Previous work on the unconditioned effects of amphetamine in rats has examined qualitative changes in behaviours which become stereotyped and quantitative changes in locomotion. Stereotyped behaviours have been adopted as a model of raised caudate-putameri function whilst locomotion has been adopted as a model of raised mesolimbic dopamine function. These models have been used to study drugs which are effective in the treatment of schizophrenia. Only locomotion is reliably antagonised by all classes of antipsychotic drugs, although it has been hypothesised that, under some doses of amphetamine, locomotion may also become stereotyped. The Lyon-Robbins hypothesis of the behavioural effects of amphetamine predicts competition between the output of the mesolimbic and caudate-putamen, and would predict that stereotyped locomotion represents a 'blending' of mesolimbic and caudate-putamen behavioural output. An experiment was conducted to test the Lyon-Robbins hypothesis using contrast-based image analysis to determine the spatio-temporal characteristics of open-field locomotion. A further four experiments examined the effects of a classic antipsychotic (haloperidol), the atypical antipsychotics (clozapine and sulpiride) and a putative antipsychotic (a 5-HT3 antagonist, ondansetron) on open-field locomotor routes taken by rats following treatment with 3.5mg/kg amphetamine. Measures of stereotyped locomotion derived from image analysis were supported by a novel form of behavioural analysis based on multi-dimensional scaling which provided an integrated analysis of behavioural change following drug treatment. Haloperidol blocked locomotion and stereotyped behaviours including stereotyped locomotion, whereas clozapine, sulpiride and ondansetron blocked locomotion but not stereotyped locomotion and in some cases increased stereotyped behaviours. This suggests that stereotyped locomotion represents synergistic functioning of both mesolimbic and caudate-putamen systems, when the output from the caudate-putamen is insufficient to over-ride that of the mesolimbic system. Antagonism of a 5-HT3 enhancement of mesolimbic locomotor activity by ondansetron allowed latent 5-HT and dopamine mediated behaviours to be expressed. This effectively mimicked a leftwards shift of the amphetamine dose response curve, hypothesised as amplification of the caudate-putamen output. These findings lend support to the Lyon-Robbins hypothesis of the behavioural effects of amphetamine.

Schizophrenia is a chronic, common and debilitating illness which causes serious psychosocial impairments. Despite the adverse impact of schizophrenia on public health, progress in understanding its pathophysiology is frustratingly slow, which hinders discovery of new therapeutic mechanisms. The major factors that have impeded this exploration are the complex neurobiology of higher brain function and the ethical and practical difficulties of investigating the living brain. Thus, animal models are useful to investigate the pathophysiology and therapeutics of schizophrenia and related conditions. A useful animal model is an important tool to illuminate pathophysiology and signpost a target for treatment development. But animal models also have limitations and not all the phenotypic traits thought relevant to schizophrenia are expressed in all models. However, in-bred mouse strains have proved useful in the field of research into neurodevelopmental disorders. Therefore, in the first part of this thesis, behavioural and protein expression of C57BL/6N and 129 X1/SvJ mice were compared. The 129X1/SvJ strain, like the C57BL/6N strain, is a widely used background strain for behavioral research. Both 129X1/SvJ and C57BL/6N are routinely used in gene-targeting research. The results suggested that C57BL/6N mice mimic aspects of schizophrenia, at least in comparison with 129X1/SvJ mice. Therefore C57BL/6N mouse may have application in pre-translational screening of new treatments for schizophrenia. Oxytocin has been proposed as a possible treatment for neurodevelopmental conditions such as schizophrenia. However, there are gaps in the understanding of its therapeutic potential, in particular the extent to which it may have effects on non-social as well as social behaviors in both sexes. In the second part of the thesis, female and male C57BL/6N mice were used to study the effects of oxytocin on social and non-social behaviours relevant to schizophrenia. Oxytocin generally ‘improved’ behaviours analogous to those reported to be impaired in neurodevelopmental disorders, but effects were observed at different doses in each sex. The work here suggests oxytocin has potential for treatment of both social and non-social features of schizophrenia. Further research into the clinical application of this peptide hormone, which may in turn significantly extend treatment options across a spectrum of neurodevelopmental conditions, should be encouraged. / published_or_final_version / Psychiatry / Doctoral / Doctor of Philosophy

abstract / Psychiatry / Doctoral / Doctor of Philosophy

No description available.

published_or_final_version / Medicine / Master / Doctor of Medicine

published_or_final_version / abstract / toc / Clinical Psychology / Master / Master of Social Sciences

published_or_final_version / abstract / toc / Psychiatry / Master / Master of Philosophy

published_or_final_version / abstract / toc / Clinical Psychology / Master / Master of Social Sciences

No description available.

Thesis (M.A.)-University of KwaZulu-Natal, 2007.