Full length articleEnvironmental enrichment reverses memory impairment induced by toluene in mice
Introduction
Inhalant abuse is a health problem in both developed and developing countries (Dell et al., 2011). Inhalants are among the main drugs of choice for young people, with an age of onset between 10 and 17 years (Dell et al., 2011). In Mexico, recent surveys have detected inhalant abuse in socially marginalized populations as well as an increasing prevalence among young students living at home (Cruz, 2014, Villatoro et al., 2011). Toluene-based products (paint thinner, glues, and Activo [a toluene-enriched formulation distributed by drug dealers]) are the most commonly used for intoxication in Mexico (Villatoro et al., 2011). Toluene exposure has been associated with many health effects, mainly neurotoxicity and neuropsychiatric disorders (Ridenour et al., 2007). Despite their important deleterious health consequences, inhalants continue to be one of the least studied psychoactive substances. Therefore, treatment and prevention research has only recently emerged (Howard et al., 2011).
Significant memory and attention impairments have been described as the most disabling effects of inhalant abuse (Filley et al., 2004, Howard et al., 2011). Similarly, preclinical studies have found memory disruptions in various toluene administration patterns. For instance, exposure to a low toluene concentration (80 ppm, 6 h/day) for four weeks led to memory deficiencies in rats subjected to the Morris water maze (von Euler et al., 2000). Repeated exposure to a high toluene concentration (6000 ppm) also resulted in memory deficits in rats that were evaluated with the object recognition test and inhibitory avoidance task (Huerta-Rivas et al., 2012). Additionally, intraperitoneal administration of toluene (600 and 750 mg/kg for 9 days) resulted in memory impairment in mice that were subjected to the object recognition test (Lin et al., 2010).
Pharmacological and psychosocial interventions have been tested among inhalant users (Dell and Hopkins, 2011, Howard et al., 2011, Shaw et al., 2011); nevertheless, their impact on memory performance is still unclear. At the preclinical level, environmental enrichment (EE) is a housing condition that adds objects to a subject's environment to increase the levels of sensory, cognitive, and motor stimuli. Under these housing conditions, delayed onset and reversal of cognitive deficits have been observed in various models of memory (For review, see Nithianantharajah and Hannan, 2006, Hannan, 2014). For instance, mice with EE showed improved performance compared to mice under standard housing conditions in the Morris water maze, T-maze and radial arm water maze (Nithianantharajah and Hannan, 2006, Pang and Hannan, 2013, van Praag et al., 2000). Additionally, EE exposure improves memory in animal models of pathological conditions, such as brain injury or trauma, and in mice with poor learning task performance (Hannan, 2014, van Praag et al., 2000). Moreover, previous findings showed that improved memory is associated with enhanced neurogenesis (Kempermann et al., 1998, van Praag et al., 1999). Repeated toluene administration (2000 ppm for four weeks) reduced neurogenesis in the dorsal hippocampus, whereas EE reversed toluene-induced alterations in doublecortin-labeled cells (Paez-Martinez et al., 2013). Furthermore, EE has shown the ability to reverse the negative effects induced by some drugs of abuse, such as cocaine, heroin and amphetamine (Bardo et al., 2001, El Rawas et al., 2009, Solinas et al., 2008, Solinas et al., 2010). Hence, the overall purpose of this study was to screen toluene-induced memory impairment at different extents of exposure. Then, we evaluated the putative positive effect of EE to reverse memory impairment induced by chronic toluene exposure.
Memory is a cognitive process that involves several neurotransmitters, including GABA and glutamate (Kandel et al., 2013, Mohler, 2007). Alterations in GABA and glutamate levels have been observed after toluene exposure. For instance, acute 2000 ppm toluene exposure decreased extracellular GABA levels within the globus pallidus (Stengard and O'Connor, 1994), while in adolescent rats, a high toluene concentration (12,000 ppm) decreased the GABA levels in the hippocampus and striatum (O'Leary-Moore et al., 2007). Similarly, in adult rats, toluene (12,000 ppm) reduced the GABA levels in the striatum and frontal cortex (O'Leary-Moore et al., 2009). On the other hand, acute exposure to 12,000 ppm toluene decreased the glutamate levels in the hippocampus of adolescent rats, but not in the hippocampus of adult rats (O'Leary-Moore et al., 2007). Repeated toluene exposure (8000 and 12,000, for 7 days) in adolescent rats reduced the glutamate levels in the prefrontal cortex 1 day after the last exposure, while this exposure enhanced the glutamate levels in the hippocampus 7 days after stopping toluene administration (Perrine et al., 2011). Accordingly, in the second part of this study, we evaluated the putative changes in these neurotransmitters after both repeated toluene exposure and the EE paradigm.
