The role of the glucocorticoids in developing resilience to stress and addiction

Abstract

There is emerging evidence that individuals have the capacity to learn to be resilient by developing protective mechanisms that prevent them from the maladaptive effects of stress that can contribute to addiction. The emerging field of the neuroscience of resilience is beginning to uncover the circuits and molecules that protect against stress-related neuropsychiatric diseases, such as addiction. Glucocorticoids (GCs) are important regulators of basal and stress-related homeostasis in all higher organisms and influence a wide array of genes in almost every organ and tissue. GCs, therefore, are ideally situated to either promote or prevent adaptation to stress. In this review, we will focus on the role of GCs in the hypothalamic-pituitary adrenocortical axis and extra-hypothalamic regions in regulating basal and chronic stress responses. GCs interact with a large number of neurotransmitter and neuropeptide systems that are associated with the development of addiction. Additionally, the review will focus on the orexinergic and cholinergic pathways and highlight their role in stress and addiction. GCs play a key role in promoting the development of resilience or susceptibility and represent important pharmacotherapeutic targets that can reduce the impact of a maladapted stress system for the treatment of stress-induced addiction.

Keywords: addiction; cholinergic; glucocorticoid; mifepristone; nicotinic acetylcholine receptors; orexin; resilience; stress.

Figure 1

Schematic representation of the interaction between glucocorticoids, orexins, and the cholinergic system in regulating stress responses. Stress activates the release of glucocorticoids from the adrenal gland, which then feedback into the brain and target both the HPA axis and extra-hypothalamic sites like the hippocampus and the amygdala. Orexins also activate the HPA axis and lead to the production of glucocorticoids and stimulate the release of CRF from the PVN of the hypothalamus and the central amygdala. The third player are the nicotinic receptors (nAChRs) which indirectly regulate ACTH release by acting on the PVN.

Figure 2

Glucocorticoid, orexinergic, and cholinergic activation of the brain regions involved in stress and drug addiction. Glucocorticoid receptors in the hippocampus and amygdala mediate the effects of stress and consolidation of fearful memories. GCs also modulate alcohol withdrawal in the prefrontal cortex (PFC), nucleus accumbens (NAc), and bed nucleus of the stria terminalis (BNST). Glucocorticoids (GCs) in the hippocampus also negatively regulate the hypothalamus thereby providing a central feedback mechanism. Orexins produced in the hypothalamus activate reward pathways such as the ventral tegmental area (VTA) and the NAc and brain regions involved in stress, fear, and anxiety such as the amygdala and BNST and regulate cardiovascular tone through the locus coeruleus (LC). Both GCs and orexins play similar roles in brain regions implicated in stress and reward. Glucocorticoids have been shown to directly inhibit nicotinic receptor (nAChR) activity in the hippocampus that exert an inhibitory effect on the HPA axis. The nAChRs seem to differentially orchestrate responses to stress.