Publications by authors named "Scott E Bowen"

33 Publications

The last two decades on preclinical and clinical research on inhalant effects.

Neurotoxicol Teratol 2021 Jun 2;87:106999. Epub 2021 Jun 2.

Department of Psychology, Wayne State University, 5057 Woodward Ave., Suite 7906.1, Detroit, MI 48202, USA. Electronic address:

This paper reviews the scientific evidence generated in the last two decades on the effects and mechanisms of action of most commonly misused inhalants. In the first section, we define what inhalants are, how they are used, and their prevalence worldwide. The second section presents specific characteristics that define the main groups of inhalants: (a) organic solvents; (b) aerosols, gases, and volatile anesthetics; and (c) alkyl nitrites. We include a table with the molecular formula, structure, synonyms, uses, physicochemical properties and exposure limits of representative compounds within each group. The third and fourth sections review the direct acute and chronic effects of common inhalants on health and behavior with a summary of mechanisms of action, respectively. In the fifth section, we address inhalant intoxication signs and available treatment. The sixth section examines the health effects, intoxication, and treatment of nitrites. The seventh section reviews current intervention strategies. Finally, we propose a research agenda to promote the study of (a) solvents other than toluene; (b) inhalant mixtures; (c) effects in combination with other drugs of abuse; (d) age and (e) sex differences in inhalant effects; (f) the long-lasting behavioral effects of animals exposed in utero to inhalants; (g) abstinence signs and neurochemical changes after interrupting inhalant exposure; (h) brain networks involved in inhalant effects; and finally (i) strategies to promote recovery of inhalant users.
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http://dx.doi.org/10.1016/j.ntt.2021.106999DOI Listing
June 2021

Opioid use during pregnancy can impair maternal behavior and the Maternal Brain Network: A literature review.

Neurotoxicol Teratol 2021 Jul-Aug;86:106976. Epub 2021 Apr 1.

Department of Psychology, Wayne State University, Detroit, MI 48202, USA. Electronic address:

Opioid Use Disorder (OUD) is a global epidemic also affecting women of reproductive age. A standard form of pharmacological treatment for OUD is Opioid Maintenance Therapy (OMT) and buprenorphine has emerged as the preferred treatment for pregnant women with OUD relative to methadone. However, the consequences of BUP exposure on the developing Maternal Brain Network and mother-infant dyad are not well understood. The maternal-infant bond is dependent on the Maternal Brain Network, which is responsible for the dynamic transition from a "nulliparous brain" to a "maternal brain". The Maternal Brain Network consists of regions implicated in maternal care (e.g., medial preoptic area, nucleus accumbens, ventral pallidum, ventral tegmentum area) and maternal defense (e.g., periaqueductal gray). The endogenous opioid system modulates many of the neurochemical changes in these areas during the transition to motherhood. Thus, it is not surprising that exogenous opioid exposure during pregnancy can be disruptive to the Maternal Brain Network. Though less drastic than misused opioids, OMTs may not be without risk of disrupting the neural and molecular structures of the Maternal Brain Network. This review describes the Maternal Brain Network as a framework for understanding how pharmacological differences in exogenous opioid exposure can disrupt the onset and maintenance of the maternal brain and summarizes opioid and OMT (in particular buprenorphine) use in the context of pregnancy and maternal behavior. This review also highlights future directions for evaluating exogenous opioid effects on the Maternal Brain Network in the hopes of raising awareness for the impact of the opioid crisis not only on exposed infants, but also on mothers and subsequent mother-infant bonds.
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http://dx.doi.org/10.1016/j.ntt.2021.106976DOI Listing
April 2021

Effects of inhaled combined Benzene, Toluene, Ethylbenzene, and Xylenes (BTEX): Toward an environmental exposure model.

Environ Toxicol Pharmacol 2021 Jan 24;81:103518. Epub 2020 Oct 24.

Department of Psychology, Wayne State University, Detroit, MI, USA; Center for Urban Responses to Environmental Stressors, Wayne State University, Detroit, MI, USA. Electronic address:

Combined environmental exposures to the volatile organic compounds (VOCs) Benzene, Toluene, Ethylbenzene, and Xylene (BTEX) pose clear risks to public health. Research into these risks is under-studied even as BTEX levels in the atmosphere are predicted to rise. This review focuses on the available literature using single- and combined-BTEX component inhaled solvent exposures in animal models, necessarily also drawing on findings from models of inhalant abuse and occupational exposures. Health effects of these exposures are discussed for multiple organ systems, but with particular attention on neurobehavioral outcomes such as locomotor activity, impulsivity, learning, and psychopharmacological responses. It is clear that animal models have significant differences in the concentrations, durations and patterns of exposure. Experimental evidence of the deleterious health and neurobehavioral consequences of exposures to the individual components of BTEX were found, but these effects were typically assessed using concentrations and exposure patterns not characteristic of environmental exposure. Future studies with animal models designed appropriately to explore combined BTEX will be necessary and advantageous to discovering health outcomes and more subtle neurobehavioral impacts of long-term environmental exposures.
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http://dx.doi.org/10.1016/j.etap.2020.103518DOI Listing
January 2021

Repeated toluene exposure leads to neuroadaptation in dopamine release mechanisms within the nucleus accumbens core.

Toxicol Appl Pharmacol 2020 12 2;408:115260. Epub 2020 Oct 2.

Wayne State University, Department of Psychology, Detroit, MI 48202, United States of America. Electronic address:

Background: Intentionally inhaling volatile organic solvent like toluene for its intoxicating effects continues to be a public health concern. While repeated abuse of toluene has deleterious behavioral and health effects, little is known about the actions of toluene on the dopaminergic neurotransmitter system within the central nervous system.

Method: The present study employed complementary neurochemical techniques of slice fast-scan cyclic voltammetry (FSCV) and in vivo microdialysis, to assess dopamine (DA) dynamics immediately after repeated exposure to 2000- or 4000-ppm toluene. DA D3 autoreceptor functionality, measured by FSCV with pharmacological manipulations and brain tissue content analysis with high performance liquid chromatography, were also used to account for the changes in the DA dynamics.

Results: Toluene-exposed mice had decreased stimulated DA release only in the nucleus accumbens core immediately after seven days of repeated exposure. DA uptake was decreased in the core only after 2000-ppm exposure. The differences in stimulated DA release were not attributed to alterations in intraneuronal DA levels as measured by tissue content analysis. Basal extracellular DA levels were not significantly different between the air- and toluene-treated mice. However, following an additional toluene exposure, mice had elevated extracellular DA levels in the nucleus accumbens during recovery. This potentiation in extracellular accumbal DA levels was further heightened following potassium stimulation. The accumbal DA D3 autoreceptor function did not appear to play a role as a potential mediator for these differences.

