Genetic and environmental influences on ethanol consumption: perspectives from preclinical research

Abstract

Background: Alcohol use disorders (abuse and dependence, AUD) are multifactorial phenomena, depending on the interplay of environmental and genetic variables.

Method: This review describes current developments in animal research that may help (a) develop gene therapies for the treatment of alcoholism, (b) understand the permissive role of stress on ethanol intake, and (c) elucidate why exposure to ethanol early in life is associated with a greater risk of AUD.

Results: The polymorphisms found in liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) affect the elimination of ethanol and the susceptibility to ethanol intake. A highly active ADH protects against alcoholism, an effect related to a presteady state burst in arterial acetaldehyde. Social stressors, such as repeated early maternal separation or social defeat, exert a permissive effect on ethanol intake, perhaps by altering the normal development of the hypothalamic-pituitary-adrenal axis. Ethanol exposure during gestation, infancy, or adolescence increases the likelihood of AUD later in life. Early perception of ethanol's positive and negative (anti-anxiety) reinforcing effects may play a role in this phenomenon.

Conclusions: The review underscores the advantages of using preclinical animal models of AUD and highlights points of intersection between the topics to help design a more integrated approach for the study of alcohol-related problems.

Figure 1

Upper panel Ethanol intake (gram per kilogram of body weight, g/kg) in adult mice that underwent maternal separation as infants (MS) or were reared under normal animal facility conditions (AFR). Ethanol intake was tested in a three-bottle choice procedure (6% ethanol, 10% ethanol or its vehicle, a 0.05% saccharin solution). To facilitate data visualization ethanol intake has been averaged over two 5-day blocks. Lower panel: Ethanol intake in the home cage (gram per kilogram of body weight, g/kg) of a 10% alcohol solution, by AFR and MS mice in 60-min sessions using an operant self-administration procedure. Asterisks indicate significant differences between a paired group and its corresponding unpaired control (p < 0.05). Vertical Bars indicate the standard error of the means (SEM). Adapted from: Cruz et al., (2008) Maternal separation stress in male mice: long-term increases in alcohol intake. Psychopharmacology 201, 459–468.

Figure 2

Percent time spent on a conditioned stimulus (sandpaper, CS) as a function of conditioning procedures [sandpaper paired or unpaired with administration of 1.0 g/kg ethanol] and naloxone dose at time of conditioning (0.0, 0.25, 0.75 or 1.5 mg/kg). Ethanol was administered intragastrically, naloxone was given via the intraperitoneal route. Animals (14-day old rats) were tested in a two-way, 5-min preference test (sandpaper vs. cardboard). Asterisks indicate significant differences between a paired group and its corresponding unpaired control (p < 0.05). Vertical bars represent the standard error of the means (S.E.M.). Adapted from: Nizhnikov et al., (2009) Opioid antagonists block the acquisition of ethanol-mediated conditioned preference in infant rats. Alcohol 43, 347–358. Used with permission from publishers.