ receptors. The purpose of the following series of studies was both to confirm and to extend the dual role hypothesis. The intraperitoneal administration of the 5-HT2 antagonists pizotefin (1 mg/kg), cyproheptadine (1 mg/kg), metitepine (1 mg/kg), and ketanserin (1 mg/kg) were found to inhibit lordosis behavior in ovariectomized rats that had been primed with estradiol benzoate (EB) and progesterone (P). Pipamperone was ineffective. The 5-HT₂ agonist guipazine (3 mg/kg) was ineffective alone, but it reversed the inhibitory effects of pizotefin, cyproheptadine, and ketanserin. It did not reverse the effects of metitepine. The highly selective 5-HT₂ antagonist LY53857 (0.3 mg/kg) was also found to inhibit lordosis behaviour in female rats that had been primed with EB and P. The lordosis-inhibiting effect of LY53857 (1 mg/kg) in females primed with EB and P was reversed by quipazine (3 mg/kg). The nonselective 5-HT antagonist methysergide (7 mg/kg) was found to inhibit lordosis behavior 30 min after intraperitoneal administration to females treated chronically with EB, or with EB and P. However, methysergide was found to facilitate lordosis behavior 200 and 300 min after administration to female rats treated acutely with EB. In an analysis of dose response it was found that methysergide (0.02 - 7 mg/kg) administered 30 min prior to behavioural testing produced no facilitation of lordosis in females primed with EB. However, when administered 200 min prior to testing, methysergide (1 mg/kg) produced a significant facilitation of lordosis. The administration of the 5-HT₁ A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT) inhibited lordosis behavior in ovariectomized rats primed with EB. 8-OH DPAT was ineffective at 0.01 mg/kg, whereas inhibition occurred at the 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg doses. In an evaluation of the effects of 8-OH DPAT on the expression of male sexual behaviour by females treated chronically with testosterone, 8-OH DPAT ( 1 mg/kg) increased the number of females mounting and significantly increased mount frequency. The 5-HT₁ A agonists ipsapirone (0.1 mg/kg) and gepirone (0.3 mg/kg) facilitated lordosis in females treated with EB. When administered at higher doses, ipsapirone (3.0 mg/kg) and buspirone (3.0 mg/kg) inhibited lordosis in rats treated with EB. In females treated with EB and P, ipsapirone (> 1.0 mg/kg), gepirone (> 0.3), and buspirone (> 0.3) inhibited lordosis behaviour. The newly developed 5-HT₁ A antagonist BMY 7378 (0.2 mg/kg) facilitated lordosis behaviour in females treated with EB. However, this facilitation was no longer apparent at the 5 mg/kg dose. BMY 7378 (0.04 - 5 mg/kg) was ineffective in females primed with EB and P. The 5-HTTB agonist 1 -(3-trifluoromethylphenyl)piperazine (TFMPP, 0.2 -5 mg/kg) was found to facilitate lordosis in females treated with EB. In females primed with EB and P, TFMPP (5 mg/kg) produced a significant inhibition of lordosis. The 5-HT₁ B agonist m-chlorophenylpiperazine (MCPP, 0.04 - 5 mg/kg) was ineffective in females primed either with EB or with EB and P. The 5-HT₃ Antagonist ICS 205-930 (5 mg/kg) was found to facilitate lordosis behaviour, whereas the 5-HT₃ Antagonist MDL 72222 (0.05 - 5 mg/kg ) was found to be ineffective in females primed with EB. The results of these studies tend to confirm that serotonergic activity can either inhibit or facilitate lordosis behaviour. It is suggested that the lordosis-inhibiting effects of serotonin are mediated by activity at postsynaptic 5-HTTA and possibly 5-HT₃ Receptors. The lordosis-facilitating effects of serotonin are mediated by activity at 5-HT₂ and possibly presynaptic 5-HT₁ B receptors. Finally, it is suggested that activity at somato-dendritic 5-HT₁ A autoreceptors may mediate facilitatory effects of low doses of 5-HT₁ A agonists. In closing, there is a discussion of the implications these results might hold for the understanding of the effects of serotonergic drugs on human behaviour. / Arts, Faculty of / Psychology, Department of / Graduate