Section snippets
Animals
A total of 178 mice were used in the study; there were 42 animals for the acute toluene exposure protocol, 56 animals for the repeated toluene exposure protocol, and 80 animals for EE. Inbred male Swiss Webster mice were provided from our breeding facilities (originally obtained from Taconic, Hudson, NY). The study started on postnatal day 35 to 40 of the animals (PN 35 to 40). This stage was selected because mice at this age exhibit behavioral, neurochemical and endocrine patterns of human
Acute toluene exposure impaired memory in mice
Mice exposed to a single dose of toluene had a decreased recognition index compared to control animals in the ORT (Fig. 2). This reduction was statistically significant from 2000 to 6000 ppm (F4,37 = 5.791; p < 0.001). These results suggest that a single exposure to toluene impaired memory in mice.
Mice exposed to toluene from 1000 to 4000 ppm did not have statistically significant changes in the cumulative exploration time during the first trial. Although exposure to 6000 ppm showed a tendency to
Discussion
Based on the findings of this study, acute toluene exposure induced memory impairment in adolescent mice. In addition, repeated toluene exposure also resulted in memory impairment; however, this effect did not depend on the toluene concentration used or chronicity of exposure. Remarkably, EE in animals previously exposed to toluene resulted in rescue of memory performance. Our analysis of glutamate and GABA showed that the neurotransmitters had no change after repeated exposure to toluene.
Conclusions
Detrimental effects on memory were observed in mice that had received either a single or repeated toluene administration. These effects endured even after several weeks of cessation of toluene exposure. On the other hand, EE reversed the cognitive deficits induced by toluene using an administration schedule that simulated the exposure patterns of inhalant users. Our results suggest that cognitive stimulation promotes the development of brain plasticity that can rescue cognitive alterations
Disclosure
The authors declare that there are no conflicts of interest.
Transparency document
Acknowledgements
This paper includes data from the Master's dissertation by Rocío del Carmen Solís Guillén and Bachelor's thesis by David García Jácome. Authors wish to thank to Beatriz Cruz-López, M. Yepci Guadalupe Yee-Ríos, Ariel Alaín Oros-González, Ricardo Mosco-Aquino and Susan Muñoz-Aquiahuatl for their excellent technical assistance. This study was performed with the support of the Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz NC103380.2, projects SIP-Instituto Politécnico Nacional and
References (60)
- et al.
Alterations in glutamatergic and gabaergic ion channel activity in hippocampal neurons following exposure to the abused inhalant toluene
Neuroscience
(2005) - et al.
Differential effects of inhaled toluene on locomotor activity in adolescent and adult rats
Pharmacol. Biochem. Behav.
(2010) - et al.
The object recognition task in rats and mice: a simple and rapid model in safety pharmacology to detect amnesic properties of a new chemical entity
J. Pharmacol. Toxicol. Methods
(2006) - et al.
The last decade of solvent research in animal models of abuse: mechanistic and behavioral studies
Neurotoxicol. Teratol.
(2006) - et al.
Defensive burying in rodents: ethology, neurobiology and psychopharmacology
Eur. J. Pharmacol.
(2003) One-trial object recognition in rats and mice: methodological and theoretical issues
Behav. Brain Res.
(2010)- et al.
A new one-trial test for neurobiological studies of memory in rats. 1: behavioral data
Behav. Brain Res.
(1988) - et al.
Toluene impairs learning and memory, has antinociceptive effects, and modifies histone acetylation in the dentate gyrus of adolescent and adult rats
Pharmacol. Biochem. Behav.
(2012) - et al.
Region-dependent alterations in glutamate and GABA measured by high-resolution magnetic resonance spectroscopy following acute binge inhalation of toluene in juvenile rats
Neurotoxicol. Teratol.
(2007) - et al.
Neurochemical changes after acute binge toluene inhalation in adolescent and adult rats: a high-resolution magnetic resonance spectroscopy study
Neurotoxicol. Teratol.
(2009)
Environmental enrichment increases doublecortin-associated new neurons and decreases neuronal death without modifying anxiety-like behavior in mice chronically exposed to toluene
Behav. Brain Res.
Enhancement of cognitive function in models of brain disease through environmental enrichment and physical activity
Neuropharmacology
Binge toluene exposure alters glutamate, glutamine and GABA in the adolescent rat brain as measured by proton magnetic resonance spectroscopy
Drug Alcohol Depend.
On whether the environmental enrichment may provide cognitive and brain reserves
Brain Res. Rev.
Environmental enrichment induces neuroplastic changes in middle age female Balb/c mice and increases the hippocampal levels of BDNF, p-Akt and p-MAPK1/2
Neuroscience
Reliability of use, abuse, and dependence of four types of inhalants in adolescents and young adults
Drug Alcohol Depend.
Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice
Exp. Neurol.
Toluene inhibits hippocampal neurogenesis in adult mice
Pharmacol. Biochem. Behav.
Performance of different mouse strains in an object recognition task
Behav. Brain Res.
Prevention and treatment of drug addiction by environmental enrichment
Prog. Neurobiol.
