Introduction: Schizophrenia (SCZ) and methamphetamine-induced psychotic disorder (MPD), are psychotic disorders characterized by positive symptoms (e.g., hallucinations and delusions), negative symptoms (e.g., social withdrawal, apathy), and impaired cognitive function. Despite the overlap in the clinical presentation of SCZ and MPD, no studies have compared electroencephalography (EEG) and inflammation across these two conditions. This study aimed to investigate key differences in brain electrical activity on EEG between SCZ and MPD by investigating; (1) relative frequency (alpha, theta, beta and delta) at rest; (2) cognitive performance and relative frequency activity during the continuous performance task (CPT) and cued target detection task (CTD); (3) differences in the P300 event-related potential waveform (ERP), a measure of attention, during the CPT and CTD; (4) cognitive performance and relative frequency and ERP (N170, P300) during the STROOP task, a measure of working memory and executive function; (5) the associations of (neuro) inflammatory markers with relative frequency and the P300 ERP waveform. Methods: 104 South African individuals, between the ages of 20 and 45 years, participated in this study: 69 outpatients (38 with SCZ (8 females/30 males), 31 with MPD (7 females/24 males)), and 35 healthy controls (CON: 15 females/20 males). All participants underwent a Structured Clinical Interview for Diagnostic Systematic Manual-IV (SCID-DSM-IV), with modifications to include changes made in DSM-5. EEG band frequency oscillations were recorded during baseline conditions: resting eyes open and resting eyes closed, and cognitive tasks (CPT, CTD and the Stroop task). Blood was drawn via venepuncture and serum was used for the analysis of cytokines (interleukin (IL) -1β IL-8, IL-10, IL-12p70, tumour necrosis factor-alpha and interferon-gamma (IFN-γ)) concentrations. Statistical analysis included assessment of normality using the Shapiro- Wilk test, with univariate one-way analysis of variance (ANOVA) of parametric data, and multiple independent Kruskal-Wallis ANOVA for non-parametric data (p)

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Thesis (M. Phil.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 111-122).

The ionotropic glutamate AMPA ((R,S)-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor mediates the majority of excitatory transmission in the CNS. AMPA receptors play a crucial role in both basal neurotransmission and synaptic plasticity events (such as long-term potentiation, LTP). Compounds that ‘potentiate’ AMPA receptor function (‘Ampakines’) are known to positively modulate glutamatergic AMPA receptor-gated currents, by slowing the deactivation and desensitisation rate of the receptors, in the presence of the endogenous agonist glutamate. Ampakines have been shown to facilitate LTP induction, improve cognition, and as such have potential in the treatment of conditions such as depression and psychoses (schizophrenia). The main aim of this thesis was to investigate the functional actions of two novel Ampakines, Org 26576 and Org 24448, in the mouse brain. The studies described in this thesis were designed to address this and are outlined as follows: 1. Characterisation and validation of an in vivo semi-quantitative model of [14C]-2-deoxyglucose autoradiography in the C57Bl/6J mouse The first study sought to develop and characterise a model of [14C]-2-deoxyglucose autoradiography, to allow measurement of regional alterations in local cerebral glucose use (LCGU) in the mouse CNS. Following intraperitoneal injection of [14C]-2-deoxyglucose in C57Bl/6J mice, the radiolabelled brains were sectioned and exposed to x-ray film. The resultant autoradiograms were semi-quantitatively analysed for relative optical densities in predetermined regions of interest. The baseline LCGU values in different brain regions were found to be consistent with previously published data. The model was also able to replicate the effects of a well-characterised compound, the NMDA receptor antagonist MK-801 (0.5 mg/kg), in respect to functional cerebral changes. Characteristic effects such as prominent increases in LCGU in the limbic system, and decreases in the somatosensory cortex were reproduced in the model. Thus the semi-quantitative [14C]-2-deoxyglucose model was reproducible and accurate and thus could be further used to investigate the effects of the novel Ampakines, Org 26576 and Org 24448, on cerebral function. 