Nucleus accumbens shell neurons’ early sensitivity to cocaine is associated with future increases in drug intake

Abstract

The striatum, both dorsal and ventral, is strongly implicated in substance use disorder. Chronic consumption of abused substances, such as cocaine, can cause an oversaturation of mesostriatal dopamine, which results in alterations in the firing of striatal neurons. While most preclinical studies of drug self-administration (S-A) are focused on these alterations, individual differences in a subject's early responses to drugs can also account for substantial differences in addiction susceptibility. In this study, we modeled longitudinal pharmacokinetics using data from a previous longitudinal study (Coffey et al., 2015) and aimed to determine if firing in specific dorsal and ventral striatal subregions was subject to changes across chronic cocaine S-A, and if individual animal differences in striatal firing in response to early drug exposure correlated with increases in drug intake. We observed that the firing patterns of nucleus accumbens (NAc) core and shell neurons exhibited increasing sensitivity to cocaine over the first 6 S-A sessions and maintained a strong negative correlation between drug intake and neuronal firing rates across chronic S-A. Moreover, we observed that the early sensitivity of NAc shell neurons to cocaine correlated with future increases in drug intake. Specifically, rats whose NAc shell neurons were most inhibited by increasing levels of cocaine upon first exposure exhibited the strongest increases in cocaine intake over time. If this difference can be linked to a genetic difference, or druggable targets, it may be possible to screen for similar addiction susceptibility in humans or develop novel preemptive pharmacotherapies.