Conclusion: Our FSCV and microdialysis results suggest a neuroadaptation in DA release mechanics within the nucleus accumbens, but the exact neuronal mechanism of toluene's impact remains elusive.
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http://dx.doi.org/10.1016/j.taap.2020.115260DOI Listing
December 2020

Gestational buprenorphine exposure: Effects on pregnancy, development, neonatal opioid withdrawal syndrome, and behavior in a translational rodent model.

Drug Alcohol Depend 2019 12 17;205:107625. Epub 2019 Oct 17.

Department of Psychology, Wayne State University, Detroit, MI, 48202, USA. Electronic address:

Background: The opioid crisis has led to an increased number of pregnant opioid-dependent women receiving opioid-maintenance therapy (e.g. buprenorphine, BUP), but little is known about the consequences of gestational BUP exposure on pregnancy outcomes, maternal care, or offspring development.

Methods: Our translational rodent model began BUP exposure to adult female rats (N = 30) at least 7 days before conception and continued throughout the postpartum period. Both therapeutic low-dose (BUP-LD, 0.3 mg/kg, s.c.) and overexposure high-dose (BUP-HD, 1.0 mg/kg) doses of BUP were compared to saline control. Female rats were bred in house with drug-naïve adult male rats. The day after parturition, litters were culled to 5 males/5 females and assigned randomly to various behavioral tests and assessed either neonates or adolescents. Litter characteristics, maternal caregiving, Neonatal Opioid Withdrawal Syndrome (NOWS), offspring development and adolescent behaviors were evaluated.

Results: BUP-LD decreased maternal care, delayed offspring development, decreased offspring body weight, length, temperature, and pain sensitivity (p's < .05). BUP-HD drastically reduced maternal care and offspring survival, altered litter characteristics, and increased NOWS (p's < .05).

Conclusion: These results demonstrate that the therapeutic BUP-LD in rats was relatively safe with subtle effects on maternal care and rodent offspring. However, overexposure BUP-HD in rats produced NOWS and compromised maternal caregiving as well as rodent offspring survival. More research is critical to validate the translational implication of these findings for human opioid-dependent mothers maintained on BUP-maintenance therapy.
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http://dx.doi.org/10.1016/j.drugalcdep.2019.107625DOI Listing
December 2019

Abstinence following toluene exposure increases anxiety-like behavior in mice.

Neurotoxicol Teratol 2018 Jan - Feb;65:42-50. Epub 2017 Dec 29.

Department of Psychology, Wayne State University, Detroit, MI, USA.

The intentional misuse of volatile solvents like toluene is a persistent public health concern. Limited clinical data suggest that chronic inhalant abusers may experience signs of withdrawal, including anxiety. Behavioral withdrawal from toluene has not been examined in a preclinical model. In the current study, young adult male Swiss Webster mice were exposed to either 5000-ppm toluene vapor or air (0ppm) for 30min or 24h. Mice were tested in a battery of four behavioral tasks reflective of anxiety either immediately (0h), 24h, or 72h after the toluene exposure. Mice exposed briefly (30min) to toluene showed decreases in anxiety-like behaviors, whereas mice abstinent from toluene for 24h after a prolonged (24-h) exposure, displayed increases in anxiety-like behaviors. These increases in anxiety-like behavior were not observed 72h post toluene. However, a brief re-exposure to toluene (30min at 5000ppm) immediately before testing 24h after the prolonged exposure ameliorated behavioral differences on the plus maze task. These results of 1) decreased anxiety-like behavior immediately following acute toluene, and 2) the contrasting increase in anxiety-like behavior during abstinence from a prolonged toluene exposure, and 3) the amelioration of increases in an anxiety-like behavior following toluene re-exposure, are consistent with an interpretation of withdrawal from the single 24-hr toluene exposure. These findings support clinical reports of increased anxiety during abstinence following periods of toluene use/abuse. The results also imply that experiencing anxiety during withdrawal from toluene may contribute to the persistent use of inhalants and may be relevant to clinical treatment of inhalant abuse/addiction.
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http://dx.doi.org/10.1016/j.ntt.2017.12.010DOI Listing
October 2019

Toluene's effects on activity and extracellular dopamine in the mouse are altered by GABA antagonism.

Neurosci Lett 2017 04 10;647:67-71. Epub 2017 Mar 10.

Department of Psychology, Wayne State University, 5057 Woodward Ave, Detroit, MI, 48202, USA. Electronic address:

The abuse of inhalants like toluene continues to be widespread around the world, especially among children and teenagers. Despite its frequency of misuse, the dynamics between dopamine (DA) and gamma-aminobutyric acid (GABA) in response to toluene exposure remains unclear. To further decipher toluene's actions, we used a dynamic exposure system in combination with microdialysis to examine in vivo the effects of acutely inhaled toluene on DA release within the mouse caudate putamen (CPu). Results show that toluene inhalation produced increases in DA levels and locomotor activity. In mice that were pretreated with the GABA antagonist, bicuculline, there was no change in the locomotor response during toluene but activity was potentiated following toluene exposure. Bicuculline pretreatment increased extracellular DA levels during toluene exposure, suggesting that DA and GABA-releasing neuron interaction may play a role in the rewarding properties of toluene.
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http://dx.doi.org/10.1016/j.neulet.2017.03.004DOI Listing
April 2017

Cranial irradiation significantly reduces beta amyloid plaques in the brain and improves cognition in a murine model of Alzheimer's Disease (AD).

Radiother Oncol 2016 Jan 23;118(1):43-51. Epub 2015 Nov 23.

Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, USA.

Background And Purpose: To investigate if cranial X-irradiation reduces amyloid-β (Aβ) plaques and influences cognitive function in a transgenic mouse model of AD.

Methods And Materials: B6.Cg-Tg (APPswePSEN1dE9)85Dbo/J AD-prone mice were given cranial X-irradiation. The number of Aβ plaques, along with expression of AD specific genes (84 genes: Mouse Alzheimer's Disease RT(2) Profiler), radiation-associated cytokines (Milliplex MAP Mouse Cytokine Chemokine Immunoassay) and immunohistochemistry (IL10, IL-1β, Iba1 CD45) was assessed. Behavioral testing was performed to relate changes in Aβ burden to cognitive function using a Morris water-maze task.