The suprachiasmatic nucleus receives dense serotonergic projections from the raphe nuclei and this input has been implicated in the modulation of circadian rhythms. This input appears to have many functions including the transmission of non-photic information during the day and the modulation of photic information at night. However, it has emerged that this input may also be involved in the transmission of light information with activation of 5-HT2C receptors at night having a photo-mimetic effect. The studies described in this thesis aim to clarify the role of 5-HT2C receptors in the control of circadian rhythms in the rat model and compare their actions to light. The acute effects of 5-HT2C receptor agonist administration on clock gene expression were investigated in the rat SCN. Systemic administration of the 5-HT2A/2C agonist DOI to rats during early night induced c-fos, Per1 and Per2 expression in a manner similar to light. This response was time of day dependent with maximal induction occurring in the early night, and no response during the day. The role of 5-HT2C receptors in this response was confirmed with the use of the selective 5-HT2C receptor agonist RO-60 0175. The effect of 5-HT2C receptor activation on the phase of expression of various circadian rhythms including temperature, melatonin and clock gene expression in the SCN and periphery was examined. Both DOI administration and light exposure at night phase delayed rhythms of melatonin and temperature. Similarly, the selective 5-HT2C receptor agonist RO-60 0175 phase delayed rhythms of 6-sulphatoxymelatonin, a response which was antagonised by the 5-HT2C receptor antagonist SB-242084. The expression of functional and clock genes within the pineal was also phase delayed following both light and 5-HT2C receptor agonist administration. However, the phase of expression of clock genes within the SCN or liver did not shift in response to either a single nocturnal light pulse or agonist administration. To investigate the site of action of 5-HT2C receptor agonists, rat SCN explants were maintained in culture allowing exposure of agonists to denervated tissue. The acute effect of DOI administration at various circadian times on c-fos and Per1 expression was assessed. 5-HT2C receptor activation significantly increased Per1 expression when administered during early subjective night, but had no effect during either subjective day or late subjective night, similar to that observed in vivo. Finally, the suitability of immortalised rat SCN cells for investigation of the intracellular actions of 5-HT2C receptors in the circadian system was assessed. Using RT-PCR the expression of various serotonin receptors in the SCN2.2 cell line was compared with that observed in punches of adult rat SCN. The mRNA for 5-HT1B and 5-HT2A receptor was expressed in both the SCN2.2 cell line and the adult rat SCN. However, 5-HT2C receptor mRNA along with 5-HT3 receptor, 5-HT5A receptor and 5-HT7 receptor mRNA was expressed in the adult rat SCN tissue but not the SCN2.2 cells. These significant differences in serotonin receptor expression limit the usefulness of this cell line for further investigation. Together these experiments further implicate 5-HT2C receptors in the control of circadian rhythms. The role of these receptors appears limited to early night, with activation showing photo-mimetic responses. Furthermore, the location of action appears to be post-synaptic within the SCN, altering the core clock genes, which in turn phase delay various circadian rhythms. / Thesis(Ph.D.)-- School of Paediatrics and Reproductive Health, 2008

