[18F]-Fluorodeoxyglucose-Positron Emission Tomography in Rats with Prolonged Cocaine Self-Administration Suggests Potential Brain Biomarkers for Addictive Behavior

Abstract

The DSM5-based dimensional diagnostic approach defines substance use disorders on a continuum from recreational drug use to habitual and ultimately addicted behavior. Biomarkers that are indicative of recreational drug use and addicted behavior are lacking. We performed a translational [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) study in the multi-dimensional 0/3crit model of cocaine addiction. Addict-like (3crit) and non-addict-like (0crit) rats, which shared identical life conditions and levels of cocaine self-administration, were acquired for FDG-PET under baseline conditions and following cocaine and yohimbine challenges. Compared to cocaine-naïve control rats, 0crit animals showed higher glucose uptake in the caudate putamen (CPu) and medial prefrontal cortex (mPFC) respect to naïve controls. 3crit animals did not show this adaptive higher glucose utilization, but had lower uptake in several cortical areas. Both cocaine and yohimbine challenges affected glucose uptake in control rats in several brain sites, but not in 0crit and 3crit rats, indicating that impaired glucose mobilization in response to these challenges is not specifically associated with addictive behavior. Compared to 0crit, 3crit rats showed higher reinstatement responses, which were negatively associated with glucose uptake in the ventral tegmental area. Data indicate that cocaine non-addict- and addict-like phenotypes are associated with several potential biomarkers. Specifically, we propose that increased glucose uptake in the CPu and mPFC is a function of controlled drug use, whereas a loss of striatal and prefrontal metabolic activity and reduced uptake in cortical areas are indicative of addictive behavior.

Cocaine addicted rats show reduced neural activity as revealed by manganese-enhanced MRI

“…Our data indicate that brain activity during bingeing does not differ between 0 and 3crit rats, possibly because of the relatively rapid development of tolerance 70 that is reflected in reduced brain activity 71 . This is in line with our FDG-PET study demonstrating that 0crit and 3crit did not differ in metabolic response to an acute cocaine challenge 19 , and is consistent with the interpretation that differences in addictive-like behavior between 0 and 3crit rats is independent from the primary reinforcing effect of cocaine 15 . Previous studies have also used MEMRI to examine cocaine-induced brain activation.…”

“…Compared to our recent report using FDG-PET, the results presented here provide a different perspective on brain activity associated with addiction vulnerability and resilience, broadening the quality and quantity of information. Our results corroborate the generally reduced cortical activity found in 3crit compared to cocainenaïve rats, while 0crit had an activity level similar to controls 19 . However, our MEMRI approach revealed a much broader effect, including several cortices and sub-cortical nuclei.…”

“…For instance, while the current study found no group differences in ∆T1 in the PFC and reduced ∆T1 (i.e. activity) in the CPu of 3crit, with 18 FDG we reported increased glucose uptake in both PFC and CPu of 0crit 19 . This suggests that 18 FDG and MEMRI may capture different aspects of brain activity, in which 18 FDG gives a measure of the energy consumption not exclusively associated with neural transmission while MEMRI reflects Ca 2+ influx and hence neuronal depolarization.…”

“…3A). As observed in earlier studies 17,19,38,53,54 , as a consequence of cocaine exposure, average body weight was higher in the cocaine-naïve AgeControl group compared to 0crit and 3crit, but it remained stable in each group throughout the www.nature.com/scientificreports/ performed two ad-libitum CSA sessions: one before and one after MnCl 2 administration. As expected, addictlike rats (3crit) earned more infusions than non-addict-like rats (0crit) at both time points but importantly, the responses and reinforcers earned during these self-administration tests were similar before and after MnCl 2 treatment (group effect [F(1,34) = 9.11; p = 0.0048], time effect [F(1,34) = 1.11; p = 0.3], group by time interaction [F(1,34) = 0.38; p = 0.54], Fig.…”

“…The 0/3crit model of addiction adopted here is intended to study individual predisposition to show addiction-like behavior independent of the amount of cocaine consumed 15,16 . Therefore, in line with our previous studies 17,19 , a maximum of 35 infusions per session was allowed during SA training. Sessions were run five days a week.…”