42.02 In vivo dopamine release in adenosine A2A receptor knockout mice during acute cocaine administration Wells L A 1, Opacka-Juffry J 2, Hourani S M O 1, Kitchen I 1 1-SBMS, University <strong>of</strong> Surrey, Guildford, UK., 2-SHLS, Roehampton University, London, Uk. Adenosine A2A receptor knockout mice show an altered addiction phenotype with respect to psychostimulants. A significant reduction in self-administration <strong>of</strong> cocaine in A2A receptor knockout mice has been reported. To determine whether this is associated with altered accumbal dopamine (DA), we have studied the effects <strong>of</strong> acute cocaine administration on extracellular DA in the nucleus accumbens (NAc), using in vivo microdialysis in A2A receptor knockout mice. In addition, we have monitored locomotor behaviour and stereotypy during the dialysis procedures. A significant enhancement in locomotor activity was seen in cocainetreated knockout mice compared to cocaine-treated wild-type mice (3- way ANOVA p
43.02 Neuroleptic treatment worsens cognitive function and Alzheimertype pathology in dementia patients Rabai E, King E, Smith M Z, Nagy Z Erzsebet Rabai, Zsuzsanna Nagy, Department <strong>of</strong> Clinical <strong>Neuroscience</strong>, <strong>Neuroscience</strong> Division, The Medical School, University <strong>of</strong> Birmingham, Vincent Drive, Birmingham, B15 2TT, , Elizabeth King, Maria Z Smith, OPTIMA, Radcliffe Infirmary NHS Trust, Oxford OX2 6HE Neuroleptics, <strong>of</strong>ten used in the management <strong>of</strong> psychotic symptoms in Alzheimer’s disease patients might contribute to cognitive deterioration. In this study, we analysed the effect <strong>of</strong> neuroleptic treatment on memory functions and the expression <strong>of</strong> AD-related proteins in 86 AD patients. The cognitive status <strong>of</strong> the patients has been assessed not more than 6 months prior to death. After necropsy, diagnoses were confirmed using the CERAD protocol and the Braak staging. Quantitative immunohistochemistry was used to measure hyperphosphorylated tau, PHF tau, and beta-amyloid in the hippocampus. The cognitive scores <strong>of</strong> neuroleptic treated patients in the early stages <strong>of</strong> AD were significantly lower than those <strong>of</strong> patients who received no neuroleptic treatment. The recent memory and learning memory scores show a similar effect. The remote memory scores are not significantly different between the two groups. The treatment had no significant effect on the expression <strong>of</strong> hyperphosphorylated tau in any region <strong>of</strong> the hippocampus, except CA4. In contrast, the expression <strong>of</strong> PHF tau in the CA2/3, CA4 and the dentate gyrus is significantly higher in the neuroleptic treated patients than in the matched controls. There was no difference in beta-amyloid deposition. We conclude that the worsening <strong>of</strong> memory functions induced by neuroleptic therapy in demented patients is associated with increased amounts <strong>of</strong> AD-type pathology in the hippocampus. 43.03 The effect <strong>of</strong> a fibroblast growth factor receptor agonist on the betaamyloid(25-35) treated hippocampus. Corbett N J, Gabbott P L, Stewart M G, Klementiev B, Davies H A, Colyer F M, Novikova T, Berezin V, Bock E The Open University,, Department <strong>of</strong> Biology,, Milton Keynes,, MK7 6AA The accumulation <strong>of</strong> β-amyloid (Aβ) is thought to underlie the characteristic neuropathology <strong>of</strong> Alzheimer’s disease (AD). Active glycogen synthase kinase-3β (GSK-3β) phosphorylates amyloid precursor protein (APP) causing Aβ accumulation. Fibroblast Growth Loop (FGL) acts as a fibroblast growth factor receptor 1 (FGFR1) agonist that inactivates GSK- 3β. To demonstrate whether FGL reduces Aβ-induced hippocampal neurodegeneration, a fragment <strong>of</strong> Aβ (25-35) was injected intracerebroventricularly (icv) at 5mg/15μl into rats (n=12). Eight days after Aβ injection, animals received either a subcutaneous injection <strong>of</strong> FGL (10.8mg/kg) or distilled water (dw) every 3 days (Aβ-FGL, Aβ–dw groups respectively). Another group (dw-FGL: n=6) had dw injected icv followed by FGL treatment whilst the control group (dw-dw: n=6) received dw icv followed by dw treatment. On day 25, animals were transcardially perfused with 2% paraformaldehyde and 3.75% acrolein in 0.1M phosphate buffer (pH 7.4). Serial coronal sections were prepared from the hippocampi <strong>of</strong> each animal. Using the Cavalieri method applied to a 1:4 series <strong>of</strong> 50μm Nissl sections, the total hippocampal volumes <strong>of</strong> 4 animals per group were determined. Results indicated that dw-FGL animals had smaller hippocampi (57.43±6.32mm3) than dw-dw controls (68.64±3.35mm3) and