Although genes in the Norepinephrine and CRH systems have not been tested for AD to the extent that GABA and glutamate have, there is evidence to suggest that the Norepinephrine and CRH systems have a functional role in the etiology of AD. Previous findings have shown that stress system disturbances are observed in AD and are involved in alcohol-induced neurotoxicity and cognitive deficits 34. The Hypothalamic-pituitary-adrenal (HPA) axis activation influences reward pathways 35 and GABAA receptor function involved in ethanol sensitivity 36. Evidence for genetic factors is supported by family studies showing altered HPA response to ethanol 37, 38, animal studies linking a CRH haplotype in alcohol consumption 39, and clinical studies associating CRHR1 variants with drinking patterns 40, 41. Findings of HPA axis disturbance in drinking or abstinent AD individuals, however, are inconsistent and difficult to interpret, with both heightened and reduced activity reported 34, 42. Moreover, acute and chronic alcohol use differ in their effects on HPA axis activity, with disturbed activity in AD potentially due in part to the impact of chronic alcohol consumption on brain regions
