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The Long-Term Effects of Fluoxetine on Stress- Related Behaviour and Acute Monoaminergic

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The Long-Term Effects of Fluoxetine on Stress- Related Behaviour and Acute Monoaminergic The long-term effects of fluoxetine on stress- related behaviour and acute monoaminergic stress response in stress sensitive rats Nico Johan Badenhorst BChD 24307734 Dissertation submitted in partial fulfilment of the requirements for the degree Magister Scientiae in Pharmacology at the Potchefstroom Campus of North-West University Supervisor: Prof C.B. Brink Co-supervisor: Prof L. Brand Assisting Supervisor: Prof B.H. Harvey November 2014 Abstract: Fluoxetine and escitalopram are the only antidepressants approved by the Food and Drug Administration of the United States of America (FDA) for treatment of major depression in children and adolescents. Both drugs are selective serotonin reuptake inhibitors (SSRIs). In recent years there has been a growing concern over the long-term developmental effects of early-life exposure to SSRIs. The current study employed male Flinders Sensitive Line (FSL) rats, a well described and validated translational model of depression, to investigate the long term effects of pre- pubertal fluoxetine exposure. First we examined the effect of such early-life exposure on the development of depressive-like behaviour, locomotor activity and anxiety-like behaviour as manifested in early adulthood. Next, the current study investigated the effect of pre-pubertal fluoxetine exposure on the acute monoaminergic stress response, as displayed later in life. Animals received either saline (vehicle control), or 10 mg/kg/day fluoxetine from postnatal day (ND+) 21 to ND+34 (pre-puberty). The treatment period was chosen to coincide with a developmental phase where the serotonergic system’s neurodevelopment had been completed, yet the noradrenergic and dopaminergic systems had not, a scenario comparable to neurodevelopment in human adolescents. Both behavioural and in vivo intra- cerebral microdialysis experiments were conducted after ND+60 (early adulthood). On ND+60 rats allocated to behavioural experiments were evaluated for depressive-like behaviour in the forced swim test (FST), locomotor activity in the open field test (OFT), and anxiety-like behaviour in the OFT. Corticosterone concentrations were shown to be significantly higher in male FSL rats exposed to a 10 minute forced swim stress when compared to male FSL rats not exposed to a forced swim stress on ND+60. In the microdialysis experiments the rats were exposed to an acute 10 minute forced swim stress and the concentrations of the monoamines and their metabolites were measured before, during, and after the acute stressor. Relative to saline-treated (control) rats, fluoxetine-treated FSL rats did not show long-term changes in immobility in the FST (i.e. no anti-depressant-like activity) on ND+60. Like-wise anxiety-like behaviour in the OFT did not change. However, a significant decrease in locomotor activity was observed in fluoxetine-treated FSL rats compared to saline-treated (control) rats. These data suggest that a long-lasting anti-depressant-like effect of fluoxetine may be masked by the effect on locomotor activity. With measurements from the microdialysis experiments a significant attenuation of the noradrenergic stress response was P a g e | ii observed in fluoxetine-treated rats compared to saline controls. A similar picture was observed for 5-hydroxyindole-3-acetic acid (5-HIAA), a metabolite of serotonin (5-HT), although the latter was not statistically significant. At baseline, before the stressor, significant increase in dopamine (DA) levels were observed in fluoxetine treated rats when compared to saline controls, suggesting that enhanced dopamine neurotransmission may comprise a long-term effect of pre-pubertal fluoxetine treatment. There were no discernible differences in homovanilllic acid (HVA) concentrations between fluoxetine-treated rats and saline controls. In conclusion significant developmental effects of pre-pubertal fluoxetine exposure were observed later in life and these findings warrant further investigation. Keywords: Depression, Neurodevelopment, Fluoxetine, Flinders Line Sensitive rat, Monoaminergic stress response, Depressive-like behaviour, Locomotor activity. P a g e | iii Opsomming: Fluoksetien en essitalopram is die enigste antidepressante wat deur die “Voedsel en Geneesmiddel Administrasie (“Food and Drug Administration” - FDA) van die Verenigde State van Amerika goedgekeur is vir die behandeling van major depressie in kinders en adolosente. Beide hierdie middels is selektiewe serotonienheropname-inhibeerders (SSHI’s). In die laaste aantal jare was daar ʼn toenemende kommer oor die langtermyn ontwikkelingseffekte van vroeë-lewe blootstelling aan SSHI’s. Die huidige studie het gebruik gemaak van manlike Flinders Sensitiewe