Rats exposed to intermittent ethanol during late adolescence exhibit enhanced habitual behavior following reward devaluation

Highlights

• Exposure to ethanol in early adolescence led to persistent goal-directed behavior.

• Late adolescent ethanol exposure increased habit formation in adulthood.

• Adolescent ethanol-induced change to habit formation was not sex-dependent.

Abstract

The brain undergoes substantial maturation during adolescence, and repeated exposure to ethanol at this time has been shown to result in long-lasting behavioral and neural consequences. During the broad period of adolescence, different neuronal populations and circuits are refined between early and late adolescence, suggesting the possibility that ethanol exposure at these differing times may lead to differential outcomes. The goal of the current study was to evaluate the impact of adolescent intermittent ethanol (AIE) during early and late adolescence on the formation of goal-directed and habitual behavior in adulthood. Male and female Sprague–Dawley rats were exposed to ethanol via intragastric gavage (4.0 g/kg, 25% v/v) every other day from postnatal day (P) 25–45 or P45–65, considered early and late adolescence, respectively. In adulthood (~P70 early or ~ P90 late), rats were gradually food-restricted and began operant training on a fixed ratio 1 schedule. Rats were then transitioned onto random interval schedules and eventually underwent a sensory-specific satiation procedure as a model of reward devaluation. Few differences as a result of adolescent ethanol exposure were found during instrumental training. Following reward devaluation, rats exposed to water and ethanol during early adolescence exhibited reductions in lever pressing, suggestive of a goal-directed response pattern. In contrast, late AIE males and females demonstrated persistent responding following both devalued and non-devalued trials, findings representative of a habitual behavior pattern. The shifts from goal-directed to habitual behavior noted only following late AIE contribute to the growing literature identifying specific behavioral consequences as a result of ethanol exposure during distinct developmental periods within adolescence. More work is needed to determine whether the greater habit formation following late AIE is also associated with elevated habitual ethanol consumption.

Introduction

In the United States, approximately 55% of the population that is 12 years or older consumes alcohol at least monthly, with roughly 15 million people meeting the criteria for dependence and an alcohol use disorder (AUD) in 2018 (Substance Abuse and Mental Health Services Administration, 2019). Alcohol use is commonly initiated during early adolescence (Morean, Corbin, & Fromme, 2012; Morean, L'Insalata, Butler, McKee, & Krishnan-Sarin, 2018; Ohannessian, Finan, Schulz, & Hesselbrock, 2015), and an earlier age of initiation is a strong predictor of the development of an AUD (Patrick & Schulenberg, 2013). Adolescents also exhibit high rates of heavy drinking, with approximately 1.2 million adolescents aged 12–17 years old engaging in binge drinking during the previous month, defined as 4 or more drinks per occasion for females and 5 for males (Substance Abuse and Mental Health Services Administration, 2019). Consumption can reach even higher levels, particularly later in adolescence. As recently reported by Patrick and Terry-McElrath (2019), up to 11% of late adolescents/emerging adults in the United States consume 10–15 drinks or more per occasion, a drinking pattern termed “high-intensity drinking”. With a significant portion of the adolescent population in the United States binge drinking and consuming alcohol in large quantities, it is important to understand the long-term impacts of these drinking patterns.

The consequences of early initiation of drinking and binge/high intensity consumption in adolescence have been thoroughly studied in terms of relatively immediate effects in humans (for review see, White & Hingson, 2013). However, study of the long-lasting impact of adolescent drinking is difficult in humans due to practical and ethical limitations. In studies examining consumption of alcohol (i.e., ethanol) using rodent models, consummatory behavior of adolescents is often greater than that of adults (Doremus, Brunell, Rajendran, & Spear, 2005; Vetter-O’Hagen, Varlinskaya, & Spear, 2009), suggesting some potential conservation of underlying biological contributors to these age differences across species.

In recent years, research using animal models and different routes of ethanol administration has revealed a variety of long-term behavioral, neural, and epigenetic changes that persist into adulthood following adolescent intermittent ethanol (AIE) exposure (for review, see Crews et al., 2019). Consistent behavioral effects of AIE include increased general (Pandey, Sakharkar, Tang, & Zhang, 2015; Sakharkar et al., 2019; Varlinskaya, Hosová, Towner, Werner, & Spear, 2020) and social anxiety-like behaviors (Dannenhoffer et al., 2018; Varlinskaya, Truxell, & Spear, 2014), reduced sensitivity to the aversive properties of ethanol (Saalfield & Spear, 2015; Varlinskaya et al., 2014; Williams, Nickel, & Bielak, 2018), impaired fear conditioning (Bergstrom, McDonald, & Smith, 2006; Broadwater & Spear, 2013), as well as elevated ethanol intake in adulthood under some circumstances (see Towner & Varlinskaya, 2020 for references).

