Abstract
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 the PLCB1 gene to cocaine addictive properties using Plcb1+/− mice. First, we performed a general phenotypic characterization and found that Plcb1+/− mice showed normal behavior, although they had increased anxiety and impaired short-term memory. Subsequently, mice were trained for operant conditioning, self-administered cocaine for 10 days, and were tested for cocaine motivation. After 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. 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.
Highlights
Cocaine is the most used psychostimulant illicit drug worldwide [1], causing severe health problems that include the development of cocaine addiction in around 15–16% of cocaine users [2]
We found that cocaine increased the expression of PLCB1 both in human dopaminergic neuron-like cells after acute cocaine exposure and in postmortem samples of the nucleus accumbens (NAc) of cocaine abusers [6]
Behavioral tests for phenotype characterization First, we confirmed by western blot that protein levels of Plcb1 one dose of cocaine increased to fixed ratio 3 (FR3), the number of infusions was stable across sessions in WT and Plcb1+/− mice
Summary
Cocaine is the most used psychostimulant illicit drug worldwide [1], causing severe health problems that include the development of cocaine addiction in around 15–16% of cocaine users [2]. Cocaine addiction is a complex psychiatric disorder that results from the interaction of genetic, epigenetic, and environmental risk factors [3]. We found that cocaine increased the expression of PLCB1 both in human dopaminergic neuron-like cells (differentiated SH-SY5Y cells) after acute cocaine exposure and in postmortem samples of the nucleus accumbens (NAc) of cocaine abusers [6]. This gene was found over-expressed in the same brain region in mice after cocaine administration for 7 days and during withdrawal [8]. All this evidence suggest that PLCB1 may play a role in cocaine addiction
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