Aβ-dw animals (66.45±2.27mm3), whilst the Aβ-FGL group (62.05±1.81mm3) was not different to any group. The results demonstrate the effect <strong>of</strong> Aβ and FGL on total hippocampal volume. Ongoing studies aim to interpret these volume changes in terms <strong>of</strong> quantitative alterations in the neuronal and synaptic circuitry <strong>of</strong> the hippocampus in this model <strong>of</strong> AD. 43.04 Aggregation <strong>of</strong> beta amyloid (1-28) and ultrastructural effects following intracerebral injection into the avian brain Evans D S, Gabbott P L, Davies H A, Colyer F M, Stewart M G Department <strong>of</strong> Biological Sciences, , The Open University, , Walton Hall, , Milton Keynes, , MK7 6AA Beta amyloid (Aβ) accumulation is implicated in the synaptic and neuronal pathology underlying the cognitive deficits found in Alzheimer’s disease. Self-aggregation <strong>of</strong> Aβ leads to the formation <strong>of</strong> plaques in the brains <strong>of</strong> affected individuals. By using fluorescence microscopy, scanning and transmission electron microscopy we have investigated: (i) the temporal aggregation pr<strong>of</strong>ile <strong>of</strong> Aβ fragment 1-28 tagged with Hi-Lyte Fluor 555 (Aβfluor) over a period <strong>of</strong> 7 days in vitro, and (ii) the ultrastructural effects <strong>of</strong> Aβfluor injected intracerebrally into the avian brain. Optimal aggregation <strong>of</strong> Aβfluor (assessed by the presence <strong>of</strong> fibres and smaller aggregated structures) occurred after 3 days. Intracerebral injections <strong>of</strong> Aβfluor were made into the intermediate medial mesopallium (IMM) <strong>of</strong> day old chicks (n=4). Following a 48 hour survival period, the chicks were either transcardially perfused with aldehyde fixatives for ultrastructural observation or decapitated and the brains rapidly excised and frozen in isopentane, and serial tissue sections (50µm thick) cut through each injection site. The lateral diffusion <strong>of</strong> Aβfluor from the injection site was defined quantitatively at 7 injection sites. The mean maximum lateral diffusion distance from the centre <strong>of</strong> the injection sites was 113µm (±40.6 SD) with a range <strong>of</strong> 53-197µm. Compared with double distilled water injected controls, qualitative ultrastructural observations immediately adjacent to the Aβfluor IMM injection sites revealed extensive apoptosis <strong>of</strong> neuronal and glial cell types and widespread synaptic and dendritic dystrophy. Current studies are investigating the effect <strong>of</strong> Aβ injection on synapse density in chick brain regions involved in cognitive behaviours. 43.05 Deprivatives <strong>of</strong> rer peptide as potential theraputic agents in Alzheimer's disease Lancashire C L, Mileusnic R, Rose S R The Open University, , Milton Keynes, MK7 6AA, UK The discovery <strong>of</strong> an effective agent to alleviate the cognitive and memory deficits in Alzheimer’s disease (AD) is a high priority. As the amyloidogenic processing <strong>of</strong> APP is crucial for the development <strong>of</strong> AD, focussing on APP and endeavouring to find ways <strong>of</strong> restoring its function is a rational approach for development <strong>of</strong> new neuroprotective strategies. Thus, peptidomimetics derived from the amyloid precursor protein (APP) might become <strong>of</strong> considerable interest as potential therapeutic agent in the early stages <strong>of</strong> Alzheimer’s disease. We reported that in animals rendered amnestic by Aβ memory was rescued by the tripeptide Arg-Glu-Arg (RER), part <strong>of</strong> the growth-promoting domain <strong>of</strong> APP. A protected form <strong>of</strong> RER, when injected peripherally, is rapidly transported across the blood-brain-barrier, and protects against memory loss induced by Aβ1-42 and Aβ25-32. In efforts both to cast light on the mode <strong>of</strong> action <strong>of</strong> the peptide, and to increase its efficacy as a potential cognitive enhancer, we have now studied the effects <strong>of</strong> various D/L-forms <strong>of</strong> the peptide. Here we report that rER (where the lower case indicates the D-isomeric form <strong>of</strong> the amino acid), protects against Aβ induced memory loss when injected peripherally up to 12hr prior to the training task, and thus becomes <strong>of</strong> considerable interest as the basis for a potential therapeutic agent in the early stages <strong>of</strong> Alzheimer’s Disease. Conflict <strong>of</strong> Interest disclosure: RM and SPRR are named as inventors <strong>of</strong> the tripeptides described (UK Patent Number GB2391548 owned by The Open University). Research was partially funded by Talisker. Page 65/101 - 10/05/2013 - 11:11:03
Change language