ADX-47273, a mGlu5 receptor positive allosteric modulator, attenuates deficits in cognitive flexibility induced by withdrawal from ‘binge-like’ ethanol exposure in rats
| Autor: | Wojciech Danysz, Sylwia Talarek, Ewa Gibula-Bruzda, Anna Bodzon-Kulakowska, Joanna Listos, Piotr Suder, Kinga Gawel, Jolanta Kotlinska, Marta Marszalek-Grabska, Ewa Kędzierska |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Allosteric modulator Receptor Metabotropic Glutamate 5 Spatial Learning Hippocampus Reversal Learning Motor Activity 03 medical and health sciences Behavioral Neuroscience Cognition 0302 clinical medicine Allosteric Regulation Piperidines ADX-47273 Internal medicine medicine Animals Rats Wistar Oxadiazoles Ethanol Glutamate receptor Long-term potentiation Rats Substance Withdrawal Syndrome Barnes maze 030104 developmental biology Metabotropic receptor Endocrinology NMDA receptor Psychology Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Behavioural Brain Research. 338:9-16 |
| ISSN: | 0166-4328 |
| DOI: | 10.1016/j.bbr.2017.10.007 |
| Popis: | Repeated exposure to and withdrawal from ethanol induces deficits in spatial reversal learning. Data indicate that metabotropic glutamate 5 (mGlu5) receptors are implicated in synaptic plasticity and learning and memory. These receptors functionally interact with N-methyl- d -aspartate (NMDA) receptors, and activation of one type results in the activation of the other. We examined whether ( S )-(4-fluorophenyl)(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-piperidin-1-yl (ADX-47273), a positive allosteric modulator (PAM) of mGlu5 receptor, attenuates deficits in reversal learning induced by withdrawal (11-13 days) from ‘binge-like’ ethanol input (5.0 g/kg, i.g. for 5 days) in the Barnes maze (a spatial learning) task in rats. We additionally examined the effects of ADX-47273 on the expression of the NMDA receptors subunit, GluN2B, in the hippocampus and prefrontal cortex, on the 13th day of ethanol withdrawal. Herein, withdrawal from repeated ethanol administration impaired reversal learning, but not the probe trial. Moreover, ADX-47273 (30 mg/kg, i.p.) given prior to the first reversal learning trial for 3 days in the Barnes maze, significantly enhanced performance in the ethanol-treated group. The 13th day of ethanol abstinence decreased the expression of the GluN2 B subunit in the selected brain regions, but ADX-47273 administration increased it. In conclusion, positive allosteric modulation of mGlu5 receptors recovered spatial reversal learning impairment induced by withdrawal from ‘binge-like’ ethanol exposure. Such effect seems to be correlated with the mGlu5 receptors mediated potentiation of GluN2B-NMDA receptor mediated responses in the hippocampus and prefrontal cortex. Thus, our results emphasize the role of mGlu5 receptor PAM in the adaptive learning impaired by ethanol exposure. |
| Databáze: | OpenAIRE |
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