Cocaine self-administration increases impulsive decision-making in low-impulsive rats associated with impaired functional connectivity in the mesocorticolimbic system.

Impulsivity is often considered a risk factor for drug addiction; however, not all evidence supports this view. In the present study, we used a food reward delay-discounting task (DDT) to categorize rats as low-, middle-, and high-impulsive but failed to find any difference among these groups in the acquisition and maintenance of cocaine self-administration, regardless of electrical foot-shock punishment. Additionally, there were no group differences in locomotor responses to acute cocaine in rats with or without a history of cocaine self-administration. Unexpectedly, chronic cocaine self-administration selectively increased impulsive choice in low-impulsive rats. Resting-state fMRI analysis revealed a positive correlation between impulsivity and cerebral blood volume in the midbrain, thalamus, and auditory cortex. Using these three regions as seeds, we observed a negative correlation between impulsivity and functional connectivity between the midbrain and frontal cortex, as well as between the thalamus and frontal cortex (including the orbitofrontal, primary, and parietal cortices) in low-impulsive rats. These correlations were attenuated following chronic cocaine self-administration. RNAscope in situ hybridization assays revealed a significant reduction in DA D1, D2, and D3 receptor mRNA expression in the corticostriatal regions of low-impulsive rats after cocaine self-administration. Our findings challenge the widely held view that impulsivity is a vulnerability factor for cocaine addiction. Instead, chronic cocaine use appears to selectively increase impulsive choice decision-making in low-impulsive rats, associated with reduced functional connectivity and DA receptor expression in the mesocorticolimbic DA network. Impulsivity has long been considered a risk factor for substance use disorders (SUD). However, findings across different impulsivity measures have been inconsistent or controversial. In this study, we did not find evidence supporting the notion that preexisting choice impulsivity is a predictive factor for compulsive cocaine self-administration. Instead, we found that chronic cocaine self-administration led to a significant increase in impulsive choice decision-making in normally low-impulsive rats. This increase was associated with reduced functional connectivity and reduced dopamine receptor expression in the dopamine-related network. Our findings suggest that choice impulsivity does not predict SUD; rather, chronic cocaine use is a risk factor for developing impulsive behavior in healthy individuals.