Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats
A growing body of evidence suggests that negative modulation of γ-aminobutyric acid (GABA) GABAA α5 receptors may be a promising strategy for the treatment of certain facets of cognitive impairment; however, selective modulators of GABAA α5 receptors have not yet been tested in “schizophrenia-relevant” cognitive assay/model systems in animals.
The objectives of this study were to investigate the potential of RO4938581, a negative modulator of GABAA α5 receptors, and to attenuate cognitive impairments induced following sub-chronic (sub-PCP) and early postnatal PCP (neo-PCP) administration in the novel object recognition (NOR) and intra-extradimensional shift (ID/ED) paradigms in rats. Complementary in vitro, ex vivo and in vivo studies were performed to confirm negative modulatory activity of RO4938581 and to investigate animal model validity, concept validity and potential side effect issues, respectively.
In vitro studies confirmed the reported negative modulatory activity of RO4938581, whilst immunohistochemical analyses revealed significantly reduced parvalbumin-positive cells in the prefrontal cortex of sub-PCP- and neo-PCP-treated rats. RO4938581 (1 mg/kg) ameliorated both sub-PCP- and neo-PCP-induced cognitive deficits in NOR and ID/ED performance, respectively. In contrast, QH-II-066 (1 and 3 mg/kg), a GABAA α5 receptor positive modulator, impaired cognitive performance in the NOR task when administered to vehicle-treated animals. Additional studies revealed that both RO4938581 (1 mg/kg) and QH-II-066 (1 and 3 mg/kg) attenuated amphetamine-induced hyperactivity in rats.
Taken together, these novel findings suggest that negative modulation of GABAA α5 receptors may represent an attractive treatment option for the cognitive impairments, and potentially positive symptoms, associated with schizophrenia.
KeywordsGABA alpha5 receptors Negative allosteric modulator Sub-chronic PCP Early postnatal PCP Novel object recognition Attentional set shifting Cognition Rat
The authors would like to thank Sascha Bull, Kate Pedersen, Tanja Bruun, Annette Bjorn, Jytte S. Pedersen, Kirsten Assing, Kirsten Jørgensen, Mona Elster, Pia Møller Carstensen, Pia Maribo Sørensen, Claus Black Jensen and Mats Garmer for excellent technical assistance. The authors are also grateful to Dr. Pascal Goetghebeur and Christian Spang Pedersen for helpful comments to the revised manuscript.
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