Chronic cocaine administration upregulates FKBP5 in the extended amygdala of male and female rats

Abstract

Background: Dysregulation of glucocorticoid receptors has been implicated in addiction and stress-related disorders. FKBP5 is a co-chaperone of the glucocorticoid receptor and regulates receptor sensitivity. While FKBP5 is known to be involved in mood-and stress-related disorders, less is known regarding FKBP5 and cocaine abuse. This study investigated the regulation of FKBP5 expression in the extended amygdala and paraventricular nucleus of the hypothalamus, regions important in the control of stress-responses and HPA axis function, following chronic and acute cocaine administration. Methods: Adult male and female rats received saline or cocaine three times per day for 1 or 14 days. Brain tissue was collected 30 minutes, 24 hours, 48 hours, 7 days or 14 days following the final injection. FKBP5 mRNA was measured by qRT-PCR in the central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (BNST) and paraventricular nucleus (PVN). Results: FKBP5 mRNA levels were significantly elevated as a result of chronic cocaine administration in both males and females in the PVN and BNST 30 minutes and 24 hours after the final injection. In females, FKBP5 was also elevated in the CeA. Following acute cocaine, FKBP5 gene expression was unaltered except for elevated levels in the BNST of females at 24 hours of withdrawal. Conclusions: These results demonstrate that FKBP5 mRNA is regulated by cocaine administration. Increased FKBP5 expression may play a role in the dysregulation of the stress axis following chronic cocaine exposure, contributing to the negative affective symptoms of cocaine withdrawal.

Effects of Sex and Estrous Cycle on the Time Course of Incubation of Cue-Induced Craving following Extended-Access Cocaine Self-Administration

“…In the past several years, there has been a shift toward systematically studying sex differences in preclinical addiction models. Recent studies have identified sex differences in mRNA and protein expression in stress systems and glutamatergic signaling pathways within the reward circuitry following cocaine exposure ( Connelly and Unterwald, 2019 , 2020 ; Castro-Zavala et al, 2020 ). Such studies will lay the foundation for future work focused on identifying cellular and synaptic mechanisms driving sex differences in behavioral responding to cocaine.…”

DNA methylation mediates the effect of cocaine use on HIV severity

“…Some studies also showed that genetic variants on CX3CR1 were associated with HIV susceptibility and rapid HIV progression to AIDS [79]. cg25114611, located in the promoter region of FKBP5, is also biologically plausible, given the implication for chronic cocaine administration upregulating FKBP5 expression in rats [80].…”

Emerging non-invasive neuroplastic-targeting therapies for substance use disorder treatment

“…12 It also appears that the extended amygdala, which influences the hypothalamic-pituitary-adrenal (HPA) axis, a key component in the stress response, is altered with chronic substance use. 15 Researchers believe elevated levels of a FKBP5 protein in the extended amygdala, as seen in rats following chronic cocaine use, 15 may lead to a loss of negative feedback yielding overactivity of the HPA axis, 16 resulting in more severe negative affective symptoms of cocaine withdrawal. 15 This may lead to an increased drive for relapse.…”

“…15 Researchers believe elevated levels of a FKBP5 protein in the extended amygdala, as seen in rats following chronic cocaine use, 15 may lead to a loss of negative feedback yielding overactivity of the HPA axis, 16 resulting in more severe negative affective symptoms of cocaine withdrawal. 15 This may lead to an increased drive for relapse. 15 While these studies illustrate the nature of the brain's response to substances of abuse, others demonstrate how long these effects last.…”