Abstract
Background. Antipsychotic drugs are the mainstay of treatment for patients diagnosed with schizophrenia. However, while psychotic symptoms are reasonably well controlled by antipsychotic medication, negative symptoms and cognitive deficits remain an unmet clinical need (Keefe et al. Arch Gen Psychiatry. 2007; 64: 633-647, CATIE trial findings). Accumulating evidence supports glutamateric dysfunction in the pathophysiology of schizophrenia, leading to disinhibition of cortical circuitry, dysregulation of gamma oscillations and reductions in the calcium binding protein parvalbumin (PV), located on fast spiking GABAergic interneurons (Tse et al. Biol Psychiatry 2015; 77: 929–939 for recent review). The voltage gated potassium channel Kv3.1 is co-localised with PV interneurons, closely involved in this brain circuitry and found to be reduced in un-medicated patients (Yanagi et al. Mol Psychiatry 2014; 19: 573-579). Modulation of this channel may therefore provide a novel target for restoration of function in schizophrenia patients. The aim of this project is to identify selective modulators of this channel, assess their efficacy for negative symptoms and cognitive deficits in animal models and validate their mechanism of action.Methods. Several cohorts of adult female Lister-Hooded (LH) rats received PCP (2 mg/kg, sub-chronic-scPCP) or saline i.p. for 7 days, followed by 7 days washout. Rats were then tested for cognitive and social behaviour deficits following the lead Kv3.1 channel modulator, AUT00206, at 10-60 mg/kg ip or po or vehicle. AUT00206 was given acutely 30-60 min prior to testing or once daily for 21 days. Effects of AUT00206 on PV interneurons and Kv3.1 channel expression were examined using immunohistochemistry on brain free-floating sections. Prefrontal cortical slices of the prelimbic and infralimbic regions were prepared from one cohort of these rats and efficacy of AUT00206 at 10 and 20uM to modulate kainate-induced fast (20-80 Hz) network oscillations in vitro was examined. Effects of AUT00206 at 10uM on gamma oscillations in human temporal neocortex slices was also investigated. Male Sprague-Dawley rats were pre-treated with AUT00206 at 10 or 60 mg/kg or vehicle (ip) and imaged in a 7T magnet with pharmacological challenge fMRI (phMRI) before and after in-magnet administration of 30 mg/kg ketamine sc.Results. In acute studies, AUT00206 (10-60 mg/kg) restored cognitive and social behaviour deficits induced by scPCP in female LH rats. Specifically AUT00206 significantly reversed the scPCP-induced deficit in recognition memory and reversal learning at all doses (P
| Original language | English |
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| Publication status | Published - Dec 2015 |
| Event | 54 th Annual Meeting of the American College of Neuropsychopharmacology - Diplomat Resort and Spa Hollywood, Florida Duration: 6 Dec 2015 → 10 Dec 2015 |
Conference
| Conference | 54 th Annual Meeting of the American College of Neuropsychopharmacology |
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| City | Diplomat Resort and Spa Hollywood, Florida |
| Period | 6/12/15 → 10/12/15 |