Functional Connectivity of Chronic Cocaine Use Reveals Progressive Neuroadaptations in Neocortical, Striatal and Limbic Networks

Abstract

Brain imaging studies indicate that chronic cocaine users display altered functional connectivity between prefrontal cortical, thalamic, striatal, and limbic regions; however, the use of cross-sectional designs in these studies precludes measuring baseline brain activity prior to cocaine use. Animal studies can circumvent this limitation by comparing functional connectivity between baseline and various time points after chronic cocaine use. In the present study, adult male Long-Evans rats were trained to self-administer cocaine intravenously for 6-hour daily sessions over 14 consecutive days. Two additional groups serving as controls underwent sucrose self-administration or exposure to the test chambers alone. Functional magnetic resonance imaging was conducted before self-administration and after 1 and 14 days of abstinence (1d and 14d Abs). At 1d Abs from cocaine, there was increased clustering coefficient in brain areas involved in reward seeking, learning, memory, and autonomic and affective processing, including amygdala, hypothalamus, striatum, hippocampus and thalamus. Similar changes in clustering coefficient after 1d Abs from sucrose were evident in predominantly thalamic brain regions. Notably, there were no changes in strength of functional connectivity at 1d or 14d after either cocaine or sucrose self-administration. The results suggest that cocaine and sucrose can change the arrangement of functional connectivity of brain regions involved in cognition and emotion, but that these changes dissipate across the early stages of abstinence. The study also emphasizes the importance of including baseline measures in longitudinal functional neuroimaging designs seeking to assess functional connectivity in the context of substance use.

Significance Statement Although human neuroimaging studies have been invaluable in understanding the relationship between cocaine use and brain functional connectivity, they inherently lack pre-drug baseline information important to establish how cocaine use alters regional interactions. Coupling neuroimaging with rodent models of cocaine self-administration circumvents this issue by controlling variables that can confound human studies and providing pre-drug baseline information. Using such an approach, this study reveals that after cocaine use, functional connectivity patterns change as a function of abstinence duration and that these changes are observed in networks supporting reward and emotion-related cognition and behavior. These findings highlight the importance of using multiple timepoints in preclinical models of substance use to assess effects on functional connectivity.