Results: Single X-ray doses reduced the number (p=0.002) and size (p=0.01) of Aβ plaques. Low-dose fractionation produced greater 50.6% (1 Gy × 10), 72% (2 Gy × 5) and 78% (2 Gy × 10) reductions. Irradiation was associated with gene (Pkp4, 1.5-fold, p=0.004) and proteomic (MIP-2, 8-fold, p=0.0024) changes at 24-48 h. Microglia increased at 4 weeks post-irradiation (p=0.001). The reduction in Aβ burden (2 Gy × 5) was associated with cognitive improvement (p=0.012).

Conclusion: This is the first report that a clinically relevant course of external beam irradiation (2 Gy × 5) produces a significant reduction in AD-associated amyloid-β plaques with a subsequent improvement in cognitive function. However, longer-term studies are needed to define the precise underlying mechanism and longevity of this response.
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http://dx.doi.org/10.1016/j.radonc.2015.10.019DOI Listing
January 2016

Striatal dopamine dynamics in mice following acute and repeated toluene exposure.

Psychopharmacology (Berl) 2015 Jan 5;232(1):173-84. Epub 2014 Jul 5.

Department of Chemistry, Wayne State University, 5101 Cass Ave, Detroit, MI, 48202, USA.

Rationale: The abused inhalant toluene has potent behavioral effects, but only recently has progress been made in understanding the neurochemical actions that mediate the action of toluene in the brain. Available evidence suggests that toluene inhalation alters dopamine (DA) neurotransmission, but toluene's mechanism of action is unknown.

Objective: The present study evaluated the effect of acute and repeated toluene inhalation (0, 2,000, or 4,000 ppm) on locomotor activity as well as striatal DA release and uptake using slice fast-scan cyclic voltammetry.

Results: Acutely, 2,000 and 4,000 ppm toluene increased locomotor activity, while neurochemically only 4,000 ppm toluene potentiated electrically evoked DA release across the caudate-putamen and the nucleus accumbens. Repeated administration of toluene resulted in sensitization to toluene's locomotor activity effects. Brain slices obtained from mice repeatedly exposed to toluene demonstrated no difference in stimulated DA release in the caudate-putamen as compared to control animals. Repeated exposure to 2,000 and 4,000 ppm toluene caused a concentration-dependent decrease of 25-50 % in evoked DA release in the nucleus accumbens core and shell relative to air-exposed mice.

Conclusions: These voltammetric neurochemical findings following repeated toluene exposure suggest that there may be a compensatory downregulation of the DA system. Acute or repeated toluene exposure had no effect on the DA uptake kinetics. Taken together, these results demonstrate that acute toluene inhalation potentiates DA release, while repeated toluene exposure attenuates DA release in the nucleus accumbens only.
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http://dx.doi.org/10.1007/s00213-014-3651-xDOI Listing
January 2015

Repeated toluene exposure increases c-Fos in catecholaminergic cells of the nucleus accumbens shell.

Neurotoxicol Teratol 2013 Nov-Dec;40:28-34. Epub 2013 Sep 12.

Department of Psychology, Wayne State University, Detroit, MI, United States; The Behavioral Neuroscience of Social Relationships Laboratory, Wayne State University, Detroit, MI, United States. Electronic address:

Toluene is a frequently abused solvent. Previous studies have suggested that toluene acts like other drugs of abuse, specifically on the dopaminergic system in the nucleus accumbens (NAc) and ventral tegmental area (VTA) of the mesolimbic pathway. Although changes in dopamine (DA) levels and c-Fos have been observed in both acute and repeated exposure paradigms, the extent to which c-Fos is localized to catecholaminergic cells is unknown. The present study tested the effects of repeated toluene exposure (1000-4000ppm) on locomotor activity and cells containing c-Fos, tyrosine hydroxylase (TH), or both in the core and shell of the NAc, as well as the anterior and posterior VTA. We focused our study on adolescents, since adolescence is a time of great neural change and a time when individuals tend to be more susceptible to drug abuse. In early tests, toluene dose-dependently increased locomotor activity. Repeated exposure to the highest concentration of toluene resulted in sensitization to toluene's effects on locomotor activity. Although the number of cells immunopositive for c-Fos or TH did not significantly differ across groups, cells immunopositive for TH+c-Fos were higher in the NAc shell of animals exposed to 4000ppm than in animals exposed to air (control) or 1000ppm. Taken together, these findings demonstrate that repeated high dose toluene exposure increases locomotor activity as well as activation of catecholaminergic cells in the shell of the NAc.
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http://dx.doi.org/10.1016/j.ntt.2013.09.001DOI Listing
July 2014

Binge toluene exposure in pregnancy and pre-weaning developmental consequences in rats.

Neurotoxicol Teratol 2013 Jul-Aug;38:29-35. Epub 2013 Apr 15.

Department of Psychology, Wayne State University, Detroit, MI, United States.

Binge Toluene Exposure in Pregnancy and Pre-weaning Developmental Consequences in Rats. Bowen, S.E. and Hannigan, J.H. The persistent rate of abuse of inhaled organic solvents, especially among women of child-bearing age, raises the risk for teratogenic effects of maternal toluene abuse. In this study, timed-pregnant Sprague Dawley rats were exposed from Gestation Day (GD) 8 to GD20 to 12,000 or 8000 parts per million (ppm) toluene, or 0ppm (controls) for 30min twice daily, 60min total daily exposure. Pups were assessed from postnatal day (PN) 4 to PN21 using a developmental battery measuring growth (i.e., body weight), maturational milestones (e.g., eye opening & incisor eruption), and biobehavioral development (e.g., negative geotaxis & surface righting). Pups exposed in utero to 12,000ppm or 8000ppm toluene weighed significantly less than the non-exposed control pups beginning at PN4 and PN12 (respectively) until PN21. Toluene resulted in significant increases in an index of poor perinatal outcome, specifically a composite of malformations, defined "runting" and neonatal death. No significant delays were observed in reaching maturational milestones. The results reveal that brief, repeated, prenatal exposure to high concentrations of toluene can cause growth retardation and malformations in rats. A comparison of the present, conservative results with findings in previous studies implies that binge patterns of toluene exposure in pregnant rats modeling human solvent abuse can result in developmental and morphological deficits in offspring. These results do not exclude the possibility that maternal toxicity as well as teratogenic effects of toluene may contribute to outcomes. The results suggest that abuse of inhaled organic solvents like toluene may result in similar early developmental outcomes in humans.
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http://dx.doi.org/10.1016/j.ntt.2013.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713175PMC
November 2014

Investigation of calcium-stimulated adenylyl cyclases 1 and 8 on toluene and ethanol neurobehavioral actions.

