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dc.contributor.advisorHarvey, B H
dc.contributor.authorUys, Madeleine Monique
dc.date.accessioned2017-07-10T12:50:05Z
dc.date.available2017-07-10T12:50:05Z
dc.date.issued2016
dc.identifier.urihttp://hdl.handle.net/10394/25118
dc.descriptionPhD (Pharmacology), North-West University, Potchefstroom Campus, 2017en_US
dc.description.abstractPurpose: Schizophrenia and depression are neuropsychiatric disorders characterised by affective and cognitive dysfunction and are associated with altered monoaminergic and neurotrophic function. Social isolation rearing (SIR) is a neurodevelopmental rodent model of schizophrenia that reflects many of the behavioural and neurochemical features of schizophrenia, while the Flinders Sensitive Line (FSL) genetic rodent model of depression reflects various behavioural and neurochemical features of the human disorder. The α2-adrenoceptor (α2-AR) is a well-established neurobiological target for antipsychotic and antidepressant drug design, with a number of clinically used drugs presenting with α2-AR antagonism in their pharmacological profile. Selective α2C-adrenoceptor (α2C-AR) antagonism has been suggested to present with superior neuropsychiatric effects vs. non-selective α2-AR antagonism. The purpose of this study was to assess cognitive and antipsychotic-like effects of α2C-AR antagonism in the SIR model of schizophrenia, as well as cognition and antidepressant-like effects in the FSL model of depression. These pharmacological effects were compared to various reference agents, such as clozapine (CLOZ) and imipramine (IMI), as well as the non-selective α2-AR antagonist, idazoxan (IDAZ). Additionally, the behavioural and neurotrophic effects of augmenting D2-antagonist therapy with α2C-AR antagonism in the SIR model were investigated. Finally this study assessed the effects of α2C-AR antagonism on striatal (SIR) and hippocampal (FSL) monoamine levels and brain-derived neurotrophic factor (BDNF) in the respective animal models. Methods Three separate studies were conducted employing chronic treatment with the novel, highly selective α2C-AR antagonist ORM-10921. In the first study, male Sprague Dawley rats were either reared socially (SOC) or reared in social isolation (SIR) for 8 weeks following weaning. SIR rats received either vehicle (1 ml/kg), CLOZ 5 mg/kg , IDAZ 3 mg/kg or one of various doses of ORM-10921 (0.3 – 1mg/kg) subcutaneously (SC) once daily for 14 days, where after behaviour in the prepulse inhibition (PPI) test and novel object recognition test (NORT) were assessed. Post-mortem striatal monoamine levels were determined by high performance liquid chromatography (HPLC), while total striatal BDNF levels were determined by enzyme-linked immunosorbent assay (ELISA). In study 2, SIR animals received either vehicle, CLOZ, haloperidol (HAL) 2 mg/kg, ORM-10921 (0.01 or 0.03 mg/kg) or HAL + ORM-10921 (0.01 or 0.03 mg/kg) for 14 days SC. Again behaviour in the PPI test and NORT were assessed, where after post-mortem striatal BDNF levels were determined as above. The third study employed 11-week old male FSL rats that were treated with either vehicle, ORM-10921 (0.01 – 1mg/kg), IMI 15 mg/kg or IDAZ 3mg/kg administered SC or intraperitoneally for 14 days. Behaviour in the forced swim test (FST) and the NORT were subsequently assessed. In a separate group of drug treated animals, post-mortem hippocampal monoamine and BDNF levels were determined as described above. Results: α2C-AR-antagonism with ORM-10921 reversed SIR-induced deficits in PPI and object recognition memory comparable to CLOZ treatment but superior to the non-selective α2-antagonist, IDAZ. ORM-10921 increased striatal noradrenaline (NA) and decreased striatal dopamine (DA) in SIR rats, while CLOZ, but not ORM-10921 or IDAZ increased striatal BDNF. Augmentation of HAL with ORM-10921 bolstered the effects of HAL on PPI and object recognition memory, while also elevating striatal BDNF, an effect not obtained with monotherapy of either drug. ORM-10921 improved object recognition memory and decreased immobility in the FST in FSL rats. These behaviours were comparable to IMI, but superior to that of IDAZ. ORM-10921 increased serotonergic-driven swimming more than noradrenergic-driven climbing behaviour in the FST. ORM-10921 did not alter hippocampal BDNF levels after 14 days of treatment, but did increase hippocampal levels of DA, NA and serotonin. Conclusions: α2C-AR-antagonism with ORM-10921 presents with pro-cognitive, antipsychotic-like and antidepressant-like effects in the SIR and FSL translational models of schizophrenia and depression. These behavioural effects were associated with beneficial effects on dysfunctional monoamine levels in the striatum and hippocampus of SIR and FSL rats, respectively, albeit not with immediate effects on striatal and hippocampal BDNF levels. Furthermore, beneficial effects of α2C-AR-antagonism on the outcomes of D2-antagonist therapy on sensorimotor gating and cognition was evident, while these effects were correlated to increased striatal BDNF levels. The results thus suggest that α2C-AR-antagonism is a potentially valuable therapeutic strategy in the treatment of neuropsychiatric disorders characterised by cognitive and affective dysfunction associated with monoaminergic alterations, as evidenced in two translational models of neuropsychiatric illnesses. α2C-AR-antagonism also shows potential as augmentation strategy to typical antipsychotic treatmenten_US
dc.language.isoenen_US
dc.publisherNorth-West University (South Africa) , Potchefstroom Campusen_US
dc.subjectα2C-adrenoceptoren_US
dc.subjectα2C-antagonismen_US
dc.subjectSchizophreniaen_US
dc.subjectDepressionen_US
dc.subjectSocial isolation rearingen_US
dc.subjectFlinders sensitive line raten_US
dc.subjectPrepulse inhibitionen_US
dc.subjectObject recognition memoryen_US
dc.subjectForced swim testen_US
dc.subjectHippocampusen_US
dc.subjectStriatumen_US
dc.subjectBDNFen_US
dc.subjectMonoaminesen_US
dc.titleBio-behavioral characterisation of a selective α2C-receptor antagonist in animal models of schizophrenia and depressionen_US
dc.typeThesisen_US
dc.description.thesistypeDoctoralen_US


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