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.

Circadian-Dependent and Sex-Dependent Increases in Intravenous Cocaine Self-Administration inNpas2Mutant Mice

“…Fabp7 was the most highly upregulated DEG in Npas2 mutants across all regions. It regulates fatty acid uptake in astrocytes, sleep (Gerstner et al, 2017) and drug seeking under stressful conditions (Hamilton et al, 2018). Fabp7 is rhythmically expressed throughout the brain (Schnell et al, 2014) and is similarly upregulated in Arntl and Nr1d1 knock-out mice (Schnell et al, 2014;Gerstner and Paschos, 2020).…”

The Role of CaMKII and ERK Signaling in Addiction

“…Pretreatment with the FABP inhibitor SBFI26 significantly reduced ethanol consumption in mice as FABP5 and FABP7 inhibited the transport of anandamide to fatty acid amide hydrolase and elevated anandamide levels in the mouse brain, thereby increasing the preference and consumption of ethanol [ 163 ]. FABP 5/7 double knockout mice exhibit similar acquisition of cocaine-induced CPP relative to WT mice, whereas these mice do not exhibit stress-induced preference and show decreased levels of serum corticosterone under stress relative to WT mice [ 164 ]. Recent studies have reported that FABP5 knockdown in the adult rat NAc shell with RNA interference via adeno-associated viral vector attenuates cocaine self-administration and modulates the excitability of MSNs in the NAc shell [ 165 ].…”

Anti-stress neuropharmacological mechanisms and targets for addiction treatment: A translational framework

“… Rorick-Kehn et al, 2016 eCB (anandamide) enhancer URB597, Cannabidiol + + ? Gonzalez-Cuevas et al, 2018 Chauvet et al, 2014 ; Hamilton et al, 2018 ; Gonzalez-Cuevas et al, 2018 5-HT-3 antagonist Ondansetron, tropisetron + ? ?…”

“…Using this approach, they demonstrated that URB597 significantly attenuated YOH-reinstatement of cocaine seeking ( Chauvet et al, 2014 ). Targeting fatty acid binding proteins, which transport AEA intracellularly to FAAH for degradation, is a related strategy to interfere with stress-induced drug seeking ( Hamilton et al, 2018 ).…”