Neurotoxicol Teratol 2012 Sep-Oct;34(5):481-8. Epub 2012 Jul 10.

John D. Dingell VA Medical Center, Detroit, MI 48201, USA.

The abused inhalant toluene has potent behavioral effects, but only recently has progress been made in understanding the molecular pathways that mediate the action of toluene in the brain. Toluene and ethanol induce similar behavioral effects and share some targets including NMDA and GABA receptors. In studies examining neuronal actions of ethanol, mice lacking the calcium-stimulated adenylyl cyclases (ACs), AC1 and AC8 (DKO), show increased sedation durations and impaired protein kinase A (PKA) phosphorylation following acute ethanol treatment. Therefore, using DKO mice, we compared the neurobehavioral responses following toluene exposure to that of ethanol exposure to determine if these abused substances share molecular mechanisms of action. In the present study, acute sensitivity to toluene- or ethanol-induced changes in locomotor activity was evaluated in DKO and wild type (WT) mice. Mice were exposed to toluene vapor (0, 500, 1000, 2000, 6000, or 8000ppm) for 30min in static exposure chambers equipped with activity monitors. Both WT and DKO mice demonstrated increased ambulatory distance during exposure to a 2000-ppm concentration of toluene compared to respective air-exposed (0ppm) controls. Significant increases in locomotor activity were also observed during an air-only recovery period following toluene exposure in WT and DKO mice that had been exposed to 2000ppm of toluene compared to respective air controls. Sedative effects of toluene were equivalent in WT and DKO mice, both during exposure and afterwards during recovery. Although no significant differences in locomotor activity were detected in DKO compared to WT mice at individual doses tested, a significant main effect of toluene was achieved, with DKO mice demonstrating a generalized reduction in locomotor activity during the post-toluene recovery period compared to WT mice (when analyzing all doses collectively). For comparison to toluene, additional WT and DKO mice were treated with 1.0 or 2.0g/kg ethanol (i.p.) and monitored for locomotor activation. In WT mice, both doses of ethanol increased distance traveled compared to saline controls. Conversely, DKO mice demonstrated no increase in locomotor activation at 1.0g/kg, with significantly reduced distances traveled at both doses compared to ethanol-treated WT mice. These behavioral activity results suggest that acute effects of ethanol and toluene are distinct in the mechanisms by which they induce acute sedating effects with respect to AC1 and AC8 activity, but may be similar in the mechanisms subserving locomotor stimulation.
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http://dx.doi.org/10.1016/j.ntt.2012.06.005DOI Listing
February 2013

Inhalant use and inhalant use disorders in the United States.

Addict Sci Clin Pract 2011 Jul;6(1):18-31

University of North Carolina, Chapel Hill, North Carolina 27599, USA.

More than 22 million Americans age 12 and older have used inhalants, and every year more than 750,000 use inhalants for the first time. Despite the substantial prevalence and serious toxicities of inhalant use, it has been termed "the forgotten epidemic." Inhalant abuse remains the least-studied form of substance abuse, although research on its epidemiology, neurobiology, treatment, and prevention has accelerated in recent years. This review examines current findings in these areas, identifies gaps in the research and clinical literatures pertaining to inhalant use, and discusses future directions for inhalant-related research and practice efforts.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188822PMC
July 2011

Two serious and challenging medical complications associated with volatile substance misuse: sudden sniffing death and fetal solvent syndrome.

Authors:
Scott E Bowen

Subst Use Misuse 2011 ;46 Suppl 1:68-72

Department of Psychology, Wayne State University, Detroit, Michigan 48202, USA.

Volatile substance misuse is a prevalent and often overlooked behavior among adolescents, including reported use among young pregnant women. Several medical repercussions can arise from the improper use of volatile substances, yet they are often underappreciated among scientists and health professionals. This brief review reports on the recent advances made in the preclinical and clinical data about two serious medical complications surrounding volatile substance misuse: sudden sniffing death and fetal solvent syndrome. Suggestions for treatment interventions are discussed. The paper's limitations are noted.
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http://dx.doi.org/10.3109/10826084.2011.580220DOI Listing
August 2011

Binge toluene exposure alters glutamate, glutamine and GABA in the adolescent rat brain as measured by proton magnetic resonance spectroscopy.

Drug Alcohol Depend 2011 May 3;115(1-2):101-6. Epub 2010 Dec 3.

Department of Psychiatry & Behavioral Neurosciences, Brain Research and Imaging Neuroscience Division, Wayne State University, School of Medicine, Detroit, MI 48201, USA.

Despite the high incidence of toluene abuse in adolescents, little is known regarding the effect of binge exposure on neurochemical profiles during this developmental stage. In the current study, the effects of binge toluene exposure during adolescence on neurotransmitter levels were determined using high-resolution proton magnetic resonance spectroscopy ex vivo at 11.7T. Adolescent male Sprague-Dawley rats were exposed to toluene (0, 8000, or 12,000 ppm) for 15 min twice daily from postnatal day 28 (P28) through P34 and then euthanized either 1 or 7 days later (on P35 or P42) to assess glutamate (GLU), glutamine, and GABA levels in intact tissue punches from the medial prefrontal cortex (mPFC), anterior striatum and hippocampus. In the mPFC, toluene reduced GLU 1 day after exposure, with no effect on GABA, while after 7 days, GLU was no longer affected but there was an increase in GABA levels. In the hippocampus, neither GABA nor GLU was altered 1 day after exposure, whereas 7 days after exposure, increases were observed in GABA and GLU. Striatal GLU and GABA levels measured after either 1 or 7 days were not altered after toluene exposure. These findings show that 1 week of binge toluene inhalation selectively alters these neurotransmitters in the mPFC and hippocampus in adolescent rats, and that some of these effects endure at least 1 week after the exposure. The results suggest that age-dependent, differential neurochemical responses to toluene may contribute to the unique behavioral patterns associated with drug abuse among older children and young teens.
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http://dx.doi.org/10.1016/j.drugalcdep.2010.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071441PMC
May 2011

Differential effects of inhaled toluene on locomotor activity in adolescent and adult rats.

