P.828 Identification of the possible downstream pathways related to alpha7 nicotinic acetylcholine receptor in MK-801 induced schizophrenia model in rats A. Cumaoğlu1, G. Unal2, H. Bekci1, M.B. Yerer2, F. Aricioglu3 1Erciyes University, Faculty of Pharmacy- Department of Biochemistry, Kayseri, Turkey 2Erciyes University, Faculty of Pharmacy- Department of Pharmacology, Kayseri, Turkey 3Marara Uiersity, Departet of Pharaology ad Psyhopharaology Researh Uit, İstaul, Turkey BACKGROUND METHODS

Pathophysiology of schizophrenia is still remains an enigma. Recent evidence indicates that Male Wistar Hannover rats (8-12 weeks alterations in the activity of PDE4 may contribute to the cellular mechanisms underlying psychosis. and 180-250 g) were used and grouped Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase (PDE) 4 has been proposed as a as MK-801 (0.2 mg/kg, 7 days, twice a potential treatment in psychiatric conditions associated with cognitive dysfunctions and inhibition day, n=4) After a week washout period, of the PDE4 enzymes which degrades cAMP has benefit in diverse animal models with regard to rats were treated with A-582941 emotional and cognitive behaviors. Currently approved antipsychotic medications produce their (1mg/kg; ip.), CCMI (1mg/kg; ip.) and beneficial effects through antagonism of the dopamine D2 receptor and a rise in intracellular PNU-120596 (3mg/kg; ip.) i.p. for 10 cAMP levels. The conceptual linkage between the dopamine D2 receptors and PDE activity days and results were compared with through cAMP suggests potential for PDE blockers in schizophrenia which might be a novel atypical antipsychotic, Clozapine approach for unmet medical needs in schizophrenia. Glycogen synthase kinase 3 beta (GSK-3B) is (5mg/kg; ip.), as a positive control. 24h also a constitutive enzyme, which mediates intracellular signaling pathways and thought to be after the last injection the rats were relevant to schizophrenia. Recent studies revealed that GSK-3B activity increased in certain decapitated and the prefrontal cortex neuropsychiatric disorder such as schizophrenia and current antipsychotics inhibits its activity. (PFC) and the hippocampus (HC) were Alpha 7 nicotinic acetylcholine receptor (α7 nAChR) is an important part of the cholinergic system dissected. PDE4A, p-GSK-3B and GSK-3B in the brain and α7 nAChR agonists found to be beneficial in schizophrenia treatment [1]. protein expressions were evaluated by Furthermore it has been shown that α7 nAChR activity plays an important role in schizophrenia western blotting and the cAMP levels however the downstream pathways of this activation is not clear yet [2]. Therefore the aim of the were measured by ELISA. One way study was to investigate the role of α7 nAChR activity on PDE4A and GSK-3B pathways using α7 analysis of variance and post hoc nAChR agonist (A-582941), type1 positive allosteric modulator; PAM (CCMI) and type2 PAM (PNU- Duett’s test were used for statistical 120596) of α7 nAChRs. analysis. RESULTS

PDE4A protein expressions significantly increased in MK-801 induced schizophrenia model (Figure 1). All α7 nAChR ligands decreased PDE4A protein expressions and increased cAMP levels (Figure 2) in PFC which are remained unchanged in hippocampus. Furthermore, GSK-3B activity (pGSK-3B/GSK-3B) (Figure 3) sigifiatly dereased oth i PFC ad HC hih as foud to e sigifiatly ireased ith α7 nAChR ligands. Figure 1 Figure 2

Figure 3 Figure 1. Effects of α7 nAChR ligands on PDE4A protein expressions in MK-801 induced schizophrenia model in rats. A:Prefrontal Cortex, B: Hippocampus Figure 2. Effects of α7 nAChR ligands on cAMP levels in MK-801 induced schizophrenia model in rats A:Prefrontal Cortex, B: Hippocampus Figure 3. Effects of α7 nAChR ligands on GSK3-beta activity in MK- 801 induced schizophrenia model in rats A:Prefrontal Cortex, B: Hippocampus CONCLUSIONS REFERENCES

Preclinical and clinical data suggest that neuronal α7 nAChRs play an [1] Tregellas, J.R., Tanabe, J., Rojas, D.C., Shatti, S., Olincy, A., Johnson, L., important role in cognitive functions. The encouraging results of the Martin, L.F., Soti, F., Kem, W.R., Leonard, S., Freedman, R., 2011. Effects of an current study suggest that α7 nAChR receptor might play an alpha 7-nicotinic agonist on default network activity in schizophrenia. Biol important role in modulation of PDE4A and GSK-3B activities Psychiatry 69, 7–11. [2] Livingston, P.D., Srinivasan, J., Kew, J.N., Dawson, L.A., Gotti, C., Moretti, M., revealing these pathways might link to each other. Moreover, Shoaib, M., Wonnacott, S., 2009. Alpha7 and non-alpha7 nicotinic acetylcholine targeting α7 nAChRs might be a potent and novel strategy for the receptors modulate dopamine release in vitro and in vivo in the rat prefrontal treatment of schizophrenia including cognitive dysfunctions. cortex. Eur J Neurosci 29, 539–550. Contact: A. Cumaoglu, Erciyes Üniversity, Faculty of Pharmacy, Department of Biochemistry, KAYSERİ/TURKEY, [email protected]