Toluene inhalation in adolescent rats reduces flexible behaviour in adulthood and alters glutamatergic and GABAergic signalling

Abstract

Toluene is a commonly abused inhalant that is easily accessible to adolescents. Despite the increasing incidence of use, our understanding of its long-term impact remains limited. Here, we used a range of techniques to examine the acute and chronic effects of toluene exposure on glutameteric and GABAergic function, and on indices of psychological function in adult rats after adolescent exposure. Metabolomics conducted on cortical tissue established that acute exposure to toluene produces alterations in cellular metabolism indicative of a glutamatergic and GABAergic profile. Similarly, in vitro electrophysiology in Xenopus oocytes found that acute toluene exposure reduced NMDA receptor signalling. Finally, in an adolescent rodent model of chronic intermittent exposure to toluene (10 000 ppm), we found that, while toluene exposure did not affect initial learning, it induced a deficit in updating that learning when response-outcome relationships were reversed or degraded in an instrumental conditioning paradigm. There were also group differences when more effort was required to obtain the reward; toluene-exposed animals were less sensitive to progressive ratio schedules and to delayed discounting. These behavioural deficits were accompanied by changes in subunit expression of both NMDA and GABA receptors in adulthood, up to 10 weeks after the final exposure to toluene in the hippocampus, prefrontal cortex and ventromedial striatum; regions with recognized roles in behavioural flexibility and decision-making. Collectively, our data suggest that exposure to toluene is sufficient to induce adaptive changes in glutamatergic and GABAergic systems and in adaptive behaviour that may underlie the deficits observed following adolescent inhalant abuse, including susceptibility to further drug-use.

The effect of adolescent inhalant abuse on energy balance and growth

“…The effects of inhalants on the central nervous system (CNS), including cognition, have been relatively well studied, and it is thought that inhibited N ‐methyl‐D‐aspartate (NMDA) receptor signaling and region‐specific changes to glutamatergic and gamma‐Aminobutyric acid (GABA)‐ergic signaling underpin these effects . However, inhalants can also have a wide range of peripheral effects throughout the body, including on the renal, cardiovascular, and pulmonary systems .…”

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

“…With respect to the present study, retrieving the previously held response strategy is theoretically more important to completing between-session compared to within-session shifts because there are no reminder trials to jumpstart responding to the initial attentional set (visual cue). Interestingly, chronic exposure to 2000PPM toluene produces hippocampal cell loss that does not recover following 90 days of abstinence (Zhvania et al, 2012), and CTA alters hippocampus-dependent behaviors such as operant conditioning, delay discounting and contingency monitoring (Dick et al., 2014, Furlong et al, 2016). In attempting to explain the apparent improvement in set-shifting observed in one of our experiments, it is possible that CTA disrupted access to memories regarding the previously acquired discrimination rule via perturbations in hippocampal functioning.…”

“…Interestingly, Gmaz et al (2012) exposed Long-Evans rats to 5000 ppm toluene for 30 min and determined that the resulting brain toluene concentrations (500–1000 µmol/l) would be similar to those experienced by humans inhaling toluene-containing products. Similar exposure protocols have been used to study the effect of chronic exposure to abuse levels of toluene vapor (Moser & Balster, 1981; Bowen, Hannigan, & Cooper, 2009; Dick et al, 2014; Furlong et al, 2016). Control rats were exposed to chambers filled with air on the same schedule as above.…”

“…The few studies concerning toluene’s effects following protracted abstinence are somewhat inconsistent and results vary based on the cognitive measure tested. For example, while deficits in object recognition, operant conditioning, delay discounting, progressive ratio responding, and contingency monitoring have been observed, protracted abstinence from chronic toluene exposure does not affect Pavlovian-to-instrumental transfer, outcome devaluation, anxiety or spatial memory (Dick et al, 2014; Lin et al, 2010; Furlong et al, 2016). Further, while inhalant-induced deficits in behavioral flexibility have been detected in humans after a short abstinence period (5–9 days), their effects in a protracted abstinence rodent model are subtle (Dick et al, 2014; Furlong et al, 2016; Yuncu et al, 2015).…”

Amyotrophic lateral sclerosis—A case report and mechanistic review of the association with toluene and other volatile organic compounds

“…Subchronic exposure to toluene also leads to alterations in behavior and neurochemical functioning, which may be related in part to increased glutamatergic and decreased GABAergic responses . While compensatory upregulation of receptor expression may be beneficial in the normal brain, in those with latent neurological disease, such changes could lead to adverse events such as predisposing an individual to seizures on withdrawal from exposure …”