Functional consequences of cocaine re-exposure after discontinuation of cocaine availability

Abstract

Cocaine users exhibit a wide range of behavioral impairments accompanied by brain structural, neurochemical and functional abnormalities. Metabolic mapping studies in cocaine users and animal models have shown extensive functional alterations throughout the striatum, limbic system, and cortex. Few studies, however, have evaluated the persistence of these effects following cessation of cocaine availability. The purpose of this study, therefore, was to assess the functional effects of re-exposure to cocaine in nonhuman primates after the discontinuation of cocaine self-administration for 30 or 90 days, using the quantitative autoradiographic 2-[14C]deoxyglucose (2DG) method. Rhesus monkeys self-administered cocaine (fixed interval 3-min schedule, 30 infusions per session, 0.3 mg/kg/infusion) for 100 sessions followed by 30 (n=4) or 90 days (n=3) during which experimental sessions were not conducted. Food-reinforced control animals (n=5) underwent identical schedules of reinforcement. Animals were then re-exposed to cocaine or food for one final session and the 2DG method applied immediately after session completion. Compared to controls, re-exposure to cocaine after 30 or 90 day drug-free periods resulted in lower rates of glucose utilization in ventral and dorsal striatum, prefrontal and temporal cortex, limbic system, thalamus, and midbrain. These data demonstrate that vulnerability to the effects of cocaine persists for as long as 90 days after cessation of drug use. While there was some evidence for recovery (fewer brain areas were affected by cocaine re-exposure at 90 days as compared to 30 days), this was not uniform across regions, thus suggesting that recovery occurs at different rates in different brain systems.

Keywords: Cocaine; Functional brain activity; Re-exposure; Rhesus monkey; Self-administration.

Figure 1

Effect of re-exposure to cocaine self-administration 30 or 90 days after cessation of drug availability, compared to food-reinforced controls. The left hemisphere in Panels A–D displays the distribution of [¹⁴C]-deoxyglucose, while the right hemisphere indicates the anatomical localization of brain areas shown in the histograms below (Panels E–G). Rates of local cerebral glucose utilization (LCGU, μmol/100g/min) in response to food or cocaine self-administration are shown in Panels E–G. Asterisks represent significant differences from food controls, * P<0.05, ** P<0.01

Figure 2

Effect of re-exposure to cocaine self-administration 30 or 90 days after cessation of drug availability on rates of local cerebral glucose utilization in nonhuman primates, as compared to rates of local cerebral glucose utilization of food-reinforced control animals. The 2[¹⁴C]DG method was applied immediately after the end of the behavioral session. Shown are color-coded transformations of autoradiograms of coronal sections of nonhuman primate brain at the level of the striatum. Each color represents a range of rates of local cerebral glucose utilization (μmol/100 g per min) according to the calibration scale to the right of the autoradiograms.