Lyn- (FSL-) rotte, ’n goed beskryfde genetiese translasie-model van depressie, om die langtermyn effekte van pre-puberteit fluoksetien-blootstelling te ondersoek. Eerstens het ons ondersoek ingestel om na die effek van sodanige vroeë-lewe blootstelling op die ontwikkeling van depressie-agtige gedrag, lokomotor aktiwiteit, en angs-agtige gedrag soos gemanifesteer in vroeë volwasenheid te kyk. Tweedens het die huidige studie ondersoek ingestel om na die effekte van pre-pubertale fluoksetien-blootstelling op die akute monoaminergiese stresrespons, soos vertoon later in die lewe te bestudeer. Diere het ‘n soutoplossing (draer-kontrole) of 10 mg/kg/dag fluoksetien vanaf postnatale dag (ND+) 21 tot ND+34 (pre-puberteit) ontvang. Die behandelingsperiode was gekies om ooreen te stem met ’n periode waar die serotonergiese stelsel se neuro-ontwikkeling voltooi is, maar waar die noradrenergiese en dopaminergiese stelsels s’n nog nie ten volle ontwikkel is nie - ’n scenario vergelykbaar met die neuro- ontwikkeling in die menslike adolosent. Beide gedrag en in vivo intra-serebrale mikrodialise- eksperimente was uitgevoer na ND+60 (vroeë volwassenheid). Op ND+60 is rotte wat geallokeer was vir gedragseksperimente geëvalueer vir depressie- agtige gedrag in die geforseerde swemtoets (GST), lokomotoraktiwiteit in die oopveldtoets (OVT), en angs-agtige gedrag in die OVT. In die mikrodialise-eksperimente was rotte blootgestel aan ’n akute 10-minute geforseerde swem stres en die konsentrasies van die monoamiene en hul metaboliete was gemeet voor, tydens en na die akute stressor. Relatief tot die soutoplossing-behandelde (kontrole) rotte, het fluoksetien-behandelde FSL- rotte nie langtermyn veranderinge in immobiliteit in die GST op ND+60 vertoon nie (d.w.s. geen anti-depressant-agtige aktiwiteit nie). Soortgelyk het angs-agtige gedrag in die OVT nie verander nie. ’n Beduidende vermindering in lokomotoraktiwiteit was egter waargeneem in die fluoksetien-behandelde FSL-rotte, relatief tot die draer-behandelde (kontrole) rotte. ’n Soortgelyke beeld was waargeneem vir 5-hidroksie-indool-3-asynsuur (5-HIAA), ’n metaboliet van serotonien, alhoewel die laasgenoemde nie statisties betekenisvol was nie. P a g e | iv By die basislyn, voor die stressor, was ’n beduidende verhoging in dopamienkonsentrasies waargeneem in fluoksetien-behandelde rotte in vergelyking met soutoplossing-behandelde kontroles, wat suggereer dat verhoogde dopaminergiese neurotransmissie een van die langtermyneffekte van pre-puberteit-fluoksetien-behandeling mag wees. Daar was geen onderskeibare verskille in die homovaniliensuur (HVA)-konsentrasies tussen fluoksetien- behandelde rotte en soutoplossing-kontroles nie. Ten slotte was beduidende ontwikkelingseffekte van pre-pubertale fluoksetien-blootstelling later in die lewe waargeneem en hierdie bevindinge regverdig verdere ondersoek. Sleutelwoorde: Depressie, Neuro-ontwikkeling, Fluoksetien, Flinders Lyn Sensitiewe-rot, Monoaminergiese stresrespons, Depressief-agtige gedrag, Lokomotor aktiwiteit. P a g e | v Acknowledgements I would like to thank the following individuals for their continued support during this study. First and foremost my lovely wife, Robyn Walker May, for your unflinching support and encouragement as I try to carve out my own path. Professors Tiaan Brink, Linda Brand and Brian Harvey for providing this opportunity and for the guidance, motivation, and support during the duration and completion of the study. Dr Suria Ellis for assistance with statistical data analysis in the study. Cor Bester, Antoinette Fick, and Hylton Buntting and the rest of the North-West University Vivarium staf for overseeing the welfare of the animals in this study. Francois Viljoen for assistance with the analysis of the neurochemical data. Stephan Steyn and Jaco Schoeman for assistance with behavioural analyses. Walter Dreyer for assistance with injection of the rats during the study. My fellow post-graduate students for the support and stimulating conversations. Last but not least, my friends and family for their support and encouragement. P a g e | vi Table of Contents Abstract:................................................................................................................................ II Opsomming: ........................................................................................................................ IV Acknowledgements .............................................................................................................. VI Table of figures ..................................................................................................................... X Table of tables .................................................................................................................... XII List of abbreviations ..........................................................................................................
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