Studies using macaque monkeys to address excessive alcohol drinking and stress interactions

Abstract

The use of non-human primates (NHPs) in studies of volitional, oral self-administration of alcohol can help address the complex interplay between stress and excessive alcohol consumption. There are aspects to brain, endocrine and behavior of NHPs, particularly macaques, that provide a critical translational link towards understanding the risks and consequences of alcohol use disorders (AUDs) in humans. These include wide individual differences in escalating daily alcohol intake, accurate measures of hypothalamic-pituitary-adrenal (HPA) axis hormonal interactions, neuroanatomical specificity of synaptic adaptations to chronic alcohol, genetic similarities to humans, and the ability to conduct in vivo brain imaging. When placed in a framework that alcohol addiction is a sequence of dysregulations in motivational circuitry associated with severity of AUD, the NHP can provide within-subject information on both risks for and consequences of repeatedly drinking to intoxication. Notably, long-term adaptations in neurocircuitry that mediate behavioral reinforcement, stress responses and executive functions are possible with NHPs. We review here the substantial progress made using NHPs to address the complex relationship between alcohol and stress as risk factors and consequences of daily drinking to intoxication. This review also highlights areas where future studies of brain and HPA axis adaptations are needed to better understand the mechanisms involved in stress leading to excessive alcohol consumption. This article is part of the Special Issue entitled "Alcoholism".

Keywords: Alcohol; Allostasis; Ethanol; Monkey; Self-administration; Stress.

Figure 1. Alcohol self-administration and HPA axis interactions in nonhuman primates (NHPs)

At the apex of the HPA axis is the hypothalamic paraventricular nucleus (PVN) where corticotropin-releasing factor (CRF) and arginine-vasopressin (AVP) are released in response to real or perceived threats to homeostasis. GABA and glutamate are the principle neurotransmitters in relaying information to the PVN, and targets for alcohol pharmacology. Activation of parvocellular neurons stimulates adrenocorticotropin hormone (ACTH) release from the anterior pituitary which increases steroidogenesis from each layer of the adrenal cortex. The left-hand column highlights some of the evidence from the NHP model showing that each level of the hypothalamic-pituitary-adrenal axis is effected by long-term alcohol self-administration. The future directions (center column) are aimed at better understanding the physiological impact of alcohol at each level and the interactions among the three principal components. While this list is not exhaustive, it highlights some of the projects that have clinical implications (right-hand column). AUD: alcohol use disorder; RNST bed nucleus of the stria terminalis; CRF-BP: corticotropin-releasing factor binding protein; DOC: deoxycorticosterone; DHEAS: sulfated dihydroepiandrosterone; OXY: oxytocin