Abstract
Background and Purpose: Cocaine 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 approach: We 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 Results:
Plcb1+/- 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 Implications: To 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.