Pharmacol Biochem Behav 2010 Oct 15;96(4):438-48. Epub 2010 Jul 15.

Department of Psychology, Wayne State University, Detroit, MI 48202, USA.

Inhalant abuse is a world-wide public health concern among adolescents. Most preclinical studies have assessed inhalant effects in adult animals leaving unclear how behavioral effects differ in younger animals. We exposed adolescent (postnatal day [PN] 28) and adult (PN90) male rats to toluene using 1 of 3 exposure patterns. These patterns modeled those reported in toluene abuse in teens and varied concentration, number and length of exposures, as well as the inter-exposure interval. Animals were exposed repeatedly over 12 days to toluene concentrations of 0, 8000 or 16,000 parts per million (ppm). Locomotor activity was quantified during toluene exposures and for 30 min following completion of the final daily toluene exposure. For each exposure pattern, there were significant toluene concentration-related increases and decreases in locomotor activity compared to the 0-ppm "air" controls at both ages. These changes depended upon when activity was measured - during or following exposure. Compared to adults, adolescents displayed greater locomotor activity on the first day and generally greater increases in activity over days than adults during toluene exposure. Adults displayed greater locomotor activity than adolescents in the "recovery" period following exposure on the first and subsequent days. Age group differences were clearest following the pattern of paced, brief (5-min) repeated binge exposures. The results suggest that locomotor behavior in rats during and following inhalation of high concentrations of toluene depends on age and the pattern of exposure. The results are consistent with dose-dependent shifts in sensitivity and sensitization or tolerance to repeated toluene in the adolescent animals compared to the adult animals. Alternate interpretations are possible and our interpretation is limited by the range of very high concentrations of toluene used. The results imply that both pharmacological and psychosocial factors contribute to the teen prevalence of inhalant abuse.
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http://dx.doi.org/10.1016/j.pbb.2010.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935171PMC
October 2010

Reproductive toxicology and teratology of abused toluene.

Syst Biol Reprod Med 2010 Apr;56(2):184-200

Merrill Palmer Skillman Institute, Department of Obstetrics & Gynecology, C.S. Mott Center for Human Growth & Development, Wayne State University, Detroit, MI 48202, USA.

Toluene is an organic solvent that is widely used by industry and is ubiquitous in our environment. As a result, exposure to solvents like toluene in work-related settings (i.e., relatively constant, low-level exposures) or through inhalant abuse (i.e., relatively intermittent, high-level exposures) is increasing for many women of reproductive age. Evidence suggests that the risk for pregnancy problems, as well as developmental delays and neurobehavioral difficulties, is higher for the children of women who have been exposed to high concentrations of organic solvents during pregnancy than for those who have not. These risks appear to be higher in cases of abuse exposure to solvents such as toluene, particularly in comparison to the risk for teratogenic outcomes with occupational solvent exposure. Despite this, the reproductive toxicology and teratology following abuse of toluene and other inhalants remains under-investigated. This brief review describes the current state of our understanding of the reproductive and teratogenic risk of gestational toluene abuse. The data to date suggest that the high levels of toluene exposure typical with inhalant abuse are more detrimental to fetal development than typical occupational exposure, and preclinical paradigms can be beneficial for investigating the processes and risks of prenatal solvent exposure. While substantial research has been done on the reproductive effects of occupational exposures to organic solvents, more research is needed on the outcomes and mechanisms of exposures typical of inhalant abuse.
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http://dx.doi.org/10.3109/19396360903377195DOI Listing
April 2010

Comparison of toluene-induced locomotor activity in four mouse strains.

Pharmacol Biochem Behav 2010 Apr 6;95(2):249-57. Epub 2010 Feb 6.

Department of Psychology, Wayne State University, Detroit, MI, USA.

The mechanisms by which abused inhalants exert their neurobehavioral effects are only partially understood. In research with other drugs of abuse, specific inbred mouse strains have been useful in exploring genetic loci important to variation in behavioral reactions to these drugs. In the present investigation, mice from three inbred strains (Balb/cByj, C57BL/6J and DBA/2J) and one outbred strain (Swiss Webster) were studied for their acute and chronic sensitivity to toluene-induced changes in locomotor activity. Mice were exposed to toluene (0, 100, 2000, 8000, and 10,000 ppm) for 30 min in static exposure chambers equipped with activity monitors. In the acute condition, concentrations of toluene <8000 ppm increased ambulatory distance while the concentrations of > or =8000 ppm induced temporally biphasic effects with initial increases in activity followed by hypoactivity. Between-group differences in absolute locomotor activity levels were evident. The inbred Balb/cByj and DBA/2J strains as well as the outbred Swiss Webster strain of mice showed greater increases in activity after an acute challenge exposure to 2000 ppm than the inbred C57BL/6J strain. The same animals were then exposed 30 min/day to 8000 ppm toluene for 14 consecutive days. Re-determination of responses to 2000-ppm challenge exposures revealed that sensitization developed in locomotor activity and that the DBA/2J strain showed the greatest increase in sensitivity. These baseline differences in acute sensitivity and the differential shifts in sensitivity after repeated exposures among the inbred mouse strains suggest a genetic basis for the behavioral effects to toluene. The results support the notion that like for other drugs of abuse, using various strains of mice may be useful for investigating mechanisms that underlie risk for inhalant abuse.
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http://dx.doi.org/10.1016/j.pbb.2010.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852257PMC
April 2010

Neurochemical changes after acute binge toluene inhalation in adolescent and adult rats: a high-resolution magnetic resonance spectroscopy study.

Neurotoxicol Teratol 2009 Nov-Dec;31(6):382-9. Epub 2009 Jul 21.

Department of Psychology, Wayne State University, Detroit, MI 48201, USA.

