Adolescent Alcohol Exposure Reduces Behavioral Flexibility, Promotes Disinhibition, and Increases Resistance to Extinction of Ethanol Self-Administration in Adulthood

Abstract

The prefrontal cortex (PFC) is a brain region that is critically involved in cognitive function and inhibitory control of behavior, and adolescence represents an important period of continued PFC development that parallels the maturation of these functions. Evidence suggests that this period of continued development of the PFC may render it especially vulnerable to environmental insults that impact PFC function in adulthood. Experimentation with alcohol typically begins during adolescence when binge-like consumption of large quantities is common. In the present study, we investigated the effects of repeated cycles of adolescent intermittent ethanol (AIE) exposure (post-natal day 28–42) by vapor inhalation on different aspects of executive functioning in the adult rat. In an operant set-shifting task, AIE exposed rats exhibited deficits in their ability to shift their response strategy when the rules of the task changed, indicating reduced behavioral flexibility. There were no differences in progressive-ratio responding for the reinforcer suggesting that AIE did not alter reinforcer motivation. Examination of performance on the elevated plus maze under conditions designed to minimize stress revealed that AIE exposure enhanced the number of entries into the open arms, which may reflect either reduced anxiety and/or disinhibition of exploratory like behavior. In rats that trained to self-administer ethanol in an operant paradigm, AIE increased resistance to extinction of ethanol-seeking behavior. This resistance to extinction was reversed by positive allosteric modulation of mGluR5 during extinction training, an effect that is thought to reflect promotion of extinction learning mechanisms within the medial PFC. Consistent with this, CDPPB was also observed to reverse the deficits in behavioral flexibility. Finally, diffusion tensor imaging with multivariate analysis of 32 brain areas revealed that while there were no differences in the total brain volume, the volume of a subgroup of regions (hippocampus, thalamus, dorsal striatum, neocortex and hypothalamus) were significantly different in AIE exposed adults compared to litter-matched control rats. Taken together, these findings demonstrate that binge-like exposure to alcohol during early to middle adolescence results in deficits in PFC-mediated behavioral control in adulthood.

Adolescent binge ethanol exposure alters specific forebrain cholinergic cell populations and leads to selective functional deficits in the prefrontal cortex

“…Attentional set shifting is an assessment of cognitive flexibility that requires the rat to alter the strategy or rule that governed a previous behavior across a task dimension, and inactivation or lesions to the PFC produce deficits in set switching (Birrell and Brown, 2000; Floresco et al, 2008; Rich and Shapiro, 2007, 2009). Our data complements previous research demonstrating that AIE leads to deficits in attentional set shifting (Gass et al, 2014). Both data sets indicate that AIE leads to deficits following a cognitive set shift from either visual to spatial cues (Gass et al, 2014) or from spatial to visual cues (current data).…”

“…Our data complements previous research demonstrating that AIE leads to deficits in attentional set shifting (Gass et al, 2014). Interestingly, both data sets indicate that AIE leads to deficits following a cognitive shift from visual to spatial cues (Gass et al, 2014) and from spatial to visual cues (current data).…”

“…Alcohol exposure during adolescence has been tied to drug abuse vulnerability, as well as disruptions in cognitive functioning (DeWit et al, 2000; Jacobus and Tapert, 2013; Lisdahl et al, 2013). In rodents, exposure to ethanol (EtOH) during early adolescence has been linked to decreased behavioral inhibition and impairments in behavioral flexibility that are sustained into adulthood (Coleman et al, 2014; Gass et al, 2014; Doremus-Fitzwater and Spear, 2016). This distinctive behavioral phenotype results from sustained neural changes in critical brain regions such as the prefrontal cortex (Floresco et al, 2008; Fernandez et al, 2016; Vargas et al, 2014; Liu and Crews, 2015).…”

Binge drinking impacts dorsal striatal response during decision making in adolescents

“…Wilcox et al (2014) found that in the dorsal striatum of binge-drinking rodents, there was a decrease in the frequency of GABA(A) receptor mediated inhibitory postsynaptic currents in medium spiny neurons. This is accompanied by findings of decreased behavioral control and resistance to extinction during adulthood in adolescent rodents exposed to binge levels of alcohol (Gass et al, 2014). These findings may help explain how a decrease in risky selection brain activation in the dorsal striatum could lead to increases in future risk taking, and continued alcohol consumption.…”

Alcohol use in adolescence, impulsivity, and risk-taking behavior in Wistar rats.

“…Although this protocol measures a similar but not equal construct (Green, Myerson, Holt, Slevin, & Estle, 2004;Holt, Green, & Myerson, 2003), this alternative approach must be considered. Vapor inhalation is another viable option for assessing the effects of alcohol on disinhibition and anxiety-like behavior in adolescent rats (Gass et al, 2014).…”