Degree Name

Doctor of Philosophy


School of Health Sciences - Faculty of Health and Behavioural Sciences


Schizophrenia is a disorder which continues to intrigue scientists in regards to its complex pathological mechanisms underlying the range of symptoms suffered by patients. Current treatments for the disorder do not provide complete relief or cure for symptoms. Evidence suggests schizophrenia has its origins in early brain development, although the onset of psychosis is not until late adolescence/early adulthood. Hypofunction of N-methyl-D-aspartate (NMDA) receptors has also been strongly implicated in the disorder since NMDA receptor antagonists like phencyclidine (PCP) and ketamine elicit a schizophrenia-like psychosis in healthy individuals, and worsen symptoms in schizophrenia patients. Perinatal PCP treatment in rats is therefore potentially a very good developmental animal model for studying pathological processes which may be involved in schizophrenia, and findings from this model may aid in the development of effective treatments for the disorder. This study aimed to determine if early brain developmental disruption from PCP alters the developmental expression of key neurotransmitter receptors involved in schizophrenia. This was achieved by examining NMDA, GABA and M1/4 receptor binding levels in rats at several time-points (1 day, 1 week, 3 weeks and 10 weeks) following PCP treatment (10mg/kg, s.c) on postnatal days 7, 9 and 11. Locomotor activity, social interaction as well as anxiety and depression-like behaviours were also tested in the same animals at adulthood. The effects of adult PCP treatment on NMDA, GABAA, muscarinic M1/4, dopamine D2 receptor and dopamine transporter (DAT) binding levels were also examined. In addition, the effects of perinatal and adult PCP treatment on dopamine receptor function was assessed in a [35S]guanosine 5'-O-γ-(thiotriphosphate) ([35S]GTPγS) binding assay. Perinatal PCP treatment increased NMDA and GABAA receptor binding density in the thalamus and hippocampus compared to controls, an effect which lasted until adulthood. The prefrontal and anterior cingulate cortices also showed increased binding levels of these two receptors, mainly at adolescence. M1/4 receptor binding density was reduced in the prefrontal cortex and hippocampus one day after perinatal PCP treatment, and increased in the prefrontal cortex at adolescent and adult ages. Perinatal PCP treatment increased locomotor activity, but did not alter social interaction, anxiety-like or depression-like behaviours. Adult PCP treatment produced only minor changes in those same neurotransmitter receptors mentioned above, although this treatment increased D2 receptor binding density in the caudate putamen and nucleus accumbens, and increased DAT binding density in the ventral tegmental area and caudate putamen. Neither perinatal nor adult PCP treatment altered the function of dopamine receptors. This study has shown that perinatal PCP treatment alters the expression of several neurotransmitter receptors in many brain regions and affects behaviour long after treatment cessation. Disinhibition of pyramidal neurons from reduced GABAergic output may be a pathological mechanism underlying behavioural effects seen after perinatal PCP treatment. In contrast, the same dose of PCP given to adult rats produced only minor changes in receptor binding density in few brain regions. Therefore, disrupting brain development at an early stage can have long-lasting consequences which are relevant to the study of psychiatric disorders such as schizophrenia, which is thought be a neurodevelopmental disorder, involving NMDA receptor hypofunction.

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