Inhalant abuse in young people is a growing public health concern. We reported previously that acute toluene intoxication in young rats, using a pattern of exposures that approximate abuse patterns of inhalant use in humans, significantly altered neurochemical measures in select brain regions. In this study, adolescent and young adult rats were exposed similarly to an acute (2 x 15 min), high dose (8000-12,000 ppm) of toluene and high-resolution magic angle spinning proton magnetic resonance spectroscopy (HR-MAS 1H-MRS) was used to assess neurochemical profiles of tissue samples from a number of brain regions collected immediately following solvent exposure. The current investigation focused on N-acetyl-aspartate (NAA), choline-containing compounds, creatine, glutamate, GABA, and glutamine. Contrary to our predictions, no significant alterations were found in the levels of NAA, choline, creatine, glutamate, or glutamine in adolescent animals. In contrast to these minimal effects in adolescents, binge toluene exposure altered several neurochemical parameters in young adult rats, including decreased levels of choline and GABA in the frontal cortex and striatum and lowered glutamine and NAA levels in the frontal cortex. One of the more robust findings was a wide-ranging increase in lactate after toluene exposure in adult animals, an effect not observed in adolescents. These age-dependent effects of toluene are distinct from those reported previously in juvenile rats and suggest a developmental difference in vulnerability to the effects of inhalants. Specifically, the results suggest that the neurochemical response to toluene in adolescents is attenuated compared to adults, and imply an association between these neurochemical differences and age-influenced differences in solvent abuse in humans.
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http://dx.doi.org/10.1016/j.ntt.2009.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2771649PMC
January 2010

Alterations in rat fetal morphology following abuse patterns of toluene exposure.

Reprod Toxicol 2009 Apr 21;27(2):161-9. Epub 2009 Jan 21.

Department of Psychology, Wayne State University, Detroit, MI 48202, USA.

Toluene is a commonly abused organic solvent. Inhalant abusers are increasingly women in their prime childbearing years. Children born to mothers who abused solvents during pregnancy may exhibit characteristics of a "fetal solvent syndrome" which may include dysmorphic features. This study examined the teratological effects of an abuse pattern of binge toluene exposure during gestation on skeletal and soft tissue abnormalities, body weight, and body size in fetal rats. Pregnant Sprague-Dawley rats were exposed for 30 min, twice daily, from gestational day (GD) 8 through GD20 to either air (0 ppm), 8000 ppm, 12,000 ppm, or 16,000 ppm toluene. Two-thirds of each litter was prepared for skeletal examination using Alizarin Red S staining while the remaining third of each litter was fixed in Bouin's solution for Wilson's soft tissue evaluation. Exposure to toluene at all levels significantly reduced growth, including decreases in placental weight, fetal weight, and crown-rump length. In addition, numerous gross morphological anomalies were observed such as short or missing digits and missing limbs. Skeletal examination revealed that ossification of the extremities was significantly reduced as a result of toluene exposure at all levels. Specific skeletal defects included misshapen scapula, missing and supernumerary vertebrae and ribs, and fused digits. Soft tissue anomalies were also observed at all toluene levels and there was a dose-dependent increase in the number of anomalies which included cryptorchidism, displaced abdominal organs, gastromegaly, distended/hypoplastic bladder, and delayed cardiac development, among others. These results indicate that animals exposed prenatally to levels and patterns of toluene typical of inhalant abuse are at increased risk for skeletal and soft tissue abnormalities.
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http://dx.doi.org/10.1016/j.reprotox.2009.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680795PMC
April 2009

Abuse pattern of gestational toluene exposure alters behavior in rats in a "waiting-for-reward" task.

Neurotoxicol Teratol 2009 Mar-Apr;31(2):89-97. Epub 2008 Nov 17.

Department of Psychology, Wayne State University, Detroit, MI 48202, USA.

Toluene abuse during pregnancy is a world-wide public health concern although the neurobehavioral teratogenic effects of toluene at the high concentrations and binge-like exposure patterns typical of abuse remain understudied. We assessed the effects of binge prenatal toluene exposure on behavior reflective of impulsivity in rat offspring using a "waiting-for-reward" operant task. Timed-pregnant Sprague-Dawley rats were exposed for 15 min, twice daily, from gestational day (GD) 8 through GD20 to either air, 8000 ppm, 12,000 ppm or 16,000 ppm toluene in a static exposure system. At postnatal day 60, male and female offspring were trained to stable lever pressing in a standard fixed-ratio 50 (FR50) paradigm. A wait requirement was then introduced such that after each FR completion, a "free" pellet was delivered at increasing time intervals (2 s, 4 s, 6 s, etc.) until the rat pressed another lever which reinstated the FR50 component ("FR Reset"). A pattern of increased FR Resets and fewer total pellets received overall and during the wait component is interpretable as "impulsivity." The "wait" component assessment was repeated after the rats had been injected with varying doses of amphetamine. Consistent with our hypotheses, repeated binge prenatal toluene exposure appeared to increase impulsivity based upon decreases in the total number of free pellets received and mean waiting time. However, a toluene dose-dependent decrease in the number of FR Resets and in response rates under all conditions indicated there was a general impairment in performance in rats exposed prenatally to higher doses of toluene. Also, prenatal exposure to 12,000 ppm and 16,000 ppm toluene resulted in a hyposensitivity to the stimulatory effects of the amphetamine challenge in male rats. For female rats, amphetamine further interfered with performance on the task. These results suggest that acute binge prenatal toluene exposure alters performance in this task but the results are not consistent with increased impulsivity or impaired behavioral inhibition. These outcomes in young adult rats also suggest that there may be long-term behavioral deficits due to prenatal toluene exposure.
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http://dx.doi.org/10.1016/j.ntt.2008.11.002DOI Listing
August 2009

Abuse pattern of toluene exposure alters mouse behavior in a waiting-for-reward operant task.

Neurotoxicol Teratol 2009 Jan-Feb;31(1):18-25. Epub 2008 Sep 17.

Department of Psychology, Wayne State University, Detroit, Michigan, USA.

Inhaling solvents for recreational purposes continues to be a world-wide public health concern. Toluene, a volatile solvent in many abused products, adversely affects the central nervous system. However, the long-term neurobehavioral effects of exposure to high-concentration, binge patterns typical of toluene abuse remain understudied. We studied the behavioral effects of repeated toluene exposure on cognitive function following binge toluene exposure on behavioral impulse control in Swiss Webster mice using a "wait-for-reward" operant task. Mice were trained on a fixed-ratio (FR) schedule using sweetened milk as a reward. Upon achieving FR15, a wait component was added which delivered free rewards in the absence of responses at increasing time intervals (2s, 4s, 6s, etc...). Mice continued to receive free rewards until they pressed a lever that reinstated the FR component (FR Reset). Once proficient in the FR-Wait task, mice were exposed to either 1000 ppm, 3600 ppm or 6000 ppm toluene, or 0ppm (air controls) for 30 min per day for 40 days. To avoid acute effects of toluene exposure, behavior was assessed approximately 22-23 h later. Repeated toluene exposure decreased response rates, the number of FR resets, and increased mean wait time, resulting in a higher response-to-reinforcer ratio than exhibited by controls. Mice receiving the higher exposure level (6000 ppm) showed a dramatic decrease in the number of rewards received, which was reversed when toluene exposure ceased. Mice receiving the lower exposure level (1000 ppm) showed little change in the number of rewards. These results indicate that repeated binge exposures to high concentrations of toluene can significantly interfere with performance as measured by a waiting-for-reward task, suggesting a significant impact on cognitive and/or psychomotor function.
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http://dx.doi.org/10.1016/j.ntt.2008.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2643065PMC
March 2009

Time course of the ethanol-like discriminative stimulus effects of abused inhalants in mice.

