Abuse-like toluene exposure during early adolescence alters subsequent ethanol and cocaine behavioral effects and brain monoamines in male mice.

Currently, there is a gap in understanding the neurobiological impact early adolescent toluene exposure has on subsequent actions of other drugs. Adolescent (PND 28-32) male Swiss-Webster mice (N = 210) were exposed to 0, 2000, or 4000 ppm of toluene vapor for 30 min/day for 5 days. Immediately following the last toluene exposure (PND 32; n = 15) or after a short delay (PND 35; n = 15), a subset of subjects' brains was collected for monoamine analysis. Remaining mice were assigned to one of two abstinence periods: a short 4-day (PND 36) or long 12-day (PND 44) delay after toluene exposure. Mice were then subjected to a cumulative dose response assessment of either cocaine (0, 2.5, 5, 10, 20 mg/kg; n = 60), ethanol (0, 0.5, 1, 2, 4 g/kg; n = 60), or saline (5 control injections; n = 60). Toluene concentration-dependently increased locomotor activity during exposure. When later challenged, mice exposed previously to toluene were significantly less active after cocaine (10 and 20 mg/kg) compared to air-exposed controls. Animals were also less active at the highest dose of alcohol (4 g/kg) following prior exposure to 4000 ppm when compared to air-exposed controls. Analysis of monoamines and their metabolites using High Pressure Liquid Chromatography (HPLC) within the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), dorsal striatum (dSTR), and ventral tegmental area (VTA) revealed subtle effects on monoamine or metabolite levels following cumulative dosing that varied by drug (cocaine and ethanol) and abstinence duration. Our results suggest that early adolescent toluene exposure produces behavioral desensitization to subsequent cocaine-induced locomotor activity with subtle enhancement of ethanol's depressive effects and less clear impacts on levels of monoamines.

Maternal care behavior and physiology moderate offspring outcomes following gestational exposure to opioids.

The opioid epidemic has resulted in a drastic increase in gestational exposure to opioids. Opioid-dependent pregnant women are typically prescribed medications for opioid use disorders ("MOUD"; e.g., buprenorphine [BUP]) to mitigate the harmful effects of abused opioids. However, the consequences of exposure to synthetic opioids, particularly BUP, during gestation on fetal neurodevelopment and long-term outcomes are poorly understood. Further, despite the known adverse effects of opioids on maternal care, many preclinical and clinical studies investigating the effects of gestational opioid exposure on offspring outcomes fail to report on maternal care behaviors. Considering that offspring outcomes are heavily dependent upon the quality of maternal care, it is important to evaluate the effects of gestational opioid exposure in the context of the mother-infant dyad. This review compares offspring outcomes after prenatal opioid exposure and after reduced maternal care and integrates this information to potentially identify common underlying mechanisms. We explore whether adverse outcomes after gestational BUP exposure are due to direct effects of opioids in utero, deficits in maternal care, or a combination of both factors. Finally, suggestions for improving preclinical models of prenatal opioid exposure are provided to promote more translational studies that can help to improve clinical outcomes for opioid-dependent mothers.

A novel preclinical model of environment-like combined benzene, toluene, ethylbenzene, and xylenes (BTEX) exposure: Behavioral and neurochemical findings.

Environmental exposure to toxicants is a major health issue and a leading risk factor for premature mortality worldwide, including environmental exposures to volatile organic compounds (VOCs), specifically Benzene, Toluene, Ethylbenzene, and Xylene (BTEX). While exposure to these compounds individually has shown behavioral and neurochemical effects, this investigation examined the impact of exposure to combined BTEX using a preclinical model. Male Swiss Webster mice were exposed to BTEX vapors designed to approximate environmental levels in urban communities. Animals were exposed to one of four treatment conditions: a 0-ppm (air control), two BTEX groups representing levels of environmental-like exposure, and a fourth group modeling occupational-like exposure. These exposures were conducted in 1.5-h sessions, 2 sessions/day, 5 days/week, for 3 weeks. Effects on coordination (i.e., rotarod and inverted screen test), learning and memory (i.e., Y-maze), and locomotor behavior (i.e., movement during exposure) were assessed during and after exposure. Monoamine levels in the medial prefrontal cortex and nucleus accumbens were assessed immediately following exposure. Effects of BTEX exposure were found on the variance of locomotor activity but not in other behavioral or neurochemical assessments. These results indicate that the combination of inhaled BTEX at environmentally representative concentrations has demonstrable, albeit subtle, effects on behavior.

Acute exposure to abuse-like concentrations of toluene induces inflammation in mouse lungs and brain.

Toluene is an aromatic hydrocarbon commonly abused by young adolescents for its central nervous system depressant effects. Although toluene's pharmacological effects at high concentrations are relatively well-known, few studies have assessed toluene's effects on lung and brain tissues. The present study characterized the pathological effects of acute inhaled toluene exposure in the lungs and brains of male Swiss-Webster mice (N = 68). Using a static vapor exposure chamber, mice (PND 28) received a single 30-min toluene administration (0, 1000, 2000, or 4000 ppm). Lung and brain tissues were extracted 24-h post-exposure. Histology results revealed significant changes in the morphology of lung tissue (e.g., irregular cellular architecture) with the 2000- and 4000-ppm exposures expressing greater signs of pathology than control 0-ppm exposure. Markers of immune system activity (F4/80 and Ly-6G) and cellular proliferation (Ki-67) in the lung revealed no significant differences. Additionally, brain tissues were analyzed for changes of astrogliosis (glial fibrillary acidic protein [GFAP]) and oxidative stress (glutathione peroxidase [GPx]). GFAP showed increased astrogliosis in the striatum with 2000-ppm toluene showing significantly higher expression than control (p < 0.05) and a marginal effect in the hippocampus. No other markers showed significant changes. The increased signs of inflammation and cellular damage suggest that exposure to a single high concentration of toluene, typical of abuse, is capable of producing pathology in both lung and brain tissue.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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 GABAA 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.

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

BACKGROUND AND PURPOSE: To investigate if cranial X-irradiation reduces amyloid-ß (Aß) 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 Aß 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-1ß, Iba1 CD45) was assessed. Behavioral testing was performed to relate changes in Aß 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 Aß 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 Aß 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-ß 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.

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

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.

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

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.

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

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.

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

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.

Inhalant use and inhalant use disorders in the United States.

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.

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

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.

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

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.