Acute toluene exposure decreases extracellular gamma-aminobutyric acid in the globus pallidus but not in striatum: a microdialysis study in awake, freely moving rats
Eur. J. Pharmacol.
Differential effects of enrichment on learning and memory function in NR2B transgenic mice
Neuropharmacology
The neurogenic effects of an enriched environment and its protection against the behavioral consequences of chronic mild stress persistent after enrichment cessation in six-month-old female Balb/C mice
Behav. Brain Res.
Inhalation of low concentrations of toluene induces persistent effects on a learning retention task, beam-walk performance, and cerebrocortical size in the rat
Exp. Neurol.
Toluene misuse and long-term harms: a systematic review of the neuropsychological and neuroimaging literature
Neurosci. Biobehav. Rev.
Combined exposure to nicotine and ethanol in adolescent mice differentially affects anxiety levels during exposure, short-term, and long-term withdrawal
Neuropsychopharmacology
The novel object recognition memory: neurobiology, test procedure, and its modifications
Cogn. Process.
Environmental enrichment decreases intravenous self-administration of amphetamine in female and male rats
Psychopharmacology
Recognition memory for objects, place, and temporal order: a disconnection analysis of the role of the medial prefrontal cortex and perirhinal cortex
J. Neurosci.
Short-term environmental enrichment, in the absence of exercise, improves memory, and increases NGF concentration, early neuronal survival, and synaptogenesis in the dentate gyrus in a time-dependent manner
Hippocampus
Cited by (15)
Short- and long-term effects of chronic toluene exposure on recognition memory in adolescent and adult male Wistar rats
2022, Brain Research BulletinCitation Excerpt :Toluene is known to produce a wide range of detrimental effects including long-lasting neurological damage, learning and memory disorders, cerebellar dysfunction, parkinsonism, peripheral neuropathy, psycho-organic syndromes and toluene leukoencephalopathy (Cruz et al., 2020; Filley et al., 2004; Hsieh et al., 2020; Hubková et al., 2018). However, compared to other substances of abuse, relatively few studies have assessed the effects of toluene on the central nervous system particularly during adolescence, a highly vulnerable age (Bikashvili et al., 2012; Cruz et al., 2014; Montes et al., 2017; Zhvania et al., 2012). In addition, most investigations have focused on the acute effects of toluene.
Effects of environmental enrichment on recognition memory in zebrafish larvae
2022, Applied Animal Behaviour ScienceCitation Excerpt :Regarding this latter point, the benefits of environmental enrichment in reversing neuronal degeneration have shown to reverse the deleterious effect of inhalant drugs. When reared in an enriched environment, adolescent mice exposed to repeated administration of toluene showed remarkably neurogenesis recovery (Montes et al., 2017). Knockout mice deleted for gene expression of ST8SiaII, a enzyme involved in the plasticity of brain’s neuronal circuits during in the embryotic and early life-stage development, reared in a complex environment showed high level of brain structural plasticity, and, consequently, increased memory performance (Zerwas et al., 2016).
The last two decades on preclinical and clinical research on inhalant effects
2021, Neurotoxicology and TeratologyCitation Excerpt :For example, environmental enrichment reverses memory impairment, oxidative balance and behavioral sensitization caused by toluene. Moreover, placing animals in enriched environments also decreases toluene-induced neuronal death (Montes et al., 2017; Montes et al., 2019; Paez-Martinez et al., 2013b; Paez-Martinez et al., 2020). Although there are no standardized pharmacological treatments for inhalant users, Lee and colleagues found that the psychosis-like symptoms (cognitive impairment and social withdrawal) developed in mice that were repeatedly injected with toluene (750 mg/kg i.p.) during adolescence (PN 35 to PN46) can be reversed with anti-psychotics with more selective 5-HT2A receptor antagonism (risperidone) (Lee et al., 2020).
Environmental enrichment reduces behavioural sensitization in mice previously exposed to toluene: The role of D1 receptors
2020, Behavioural Brain ResearchCitation Excerpt :Standard housing (SH; control group) consisted of five animals per cage (18 × 28 × 15 cm) without any stimulation. These specific EE conditions and time periods of housing have shown positive effects on neurochemical and behavioural responses in mice exposed to toluene [27,30,31]. When spending time in EE or SH, animals were not exposed to toluene.
Environmental enrichment restores oxidative balance in animals chronically exposed to toluene: Comparison with melatonin
2019, Brain Research BulletinCitation Excerpt :Therefore, treatment and prevention research has only recently emerged (Howard et al., 2011). In previous studies from our lab, it was observed that environmental enrichment (EE) reversed memory impairment and reduced neuronal death in animals previously exposed to toluene (Montes et al., 2017; Paez-Martinez et al., 2013); however, the mechanisms involved are still unclear. It has been shown that NMDA receptors (channels permeable to Ca2+) are molecular targets of toluene (Cruz et al., 1998).