In der Behandlung neuropathischer und anderer chronischer Schmerzen werden trizyklische Antidepressiva bereits mit Erfolg eingesetzt, die nebenwirkungsärmeren SSRI zeigen jedoch nur einen mäßigen Erfolg. In dieser Studie gingen wir der Frage nach, inwieweit 5-HTT -/- Mäuse, die als Modell einer lebenslangen Behandlung mit SSRI gelten, in einem chronisch entzündlichen Schmerzmodell ein anderes Schmerzverhalten zeigen als Wild-typen und ob sich auf neuronaler Ebene durch das Ausschalten des 5-HT Transporters Ursachen für ein geändertes Schmerzverhalten finden lassen. Von besonderem Interesse war dabei auch, welche Rolle 5-HT in der peripheren Schmerzvermittlung zukommt. Mit standardisierten Testverfahren wurden die 5-HTT -/- Mäuse und Wildtypmäuse nach i.pl. Injektion von CFA auf zwei Schmerzqualitäten hin untersucht. Die Schmerzschwelle für taktile Reize wurde mit von Frey Haaren bestimmt, zur Testung der Hitzehyperalgesie wurde eine Infrarotwärmequelle benutzt. Anschließend wurden an dem Gewebe immunhistochemische Analysen durchgeführt und mittels HPLC der Gehalt an 5-HT in verschiedenen Gewebeproben bestimmt. Es konnte gezeigt werden, dass Mäuse mit dem Genotyp 5-HTT -/- gegenüber dem Wildtyp von einer durch CFA-Injektion induzierten Hitzehyperalgesie weitgehend unbeeinträchtigt bleiben. Gleichzeitig bestand bei den KO-Mäusen im Vergleich zu den Wildtypen eine deutlichere Abnahme der Hautinnervation sowie eine stärker ausgeprägte Verletzung von DRG-Neuronen, entsprechend einer erhöhten neuronalen Vulnerabilität gegenüber CFA. Im Gewebe der KO-Mäuse fand sich durchweg weniger 5-HT als bei Wildtypen, in DRG-Neuronen der KO-Mäuse war weiterhin weniger BDNF detektierbar. Wir postulieren, dass für die reduzierte Hitzehyperalgesie bei den KO-Mäusen unter anderem der geringere Gewebespiegel von 5-HT und damit folglich in einer Art Ursachen-Wirkungskette auch die geringeren Gewebespiegel von BDNF und 5-HIAA mit ihren entsprechenden Auswirkungen verantwortlich sind. 5-HTT -/- Mäuse als Modell für eine lebenslange Behandlung mit SSRI sind also nicht nur wie kürzlich beschrieben im neuropathischen Schmerzmodell, sondern auch in einem chronisch entzündlichen Schmerzmodell weitgehend vor einer Hitzehyperalgesie geschützt. Unter der Berücksichtigung dieser Daten sollte daher der Einsatz von SSRI in der Behandlung chronischer Schmerzen erneut überprüft werden. / Mice lacking the serotonin transporter (5-HTT-/- mice) develop reduced thermal hyperalgesia after nerve injury, concomitant with reduced serotonin (5-HT) levels in nervous tissue. Here we investigated pain behaviour in 5-HTT-/- mice compared to their wild type littermates after hind paw inflammation induced by complete Freund’s adjuvant (CFA). We used standard tests for pain behaviour, high performance liquid chromatography for measurement of 5-HT, and immunohistochemistry of hind paw skin tissue and L5 dorsal root ganglia (DRG) to measure local inflammation and nerve injury. After intraplantar CFA injection, hyperalgesia to heat was attenuated in 5 HTT-/- mice compared to wild type mice. Their 5-HT levels in nervous and adrenal tissue were reduced. An intraplantar injection of 5-HT four days after CFA transiently brought withdrawal latencies of 5-HTT-/- mice down to the level of wild type mice, thus rescuing the phenotype and supporting the role of 5-HT in the development of CFA-induced thermal hyperalgesia. The density of intraepidermal nerve fibres in plantar skin after CFA injection was reduced to a higher degree in 5-HTT-/- mice than in wild type mice, suggesting greater peripheral nerve injury in the knock-out mice during hind paw inflammation. Accordingly, a higher number of injured DRG neurons was identified by activating transcription factor 3 (ATF3) staining in 5 HTT-/- mice after CFA. We conclude that the phenotype of 5 HTT-/- mice leads to reduced inflammatory pain due to reduced tissue 5-HT levels and to greater peripheral nerve injury after inflammation. Human variants of the 5-HTT genotypes might be part of the factors determining the extent of nerve injury and hyperalgesia in inflammation.

Thesis--University of Helsinki. / Includes bibliographical references.

Thesis (Ph. D.)--University of Adelaide, Dept. of Physiology, 1984. / Includes bibliographical references (leaves 118-161).

Thesis (Ph. D.)--West Virginia University, 2008. / Title from document title page. Document formatted into pages; contains xi, 154 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 118-150).

Thesis (Ph. D.)--University of Washington, 2008. / Vita. Includes bibliographical references (leaves 112-130).

Thesis (Ph. D.)--Florida State University, 2004. / Advisor: Dr. Thomas E. Joiner, Jr., Florida State University, College of Arts and Sciences, Dept. of Psychology. Title and description from dissertation home page (viewed Sept. 23, 2004). Includes bibliographical references.

Thesis--University of Helsinki. / Includes bibliographies.