Persistent cognitive and morphological alterations induced by repeated exposure of adolescent rats to the abused inhalant toluene

Abstract

While the psychoactive inhalant toluene causes behavioral effects similar to those produced by other drugs of abuse, the persistent behavioral and anatomical abnormalities induced by toluene exposure are not well known. To mimic human “binge-like” inhalant intoxication, adolescent, male Sprague-Dawley rats were exposed to toluene vapor (5700 ppm) twice daily for five consecutive days. These rats remained in their home cages until adulthood (P60), when they were trained in operant boxes to respond to a palatable food reward and then challenged with several different cognitive tasks. Rats that experienced chronic exposure to toluene plus abstinence (“CTA”) showed enhanced performance in a strategy set-shifting task using a between-session, but not a within-session test design. CTA also blunted operant and classical conditioning without affecting responding during a progressive ratio task. While CTA rats displayed normal latent inhibition, previous exposure to a non-reinforced cue enhanced extinction of classically conditioned approach behavior of these animals compared to air controls. To determine whether CTA alters the structural plasticity of brain areas involved in set-shifting and appetitive behaviors, we quantified basal dendritic spine morphology in DiI-labeled pyramidal neurons in layer 5 of the medial prefrontal cortex (mPFC) and medium spiny neurons in the nucleus accumbens (NAc). There were no changes in dendritic spine density or subtype in the mPFC of CTA rats while NAc spine density was significantly increased due to an enhanced prevalence of long-thin spines. Together, these findings suggest that the persistent effects of CTA on cognition are related to learning and memory consolidation/recall, but not mPFC-dependent behavioral flexibility.

The Abused Inhalant Toluene Impairs Medial Prefrontal Cortex Activity and Risk/Reward Decision-Making during a Probabilistic Discounting Task

“…Probabilistic discounting training in adults is not significantly affected by adolescent exposure to toluene Previous studies suggest that toluene abuse during adolescence can impair cognitive performance in adulthood in humans (Dingwall et al, 2011;Scott and Scott, 2014;Yuncu et al, 2015), and rodents (Dick et al, 2014;Furlong et al, 2016;Braunscheidel et al, 2017). Fig.…”

“…Following completion of 2 consecutive days of training with Ͻ10 omissions per session, the time to omission was reduced to 10 s. When rats met criteria again, the lever reward probability reduced to 50%. When rats met criteria a third time, a side preference test was performed as previously described (Brady and Floresco, 2015;Braunscheidel et al, 2017). Briefly, for each of 60 trials, both levers extended simultaneously and were reinforced on an FR1 schedule.…”

“…A subset of rats were exposed to a binge-like regimen of, twice daily, 15 min exposures to 10,500 ppm toluene (12 male, 12 female) or air (12 male, 12 female) during adolescence (P39 -P43) as described previously (Braunscheidel et al, 2017). Rats were then tested with the descending odds probabilistic discounting task during adulthood.…”

“…Preclinical models of toluene intoxication report that acute exposure to toluene impairs simple behaviors such as locomotion and object recognition (Batis et al, 2010;Huerta-Rivas et al, 2012;Montes et al, 2017). Deficits in more complex forms of cognition that are mediated by the medial prefrontal cortex (mPFC) have also been observed following chronic exposure to toluene vapor, despite varying lengths of abstinence (Baydas et al, 2005;Dick et al, 2014;Furlong et al, 2016;Braunscheidel et al, 2017). These effects may be mediated in part by neurophysiological perturbations within the frontal lobes, as previous work in our lab has shown that toluene causes long-term depression of AMPA currents in mPFC neurons (Beckley and Woodward, 2011).…”

Self-Administration of Toluene Vapor in Rats

“…Research conducted over the past several years shows that toluene and other inhalants alter the structure and function of neurons within key brain regions (e.g., prefrontal cortex, nucleus accumbens, ventral tegmental area) of the reward circuitry ( Beckley et al, 2013 ; Braunscheidel et al, 2017 ; Wayman and Woodward, 2017 , 2018 ; Wu et al, 2018 ; Cruz et al, 2019 ). Although these neurophysiological alterations support the idea that that toluene’s addictive properties result from actions on reward pathways, the majority of preclinical studies that have examined the rewarding properties of toluene used passive exposure paradigms that do not mirror human inhalant abuse ( Funada et al, 2002 ; Gerasimov et al, 2003 ; Lee et al, 2006 ; Wayman and Woodward, 2018 ; Wu et al, 2018 ).…”