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ADX-47273, a mGlu5 receptor positive allosteric modulator, attenuates deficits in cognitive flexibility induced by withdrawal from ‘binge-like’ ethanol exposure in rats
- Source :
- Behavioural Brain Research. 338:9-16
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 01664328
- Volume :
- 338
- Database :
- OpenAIRE
- Journal :
- Behavioural Brain Research
- Accession number :
- edsair.doi.dedup.....298df7d3283029d1c122e5d337ae8cf6