Intermittent voluntary ethanol consumption combined with ethanol vapor exposure during adolescence increases drinking and alters other behaviors in adulthood in female and male rats
Introduction
Adolescence is defined by both physiological and psychological developments that occur over the entire second decade of life. While adolescence is associated with an increase in a number of behaviors such as peer-directed social interaction, novelty seeking, and risk taking (Spear, 2000), it is also associated with an increase in experimentation with recreational drugs (van Amsterdam & van den Brink, 2010). Alcohol is by far the most commonly used drug in adolescents, with over 90% of youth having tried alcohol at some point in their lives (Anderson & Baumberg, 2007), and 10–40% of adolescents (depending on the country) have reported binge drinking (Assanangkornchai et al., 2009, Caamaño-Isorna et al., 2008, Miller et al., 2007, Viner and Taylor, 2007, Wechsler et al., 2002). This common pattern of drinking, in adolescents, is generally defined as an episode of drinking in which five (four drinks for females) or more alcoholic beverages are consumed in a 2-h period (Courtney and Polich, 2009, Parada et al., 2011). Adolescent drinking is also a risk factor for the later onset of alcohol use disorders. Early onset of intoxication, especially prior to the age of 15 years, is in fact one of the strongest predictors of alcohol dependence, with a 4-fold increase in the likelihood of dependence in those who begin drinking before the age of 15 years compared to those who began drinking as young adults (Chuo and Pickering, 1992, Dawson et al., 2008, DeWit et al., 2000, Ehlers et al., 2006, Grant, 1998, Grant and Dawson, 1997, Grant and Dawson, 1998). One hypothesis forwarded to explain this finding suggests that early binge drinking can alter the normal course of cognitive development, leading to an increased risk for a number of psychopathologies including drug addiction (DeWit et al., 2000, York, 1999). However, an alternative theory suggests that a subset of adolescents may have an underlying propensity for making impulsive and potentially risky decisions, including an early onset of drinking (Iacono et al., 2002, Jessor and Jessor, 1975). These opposing hypotheses are difficult to disentangle in human studies. However, the development of an animal model to study the effects of adolescent alcohol exposure on behavior in adulthood could provide support for the alcohol exposure hypothesis as well as provide a better understanding of the brain mechanisms underlying the effects of adolescent drinking on development.
A recent body of literature supports a prominent role of the hypothalamic peptide hypocretin/orexin (Hcrt/OX) in homeostatic control of a number of regulatory processes including sleep/wake cycle, feeding and energy metabolism, and reward/motivated behavior (España, 2012, Sutcliffe and de Lecea, 2002, Willie et al., 2001). Additionally, experience with drugs of abuse results in upregulation of Hcrt/OX and receptor expression (Dayas et al., 2008, Kane et al., 2000, Pasumarthi et al., 2006, Sharf et al., 2008). Orexin-A (OX-A) and orexin-B (OX-B) (also known as hypocretin-1 and -2, respectively) are peptides produced by a small population of cells in the lateral and dorsomedial hypothalamus and perifornical area (de Lecea et al., 1998, Sakurai et al., 1998). These Hcrt/OX neurons have widespread projections throughout the brain (Peyron et al., 1998), including projections from the lateral hypothalamus to many areas of the mesolimbic ‘reward pathway’ (Di Chiara and Imperato, 1985, Koob and Bloom, 1988, Wise and Rompre, 1989). Additionally, both receptor subtypes and Hcrt/OX-containing nerve terminals are distributed extensively throughout the prefrontal cortex (PFC) (Cluderay et al., 2002, Fadel and Deutch, 2002, Hervieu et al., 2001). Recent evidence suggests a dichotomous role of Hcrt/OX 1 (Hcrt/OX 1R) and Hcrt/OX 2 (Hcrt/OX 2R) receptors in the brain. A number of studies have shown that signaling through the Hcrt/OX 1 and Hcrt/OX 2 receptors regulates alcohol seeking and consumption (Barson et al., 2015, Dayas et al., 2008, Jupp et al., 2011, Kim et al., 2012, Lawrence et al., 2006, Moorman and Aston-Jones, 2009, Richards et al., 2008, Shoblock et al., 2011, Smith et al., 2009, Srinivasan et al., 2012). Specifically, Hcrt/OX receptor agonists have been shown to increase ethanol consumption (Barson et al., 2015, Schneider et al., 2007), while Hcrt/OX receptor antagonists reduce drinking (Jupp et al., 2011, Lawrence et al., 2006, Moorman and Aston-Jones, 2009, Srinivasan et al., 2012). While this demonstrates a role of the Hcrt/OX system in alcohol consumption, there is currently no research investigating the effect that adolescent ethanol consumption has on the Hcrt/OX receptor expression; thus, we sought to investigate this in a rat model of adolescent alcohol exposure.
In the current study, we combine voluntary drinking of 20% unsweetened alcohol with 4-day episodes of alcohol vapor exposure, during adolescence, to simulate intermittent high-level “binge” alcohol exposure. We have shown that vapor exposure alone in Wistar rats results in moderate blood alcohol concentrations (BACs) (∼175 mg%) and robust neurobehavioral changes (Ehlers, Oguz, Budin, Wills, & Crews, 2013), but does not increase drinking in adulthood (Ehlers, Criado, Wills, Liu, & Crews, 2011). However, drinking alone results in low BACs (<50 mg%) and produces increased drinking but not robust neurobehavioral changes in adulthood (Amodeo, Kneiber, Wills, & Ehlers, 2017). Together, we expect that this dynamic model of alcohol exposure in male and female adolescents will result in both an increase in neurobehavioral changes and an increase in drinking in adulthood. Further, we investigated the potential influence of early alcohol exposure on Hcrt/OX signaling in adulthood.
Section snippets
Animals
Subjects were 48 male and 47 female Wistar rats (Charles River, Hollister, California, USA) who arrived in the laboratory on PD 22 and were housed in same-sex groups of three. The colony room was kept under a 12-h light/dark cycle (lights on at 8:00 a.m.) with behavioral testing conducted during the light phase. Rats were pair-housed prior to behavioral testing in adulthood. Lab chow was provided ad libitum at all times, except 24 h prior to the open-field conflict test. Subjects were cared for
Weight gain in male and female rats across development
As expected, weight for both male [F(30,1380) = 2858, p < 0.001] and female rats [F(30,1350) = 1263, p < 0.001] increased throughout the testing procedures. However, there was only a significant effect of exposure in males [F(1,46) = 7.050, p = 0.010] with lower mean weight for ethanol-exposed males on seven select days between PD 62–83, compared to male controls (Fig. 1A). Ethanol exposure did not affect female weight gain compared to controls.
Adolescent ethanol exposure
While there was no significant difference between
Discussion
The present study utilized a dynamic model of alcohol exposure combining intermittent voluntary ethanol consumption and intermittent vapor exposure sessions to investigate the effect on voluntary consumption in adolescence and the persistent impact it may have on neurobehavioral functioning and Hcrt/OX receptor mRNA expression in frontal cortex in adulthood. While adolescent ethanol exposure resulted in minimal changes in the behavioral tasks, early exposure did lead to increased alcohol
Conflicts of interest
None.
Acknowledgments
This work was supported by National Institute of Health (NIH) grants, U01 AA019969; R01 AA006059 to Cindy L. Ehlers from the National Institute on Alcohol Abuse and Alcoholism (NIAAA). The authors thank Phil Lau for help in statistical analyses.
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