Authors:
Scott E Bowen

Pharmacol Biochem Behav 2009 Jan 8;91(3):345-50. Epub 2008 Aug 8.

Department of Psychology, Behavioral Pharmacology and Toxicology Laboratory, Wayne State University, Detroit, MI 48202, USA.

Abused solvents have effects similar to those of abused depressant drugs. This experiment evaluated the time course of the discriminative stimulus effects of toluene and 1,1,1-trichloroethane (TRI). Mice were trained to discriminate between i.p. injections of ethanol (EtOH; 1.25 g/kg) and saline in a two-lever operant task in which responding was under the control of a fixed-ratio 20 schedule. After 20-min inhalation exposures to toluene (500-6000 ppm) or TRI (1000-12,000 ppm), stimulus generalization was examined at 0, 5, 10, 20, and 40 min post-exposure. Ethanol doses>or=0.25 g/kg produced increases in EtOH-lever responding with full substitution occurring immediately after testing for doses between 1.25 and 2.5 g/kg. Toluene and TRI produced increased EtOH-lever responding at 0-10 min post-exposure with some EtOH-lever responding occurring up to 20-min post-exposure. Response rates were not decreased for any concentration of toluene or TRI immediately following inhalant exposure but several concentrations elevated rates from 5 to 40 min post-exposure. These results confirm and extend previous studies and show these solvents produce similar effects in EtOH-lever responding but with potency differences. The time-dependent differences in EtOH-lever responding suggest that as solvents are cleared from the body, the EtOH-like subjective effects also fade.
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http://dx.doi.org/10.1016/j.pbb.2008.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2752859PMC
January 2009

Effects of abuse pattern of gestational toluene exposure on metabolism, feeding and body composition.

Physiol Behav 2008 Mar 26;93(4-5):984-93. Epub 2007 Dec 26.

College of Nursing, Wayne State University, Detroit, MI 48202, USA.

Aims: Inhalant abuse during pregnancy lowers birth weight and impedes early development. These studies explored the effects of brief, repeated, prenatal toluene exposures in pregnant female rats on body weight, metabolic rate, body composition, and food intake in their offspring.

Method: Rats were exposed to 0, 8000, 12,000, or 16,000 ppm of toluene twice daily for 15 min from gestational days 8 to 20. The effects of such exposures on post-weaning litter weights, oxygen consumption, carbon dioxide output, and body fat content were determined in 2 cohorts (n=23, n=24) of offspring. Food intakes and weight changes in response to 3 different diets (regular chow, purified diet, purified high fat diet) were examined in another cohort (n=24) from postnatal days 72 to 116.

Results: Litter weights showed a significant linear decrease as a function of toluene dose. Offspring exposed to the 16,000 ppm toluene dose displayed statistically lower energy expenditures than control rats. Male rats exposed to 8000 or 16,000 ppm toluene had significantly greater percentage of body fat as well as total body fat than the other groups. Toluene also significantly suppressed weight gain over the time chow was consumed compared to the 0 ppm control group. Finally there were trends for a main effect of toluene dose on food intake during chow and during high fat diet consumption, with rats in the 12,000 ppm group consuming more than the 0 ppm group on both diets.

Discussion: These data suggest that, in addition to other previously documented abnormalities in neurological development and behavior, the physiological regulation of metabolism and body composition in males as well as food intake and weight gain in both sexes may be altered by prenatal exposure to toluene.
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http://dx.doi.org/10.1016/j.physbeh.2007.12.016DOI Listing
March 2008

Decreased sensitivity in adolescent vs. adult rats to the locomotor activating effects of toluene.

Neurotoxicol Teratol 2007 Nov-Dec;29(6):599-606. Epub 2007 Aug 17.

Department of Psychology, Wayne State University, Detroit, Michigan, USA.

Volatile organic solvent (inhalant) abuse continues to be a major health concern throughout the world. Of particular concern is the abuse of inhalants by adolescents because of its toxicity and link to illicit drug use. Toluene, which is found in many products such as glues and household cleaners, is among the most commonly abused organic solvents. While studies have assessed outcomes of exposure to inhalants in adult male animals, there is little research on the neurobehavioral effects of inhalants in female or younger animals. In attempt to address these shortcomings, we exposed male and female Long-Evans rats to 20 min of 0, 2000, 4000, or 8000 parts per million (ppm) inhaled toluene for 10 days in rats aged postnatal (PN) day 28-39 (adolescent), PN44-PN55, or >PN70 (adult). Animals were observed individually in 29-l transparent glass cylindrical jars equipped with standard photocells that were used to measure locomotor activity. Toluene significantly increased activity as compared to air exposure in all groups of male and female rats with the magnitude of locomotor stimulation produced by 4000 ppm toluene being significantly greater for female adults than during any age of adolescence. The results demonstrate that exposure to abuse patterns of high concentrations of toluene through inhalation can alter spontaneous locomotor behavior in rats and that the expression of these effects appears to depend upon the postnatal age of testing and sex of the animal.
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http://dx.doi.org/10.1016/j.ntt.2007.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2156189PMC
February 2008

Maternal and fetal blood and organ toluene levels in rats following acute and repeated binge inhalation exposure.

Reprod Toxicol 2007 Nov-Dec;24(3-4):343-52. Epub 2007 Jun 26.

Department of Psychology, Wayne State University, Detroit, MI 48202, USA.

