Proceedings of the British Pharmacological Society at http://www.pA2online.org/abstracts/Vol6Issue4abst037P.pdf 037P Neuroprotective effect of glucagon-like peptide-1 receptor stimulation in rat model of Parkinson’s Disease is blocked by both Exendin-9-39 and Nafadotride Alexander Harkavyi1, Amjad Abuirmeileh1, Rebecca Lever1, Ann Kingsbury2, Chris Biggs3, Peter Whitton1 1The School of Pharmacy, University of London, London, UK, 2University College London, London, UK, 3University of Westminster, London, UK The glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (EX-4) has been found to be neurotrophic and neuroprotective in vitro (Perry et al., 2002) leading to the suggestion that stimulation of GLP-1 receptors could have therapeutic value in neurodegenerative disorders such as Parkinson’s disease (PD). Recently, protective effects of exendin-4 were demonstrated in two in vivo rodent models of PD (Harkavyi et al., 2008) and it has also been shown to promote neurogenesis in the rat subventricular zone (SVZ) (Bertilsson et al., 2008). Here we demonstrate that neuro-protective/trophic effects of exendin-4 in a 6-OHDA model of PD are mediated via both, GLP-1R and dopamine D3-receptors. Male Wistar rats (250-280g; n = 6 per group) were anaesthetised with isoflurane and 8µg of 6- OHDA was stereotaxically injected into the medial forebrain bundle. 7 days later rats were administered EX-4 (0.5µg kg-1 in saline) together with EX-9-39 (GLP-1R antagonist 1µg kg-1) or Nafadotride (D3 antagonist 1µg kg-1) twice daily. Another week later rats were challenged with 0.5 mg kg-1 of apomorphine to evaluate contralateral circling behaviour and were then implanted with microdialysis probes and the following day perfused with artificial cerebrospinal fluid at a rate of 1µl min-1. Samples were collected every 30 min and dopamine (DA) levels were estimated using HPLC with ECD. Rats were then sacrificed and brains processed for tyrosine hydroxylase (TH) immunohistochemistry. Rats showed no overt changes in behaviour following 6-OHDA but displayed intense circling behaviour (27 ± 5 turn/120 s) when given apomorphine (0.5mg/kg) which was greatly attenuated by EX-4 (4 ± 1 turns/120s). This decrease was reduced by co-administration of either EX9-39 (20 ± 8 turns/120 s) or nafadotride (17 ± 5 turns/120 s; P<0.01 in each case). Dialysis data demonstrates that both antagonists reduced levels of extracellular DA by 65% ± 6% with nafadotride and 88% ± 9% with EX-9-39 in 6-OHDA and EX-4 treated groups. TH immunohistochemistry showed reduced TH positive cells in groups receiving EX-4 and either of the two antagonists compared to EX-4 only groups in which TH staining was similar to controls. Our data show that protective/trophic effects of EX-4 in a rodent 6-OHDA model of PD are mediated via both GLP-1R and apparently DA D3-receptors. GLP-1Rs were recently reported to be present in the rat SVZ (Bertilsson et al., 2008) and the authors proposed that EX-4 promoted neurogenesis. Accumulating evidence suggests a D3-receptor involvement in adult neurogenesis. Our observations that the protective effects of EX-4 are blocked by the presence of a D3-receptor antagonist support the idea that EX-4 may stimulate proliferation of neural stem cells in vivo via this receptor subtype. Bertillson et al., 2008 J Neurosci Res, 86, 326-38 Harkavyi et al., 2008 J Neuroinflammation, 5, 19 Perry et al., 2002 J Pharmacol Exp Ther, 302, 881-8 .