2. Investigation into the effects of acute administration of the novel Ampakines Org 26576 and Org 24448 on functional activity in the murine cerebrum Following the establishment of the methodology, regional alterations in LCGU in response to the Ampakines Org 26576 and Org 24448 were investigated using [14C]-2-deoxyglucose autoradiography. Both Org 26576 and Org 24448 produced regionally selective, dose-dependent increases in LCGU in the mouse cerebrum when administered acutely (~1 hr). The compounds displayed similar yet functionally distinct profiles of activation, the highest levels of activation occurred in areas of the limbic system (hippocampus), sensory systems, and various nuclei (raphe nucleus). Their effects were blocked by pre-administration of the potent selective AMPA receptor antagonist, NBQX (10 mg/kg), which itself had minimal effects on LCGU. These data provide an anatomical basis for the cerebral activation induced by these compounds, which are directly AMPA receptor mediated. Areas activated also closely correlated with brain regions implicated in various psychiatric conditions, and as such is suggestive of a potential therapeutic benefit of these compounds in conditions such as depression and schizophrenia. 3. Investigation into the effects of chronic administration of the novel Ampakines Org 26576 and Org 24448 on functional activity, neurogenesis and receptor/signalling alterations in the murine cerebrum Following the demonstration that acute administration of Org 26576 and Org 24448 displayed regionally selective and dose-dependent alterations in LCGU, the effect of chronic administration of the Ampakines Org 26576 and Org 24448 on regional functional alterations ([14C]-2-deoxyglucose autoradiography), neurogenesis (BrdU labelling), and proteins levels (GluR, MAPK, LynK and CREB) (Western blot analysis) were investigated. Chronic administration (7 and 28 days) of Org 26576 (1 mg/kg) and Org 24448 (10 mg/kg) induced functional cerebral increases in the mouse cerebrum particularly in areas of the mesocorticolimbic system, which were not only rapid in onset, with significant effects visible after 7 days administration; but importantly were also persistent and long lasting. Chronic administration of the compounds had no significant effect on the level of neurogenesis or on the levels AMPA receptor subunits (GluR1,2,3), and signalling pathways (MAPK/LynK-CREB pathway), implicated in AMPA/Ampakine signalling, in the murine hippocampus. These data show that the Ampakines Org 26576 and Org 24448 when administered chronically can potentiate complex neural networks intimately associated with disease states, the effects of which are maintained over prolonged periods. There was no evidence that this involved an effect on neurogenesis or the MAPK/LynK-CREB signalling pathway. 4. Modulation of AMPA receptor kinetics by Org 26576 and Org 24448 influences synaptic plasticity in the murine hippocampus The ability of Org 26576 and Org 24448 to modify baseline kinetic properties of AMPA receptors and a paradigm of synaptic plasticity, LTP, in the mouse hippocampus was investigated using electrophysiology. Both Org 26576 and Org 24448 produced dose-dependant increases in fEPSP amplitude without affecting the half-width of responses, in acute hippocampal slices. Concentrations of both compounds, equating to functionally active levels witnessed in vivo, potentiated a stable form of LTP; whilst higher EC50 concentrations prevented the maintenance of LTP. These results are suggestive that Org 26576 and Org 24448 are effective in boosting the neural correlate of cognition, LTP, and may have potential in treating cognitive deficits, for example those associated with depression, schizophrenia or Alzheimer’s disease. The data presented in this thesis illustrate that the novel Ampakines Org 26576 and Org 24448 centrally modulate brain regions and circuitry intimately associated with conditions such as depression and schizophrenia (psychoses), with effects that are rapid in onset and persistent over chronic periods of administration. Specifically targeting the glutamatergic system through the use of these compounds may provide an innovative approach to treat various conditions that may be partly due to a compromise of normal excitatory glutamatergic neurotransmission.