Biological intersection of sex, age, and environment in the corticotropin releasing factor (CRF) system and alcohol

Abstract

The neuropeptide corticotropin-releasing factor (CRF) is critical in neural circuit function and behavior, particularly in the context of stress, anxiety, and addiction. Despite a wealth of preclinical evidence for the efficacy of CRF receptor 1 antagonists in reducing behavioral pathology associated with alcohol exposure, several clinical trials have had disappointing outcomes, possibly due to an underappreciation of the role of biological variables. Although he National Institutes of Health (NIH) now mandate the inclusion of sex as a biological variable in all clinical and preclinical research, the current state of knowledge in this area is based almost entirely on evidence from male subjects. Additionally, the influence of biological variables other than sex has received even less attention in the context of neuropeptide signaling. Age (particularly adolescent development) and housing conditions have been shown to affect CRF signaling and voluntary alcohol intake, and the interaction between these biological variables is particularly relevant to the role of the CRF system in the vulnerability or resilience to the development of alcohol use disorder (AUD). Going forward, it will be important to include careful consideration of biological variables in experimental design, reporting, and interpretation. As new research uncovers conditions in which sex, age, and environment play major roles in physiological and/or pathological processes, our understanding of the complex interaction between relevant biological variables and critical signaling pathways like the CRF system in the cellular and behavioral consequences of alcohol exposure will continue to expand ultimately improving the ability of preclinical research to translate to the clinic. This article is part of the special issue on Neuropeptides.

Keywords: Adolescence; CRH; Environmental enrichment; Ethanol; Sex-differences; Stress.

Fig. 1.. Sexually dimorphic components of the CRF systems.

A) Sagittal section of rodent brain depicting selected nuclei that have been shown to display sex differences in CRF expression or function. Shading indicates regions that have also been shown to display sex-dependent effects of alcohol on the CRF systems. Inserts illustrate the specific sex differences observed in each brain region. B) In female but not male rats, chronic alcohol drinking blunts the ability of LPS to increase Crf mRNA in the PVN. C) In the male but not female CeA, chronic alcohol consumption increased activation of CRF neurons. D) In the male LC, chronic alcohol consumption increases cytoplasmic expression of CRF1R, whereas in the female LC chronic alcohol consumption increases membrane-bound CRF1R. HIPP = hippocampus, PVN = paraventricular nucleus, BNST = bed nucleus of the stria terminalis, CeA = central amygdala, DR = dorsal raphe, LC = locus coeruleus, LPS = lipopolysaccharide, CRF = corticotropin releasing factor, CRF1R = CRF1 receptor.

Fig. 2.. Potential functional roles of CRF in the effects of adolescent alcohol exposure.

Schematic of the rodent and human adolescent brain under the influence of alcohol. Alcohol drinking activates CRF signaling in the adolescent brain, which may influence drug reward/aversion, stress signaling, and synaptic plasticity in the developing brain. CRF activity in these three domains may drive increased consumption of alcohol by adolescents.

Fig. 3.. Potential mechanistic role of CRF in the BLA in the protective alcohol drinking phenotype of environmental enrichment.

Schematic of the continuum of isolation to enrichment housing during adolescence. Enrichment reduces Crf mRNA in the basolateral amygdala (BLA), which may underlie the protective effects of enrichment. Enriched rodents drink less ethanol compared to group or pair housed rodents and isolated rodents drink the highest about of ethanol.