Moderate alcohol exposure during early brain development increases stimulus‐response habits in adulthood

Abstract

Exposure to alcohol during early central nervous system development has been shown variously to affect aspects of physiological and behavioural development. In extreme cases, this can extend to craniofacial defects, severe developmental delay and mental retardation. At more moderate levels, subtle differences in brain morphology and behaviour have been observed. One clear effect of developmental alcohol exposure is an increase in the propensity to develop alcoholism and other addictions. The mechanisms by which this occurs, however, are not currently understood. In this study, we tested the hypothesis that adult zebrafish chronically exposed to moderate levels of ethanol during early brain ontogenesis would show an increase in conditioned place preference for alcohol and an increased propensity towards habit formation, a key component of drug addiction in humans. We found support for both of these hypotheses and found that the exposed fish had changes in mRNA expression patterns for dopamine receptor, nicotinic acetylcholine receptor and μ-opioid receptor encoding genes. Collectively, these data show an explicit link between the increased proclivity for addiction and addiction-related behaviour following exposure to ethanol during early brain development and alterations in the neural circuits underlying habit learning.

Effects of embryonic ethanol exposure at low doses on neuronal development, voluntary ethanol consumption and related behaviors in larval and adult zebrafish: Role of hypothalamic orexigenic peptides

“…Specifically, 0.5% ethanol at 24 hpf significantly increases voluntary consumption of 10% ethanol-gelatin in the zebrafish at 6 months of age, showing the persistence of this behavioral change after only a brief period of exposing the embryo to ethanol. This result is consistent with the finding that embryonic ethanol increases the time spent in the presence of ethanol-conditioned cues in a conditioned place preference test, suggesting an increase in ethanol preference and the propensity for habit formation [15], a key component of drug addiction in humans [65]. It also agrees with our recent study, showing that exposure of adult zebrafish to ethanol in the tank water increases their voluntary consumption of the ethanol-gelatin food that elevates blood ethanol to > 150 mg/dL [37].…”

“…In recent years, the zebrafish has emerged as an important vertebrate species in behavioral neuroscience showing a great translational relevance in studies of alcohol-related disorders [10, 11]. There is evidence in this species that exposure to ethanol early in development can affect certain behaviors associated with drug abuse [12–14], causing an increase in preference for ethanol as measured in a conditioned place preference test [15], an impairment of social behavior as indicated by an increase in distance among members of the shoal [16], and an increase in locomotor activity in a novel tank [17]. While studies have yet to determine whether these behavioral effects induced by embryonic ethanol exposure are accompanied by an increase in voluntary consumption of ethanol in zebrafish, this phenomenon would be expected in light of evidence consistently showing prenatal ethanol exposure to increase the drinking of alcohol in rodents and humans [1–6].…”

“…While there are no studies in this species investigating the effect of early ethanol exposure on these orexigenic peptides, there is evidence that embryonic ethanol impairs a number of neurotransmitter systems in zebrafish, causing a reduction in dopamine and serotonin levels in adult fish [16] and altering the expression of nicotinic acetylcholine receptors and µ-opioid receptor encoding gene [15]. In our recent study describing a model of voluntary ethanol consumption in adult zebrafish [37], we demonstrated that intake of ethanol increases in the expression of the orexigenic peptides, GAL and OX, in the hypothalamus, suggesting the existence of a positive relationship between ethanol and these neuropeptides in zebrafish, similar to that described in rodents [38].…”

Pharmacological analyses of learning and memory in zebrafish (Danio rerio)

“…However, the literature describing the acute effects of ethanol exposure during adolescence or adulthood on learning and memory in zebrafish is more modest. As expected based on the rodent literature, acute and chronic exposure to moderate or high doses of ethanol during adulthood induces CPP in zebrafish (Chacon & Luchiari, 2014; Mathur et al, 2011) and exposure to ethanol during early development results in an exaggerated preference in ethanol-induced CPP during adulthood (Parker et al, 2014). These effects have largely been interpreted as corresponding primarily to the rewarding effects of ethanol, as memory impairment can be produced on simple associative learning tasks (like acquiring the association between a cue and food delivery) at comparable doses (Chacon & Luchiari, 2014) and impaired performance on a vertical column plusmaze has been reported with higher ethanol doses (Pittman & Lott, 2014).…”

“…Stimuli associated with rewarding effects often elicit approach behavior in animals and it is this response that is captured with CPP; typically duration spent in the drug-paired environment or latency to enter the environment is the primary dependent measure. CPP has been used in zebrafish to characterize the appetitive characteristics of cocaine (Darland & Dowling, 2001), nicotine (Kedikian et al, 2013), opiates (Lau et al, 2006), ethanol (Parker et al, 2014), MK801 (Swain et al, 2004), salvia (Braida et al, 2007) and others (e.g. Collier & Echevarria, 2013), described below.…”