Cocaine Self-Administration Increases Impulsive Decision-Making in Low-Impulsive Rats Associated with Impaired Functional Connectivity in the Mesocorticolimbic System.

Abstract

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 (SA), regardless of electrical footshock punishment. Additionally, there were no group differences in locomotor responses to acute cocaine in rats with or without a history of cocaine SA. Unexpectedly, chronic cocaine SA 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 SA. RNAscope in situ hybridization assays revealed a significant reduction in dopamine (DA) D₁, D₂, and D₃ receptor mRNA expression in the corticostriatal regions of low-impulsive rats after cocaine SA. Our findings challenge the widely held view that impulsivity is a vulnerability factor for cocaine use disorder. Instead, chronic cocaine use appears to selectively increase impulsive choice decision-making in normally low-impulsive rats, associated with reduced functional connectivity and DA receptor expression in the mesocorticolimbic DA network.