Fatty acid binding protein deletion prevents stress-induced preference for cocaine and dampens stress-induced corticosterone levels

Abstract

Genetic and pharmacological manipulation of endocannabinoid (eCB) signaling has previously been shown to have an important role on the rewarding properties of drugs of abuse, including cocaine. Recently, fatty acid binding proteins (FABPs) have been proposed as intracellular transporters of the endocannabinoid anandamide (AEA) as well as other bioactive lipids to their catabolic enzyme, fatty acid amide hydrolase (FAAH). The role of these transporters in modulating the brains reward system has yet to be investigated. This study examined the effects of genetic deletion of FABP 5/7 on cocaine preference, as assessed by the Conditioned Place Preference (CPP) paradigm. Male and female wild type (WT) and FABP 5/7 KO mice showed similar acquisition of cocaine CPP, with no differences found in overall locomotor activity. In addition, while male and female WT mice showed stress-induced CPP for cocaine, male and female FABP 5/7 KO mice failed to show a stress-induced preference for the cocaine-paired chamber. Additionally, serum corticosterone levels were analyzed to explore any potential differences in stress response that may be responsible for the lack of stress-induced preference for cocaine. Serum samples were obtained in animals under basal conditions as well as following a 30-min tube restraint stress. Male and female FABP 5/7 KO mice showed reduced corticosterone levels under stress compared to their WT counterparts. The reduction in corticosterone response under stress may mediate that lack of a stress-induced preference for cocaine in the FABP 5/7 KO mice. Thus, the role of FABPs may play an important role in drug-seeking behavior under stressful conditions.

Keywords: addiction; cocaine; conditioned place preference; endocannabinoid.

FIGURE 1

Cocaine CPP experimental timeline. During conditioning, subjects received treatment on Days 2, 4, 6, and 8. All subjects received vehicle injections on Days 3, 5, 7, and 9

FIGURE 2

Cocaine CPP in male and female WT and FABP 5/7 KO mice. Mean percent of time spent in drug-paired chamber on precondi-tioning day, test day, and stress-induced reinstatement day. Stress-induced reinstatement consisted of placing in conical tubes for 30 min and retesting their preference for the cocaine-paired chamber. All groups showed a significant preference for the cocaine-paired chamber on test day. Male and female WT mice showed a stress-induced reinstatement of preference for the drug-paired chamber while male and female FABP 5/7 KO mice did not. Male WT n = 15, Female WT n = 16, Male KO n = 18, Female KO n = 7. *p < .05, **p < .01, ***p < .001

FIGURE 3

Locomotor activity throughout place conditioning. All four groups displayed greater mean locomotor activity on days when administered 10 mg/kg cocaine intraperitoneally compared to saline. Male WT n = 15, female WT n = 16, Male KO n = 18, Female KO n = 7. *p < .05, **p < .01, ***p < .001

FIGURE 4

Corticosterone levels in male and female WT and FABP 5/7 KO mice under basal and stressed conditions. No changes in corticosterone were observed under basal conditions. All groups showed significantly higher corticosterone levels under stress apart from the male FABP 5/7 KO mice. Male and female FABP 5/7 KO mice show reduced corticosterone levels under stress compared to WT counterparts (p < .001). n 57 for male and female WT (for both stress and nonstress), n 54 for male and female FABP5/7 KO (for both stress and nonstress). *p < .05, ***p < .001