Inhalation of organic solvents is a persistent form of drug abuse with particular concern being the abuse of inhalants by women of child-bearing age. While studies have begun assessing postnatal outcomes of offspring exposed prenatally to inhalants, relatively little is known about the distribution of toluene in blood and body tissues of pregnant, inhalant-abusing women, or in the fetuses. The present study assessed the tissue toluene levels attained following brief toluene exposures using a pre-clinical rat model of maternal inhalant abuse. Timed-pregnant Sprague-Dawley rats were exposed to toluene at 8000 or 12,000 parts per million (ppm) for 15, 30 or 45 min/exposure. Exposures occurred twice each day from gestational day 8 (GD8) through GD20. Immediately following the second exposure on GD8, GD14 and GD20 blood was taken from the saphenous vein of the dams. Following saphenous vein blood collection on GD20, dams were sacrificed and trunk blood was collected along with maternal tissue specimens from cerebellum, heart, lung, kidney and liver. The placenta, amniotic fluid and fetal brain were also collected. Results demonstrated that maternal saphenous blood toluene levels increased as the inhaled concentration of toluene and duration of exposure increased. The maternal cerebellum, heart, kidney and liver appeared to be saturated after 30 min on GD20 such that toluene levels in those organs were equivalent across all ambient concentrations of inhaled toluene. Toluene levels also increased in fetal brain as the inhaled concentration of toluene increased and in placenta and amniotic fluid as the duration of exposure increased. Toluene levels in all tissues at GD20, except maternal lung and amniotic fluid, were higher than in maternal saphenous blood suggesting that toluene concentrated in those organs. Measurement of toluene levels in blood and other tissues following repeated toluene exposure demonstrated that toluene readily reaches a variety of potential sites of action throughout the maternal-placental-fetal unit.
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http://dx.doi.org/10.1016/j.reprotox.2007.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2137922PMC
January 2008

Gestational toluene exposure effects on spontaneous and amphetamine-induced locomotor behavior in rats.

Neurotoxicol Teratol 2007 Mar-Apr;29(2):236-46. Epub 2006 Oct 6.

Department of Psychology, Wayne State University, Detroit, MI 48202, USA.

Gestational Toluene Exposure Effects on Spontaneous and Amphetamine-Induced Locomotor Behavior in Rats. Bowen, S.E., Mohammadi, M.H., Batis, J.C., and Hannigan, J.H. Neurotoxicology and Teratology, XX, 2006. The abuse of volatile organic solvents (inhalants) continues to be a major health concern throughout the world. Toluene, which is found in many products such as glues and household cleaners, is among the most commonly abused organic solvents. The neurobehavioral teratogenic sequelae of solvent abuse (i.e., repeated, brief inhalation exposures to very high concentrations of solvents) have not been examined thoroughly. In a preclinical model of inhalant abuse, timed-pregnant Sprague-Dawley rats were exposed to 0, 8000, or 12,000 parts per million (ppm) for 15 min twice daily from gestation day 8 (GD8) through GD20. In the first experiment, separate groups of offspring were observed individually in an open-field on postnatal day 22 (PN22), PN42 or PN63. In the second experiment, other offspring given identical prenatal toluene exposures were observed in an "open-field" following an acute i.p. injection of amphetamine (0, 0.56, 1.78 mg/kg) on PN28. Automated measurements of distance traveled and ambulatory time were recorded. Prenatal toluene exposure resulted in small alterations in spontaneous activity compared to non-exposed rats. Prenatal exposure to 12,000 ppm toluene resulted in significant hyposensitivity to the locomotor stimulatory effects of the amphetamine challenge in male but not female rats on PN28. The results demonstrate that prenatal exposure to abuse patterns of high concentrations of toluene through inhalation can alter spontaneous and amphetamine-induced locomotor behavior in rats. The expression of these effects also appears to depend upon the postnatal age of testing. These results imply that abuse of organic solvents during pregnancy in humans may also produce long-lasting effects on biobehavioral development.
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http://dx.doi.org/10.1016/j.ntt.2006.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1876668PMC
June 2007

The last decade of solvent research in animal models of abuse: mechanistic and behavioral studies.

Neurotoxicol Teratol 2006 Nov-Dec;28(6):636-47. Epub 2006 Sep 20.

Department of Psychology, Wayne State University, 5057 Woodward, Detroit, MI 48202, USA.

The abuse of volatile organic solvents (inhalants) leads to diverse sequelae at levels ranging from the cell to the whole organism. This paper reviews findings from the last 10 years of animal models investigating the behavioral and mechanistic effects of solvent abuse. In research with animal models of inhalant abuse, NMDA, GABA(A), glycine, nicotine, and 5HT(3) receptors appear to be important targets of action for several abused solvents with emerging evidence suggesting that other receptor subtypes and nerve membrane ion channels may be involved as well. The behavioral effects vary in magnitude and duration among the solvents investigated. The behavioral effects of acute and chronic inhalant abuse include motor impairment, alterations in spontaneous motor activity, anticonvulsant effects, anxiolytic effects, sensory effects, and effects on learning, memory and operant behavior (e.g., response rates and discriminative stimulus effects). In addition, repeated exposure to these solvents may produce tolerance, dependence and/or sensitization to these effects.
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http://dx.doi.org/10.1016/j.ntt.2006.09.005DOI Listing
January 2007

Developmental toxicity of prenatal exposure to toluene.

AAPS J 2006 ;8(2):E419-24

Department of Psychology, Wayne State University, Detroit, MI, USA.

Organic solvents have become ubiquitous in our environment and are essential for industry. Many women of reproductive age are increasingly exposed to solvents such as toluene in occupational settings (ie, long-term, low-concentration exposures) or through inhalant abuse (eg, episodic, binge exposures to high concentrations). The risk for teratogenic outcome is much less with low to moderate occupational solvent exposure compared with the greater potential for adverse pregnancy outcomes, developmental delays, and neurobehavioral problems in children born to women exposed to high concentrations of abused organic solvents such as toluene, 1,1,1-trichloroethane, xylenes, and nitrous oxide. Yet the teratogenic effects of abuse patterns of exposure to toluene and other inhalants remain understudied. We briefly review how animal models can aid substantially in clarifying the developmental risk of exposure to solvents for adverse biobehavioral outcomes following abuse patterns of use and in the absence of associated health problems and co-drug abuse (eg, alcohol). Our studies also begin to establish the importance of dose (concentration) and critical perinatal periods of exposure to specific outcomes. The present results with our clinically relevant animal model of repeated, brief, high-concentration binge prenatal toluene exposure demonstrate the dose-dependent effect of toluene on prenatal development, early postnatal maturation, spontaneous exploration, and amphetamine-induced locomotor activity. The results imply that abuse patterns of toluene exposure may be more deleterious than typical occupational exposure on fetal development and suggest that animal models are effective in studying the mechanisms and risk factors of organic solvent teratogenicity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3231560PMC
http://dx.doi.org/10.1007/BF02854915DOI Listing
August 2006
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