Intermittent ethanol exposure during adolescence has also been reported to reduce behavioral flexibility in adulthood when measured by behaviors such as set shifting (Fernandez & Savage, 2017; Gass et al., 2014; Varlinskaya et al., 2020) and reversal learning (Coleman, He, Lee, Styner, & Crews, 2011; Coleman, Liu, Oguz, Styner, & Crews, 2014; Galaj, Kipp, Floresco, & Savage, 2019; Vetreno et al., 2020). The inability to update behavior based on previous outcomes may contribute to elevations in ethanol consumption due to a failure to reduce drinking after experiencing a negative outcome that, under normal circumstances, would curb subsequent intake. The observed behavioral inflexibility following AIE could also be associated with a greater sensitivity to form habit-like behaviors. Initial drug use, including that of ethanol, is commonly associated with goal-directed behavior that is susceptible to devaluation, whereas repeated exposure tends to produce a shift toward habitual use that becomes resistant to devaluation (Barker & Taylor, 2014; Corbit, Nie, & Janak, 2012; Leong, Berini, Ghee, & Reichel, 2016; Zapata, Minney, & Shippenberg, 2010). Thus, repeated ethanol exposure during adolescence may induce elevated ethanol consumption not only due to changes in behavioral flexibility but also via promoting habit formation, potentially resulting from alterations in brain regions underlying these behaviors. In fact, Barker and colleagues (Barker, Bryant, Osborne, & Chandler, 2017) found that AIE exposure led to a shift from goal-directed to habitual behavior in adulthood, a finding specific to females.

Goal-directed and habitual behaviors are influenced by distinct regions within the striatum (see Burton, Nakamura, & Roesch, 2015; Lipton, Gonzales, & Citri, 2019, for reviews). The dorsolateral striatum contributes to habitual responding, whereas the dorsomedial striatum is implicated in regulating goal-directed responding. Both systems are heavily influenced by the prefrontal cortex (PFC), and this top-down control has been shown to modify the development/expression of both goal-directed and habitual behavior (Smith & Laiks, 2018).

The striatum, frontostriatal connectivity, as well as dopaminergic innervation into the PFC undergo significant age-related remodeling throughout the broad adolescent period – maturation that is important for the formation of goal-directed behavior (DePasque & Galván, 2017; Hoops, Reynolds, Restrepo-Lozano, & Flores, 2018; Insel, Kastman, Glenn, & Somerville, 2017; Larsen & Luna, 2015, 2018; Somerville & Casey, 2010). Brain maturation during early adolescence is associated with reductions of volume within the striatum (Goddings et al., 2014; Lenroot et al., 2007), and increases in dopaminergic innervation (Hoops et al., 2018; Willing, Cortes, Brodsky, Kim, & Juraska, 2017) and synaptic pruning in the PFC (Drzewiecki, Willing, & Juraska, 2016; Mallya, Wang, Lee, & Deutch, 2019). In contrast, maturational changes during late adolescence and emerging adulthood are characterized by further refinement and strengthening of circuitry involving the PFC (Baker et al., 2015; Uematsu et al., 2017; van Duijvenvoorde, Westhoff, de Vos, Wierenga, & Crone, 2019). Thus, ethanol exposure during adolescence may influence different aspects of brain maturation due to the timing of that exposure. This possibility, however, has received limited attention to date (although see Alaux-Cantin et al., 2013; Desikan, Wills, & Ehlers, 2014; Saalfield & Spear, 2015; Sanchez-Roige, Peña-Oliver, Ripley, & Stephens, 2014; Varlinskaya et al., 2014; Varlinskaya et al., 2020).

The goal of the current study was to determine the impact of intermittent ethanol exposure during different adolescent developmental sub-periods on goal-directed behavior in adulthood. In order to test goal-directed behavior, we used a sensory-specific satiation procedure. With the maturation of striatal circuitry undergoing more expansive changes during early rather than late adolescence, we hypothesized that early AIE would promote habit-like responding following reward devaluation, whereas late AIE would have less of an effect. The findings from the current study suggest the opposite, with late AIE leading to significantly increased habit-like responding in adult males (along with a similar trend in females), whereas early water and ethanol exposures were associated with goal-directed responding.