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bioRxiv · 10.1101/2020.06.18.158964

Reduced cue-induced reinstatement of cocaine seeking behavior in Plcb1+/- mice

Cabana-Dominguez, J.·Martin-Garcia, E.·Gallego-Roman, A.·Maldonado, R.·Fernandez-Castillo, N.·Cormand, B.
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Abstract

Background and PurposeCocaine addiction causes serious health problems and no effective treatment is available yet. We previously identified a genetic risk variant for cocaine addiction in the PLCB1 gene and found this gene upregulated in postmortem brains of cocaine abusers and in human dopaminergic neuron-like cells after an acute cocaine exposure. Here, we functionally tested the contribution of PLCB1 gene to cocaine addictive properties in mice. Experimental approachWe used heterozygous Plcb1 knockout mice (Plcb1+/-) and characterized their behavioral phenotype. Subsequently, mice were trained for operant conditioning and self-administered cocaine for 10 days. Plcb1+/- mice were assessed for cocaine motivation, followed by 26 days of extinction and finally evaluated for cue-induced reinstatement of cocaine seeking. Gene expression alterations after reinstatement were assessed in medial prefrontal cortex (mPFC) and hippocampus (HPC) by RNAseq. Key ResultsPlcb1+/- mice showed normal behavior, although they had increased anxiety and impaired short-term memory. Importantly, after cocaine self-administration and extinction, we found a reduction in the cue-induced reinstatement of cocaine-seeking behavior in Plcb1+/- mice. After reinstatement, we identified transcriptomic alterations in the medial prefrontal cortex of Plcb1+/- mice, mostly related to pathways relevant to addiction like the dopaminergic synapse and long-term potentiation. Conclusions and ImplicationsTo conclude, we found that heterozygous deletion of the Plcb1 gene decreases cue-induced reinstatement of cocaine seeking, pointing at PLCB1 as a possible therapeutic target for preventing relapse and treating cocaine addiction.

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Cabana-Dominguez, J., Martin-Garcia, E., Gallego-Roman, A., Maldonado, R., Fernandez-Castillo, N., Cormand, B.. 2020-06-19. Reduced cue-induced reinstatement of cocaine seeking behavior in Plcb1+/- mice. https://doi.org/10.1101/2020.06.18.158964

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