Repeated Toluene Exposure Alters the Synaptic Transmission of Layer 5 Medial Prefrontal Cortex T ⁎ Silvia L

Neurotoxicology and Teratology 73 (2019) 9–14

Contents lists available at ScienceDirect

Neurotoxicology and Teratology

journal homepage: www.elsevier.com/locate/neutera

Brief communication Repeated toluene exposure alters the synaptic transmission of layer 5 medial prefrontal cortex T ⁎ Silvia L. Cruz, Mayra Torres-Flores, Emilio J. Galván

Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Calzada de los Tenorios No. 235, México City 14330, Mexico

ARTICLE INFO ABSTRACT

Keywords: Toluene is an organic solvent commonly misused by inhalation among adolescents to experience psychoactive Inhalants effects. Repeated toluene exposure produces several cognitive deficits, including working memory impairment in Toluene which the medial prefrontal cortex (mPFC) plays a central role. Among other effects, toluene antagonizes NMDA Dopamine receptors, enhance GABAA receptor-mediated responses and increases dopamine release. We have recently re- Synaptic plasticity ported that animals repeatedly exposed to toluene show increased mPFC excitability; however, alterations in Medial prefrontal cortex synaptic transmission, including long-term synaptic plasticity of glutamatergic responses have not been studied thus far. Here we used extracellular recordings to determine the effects of repeated toluene exposure (8000 ppm for 30 min, twice a day, for ten days) on the synaptic transmission converging on prelimbic layer 5 pyramidal neurons of the mPFC in adolescent male Wistar rats. Repeated toluene exposure increased mPFC's synaptic strength and reduced the inhibitory transmission assessed by input-output curves and paired-pulse inhibition

protocols, respectively. Both toluene and a selective D1 receptor antagonist blocked the ability of exogenous dopamine to induce synaptic potentiation. Repeated toluene exposure also altered the ability of NMDA to induce synaptic depression of excitatory transmission. Taken together, the changes in synaptic strength and impairment of the NMDA-mediated plasticity of the mPFC demonstrate a series of synaptic modiﬁcations of the glutamatergic transmission that may underlie the cognitive impairment resulting from repeated toluene exposure.

1. Introduction of repeated toluene inhalation include memory impairment (Huerta- Rivas et al., 2012) and increased excitability (Armenta-Resendiz et al., Inhalant misuse is the intentional inhalation of products containing 2018). Prolonged exposure to toluene is also associated with neuronal substances that are volatile at room temperature and have psychoactive structural changes. Inhalation to 8000 ppm toluene for 10 days in- effects (Balster et al., 2009). Toluene, in its pure form or as an increases the expression of GABAA α1 subunits, NR1 and NR2B subunits gredient of many commercial products, is the most commonly misused of the NMDA receptor (Williams et al., 2005). solvent. When inhaled at high concentrations (typically 5000 to Few studies have analyzed the electrophysiological alterations 12,000 ppm; Bukowski, 2001) for brief periods, toluene produces mind- caused by high toluene concentrations. Wayman and Woodward altering effects. This intentional exposure pattern contrasts with occu- (2018), showed that a single 10,500 ppm toluene inhalation session pational exposure, characterized by extended inhalation periods (8 h/ significantly reduces the firing output of layer 5/6 prelimbic neurons day, 5 days/week) to very low solvent concentrations (Bowen et al., projecting to the nucleus accumbens core. More recently, we showed 2006). that 20 exposure sessions to 8000 ppm toluene increase the excitability Depending on its concentration, toluene can act on several mole- of prelimbic layer 5 pyramidal neurons of the medial prefrontal cortex cular targets. At a low millimolar range, toluene inhibits NMDA re- (mPFC) in adolescent rats. This hyperexcitability is characterized by ceptors in a non-competitive manner (Bale et al., 2005; Cruz et al., enhanced action potential discharge mediated by a decrease in the slow

1998), is a positive allosteric modulator of GABAA and glycine receptors component of the hyperpolarization current and increased glutama- (Bale et al., 2005; Beckstead et al., 2000) and increases dopamine re- tergic activity (Armenta-Resendiz et al., 2018). lease in the mesocortical system (Gerasimov et al., 2002). Other eﬀects To the best of our knowledge, there are no studies analyzing

⁎ Corresponding author at: Departamento de Farmacobiología, Centro de Investigación y Estudios Avanzados del Instituto Politécnico Nacional, Calzada de los Tenorios No. 235, Col. Granjas Coapa C.P. 14330, Mexico. E-mail address: [email protected] (E.J. Galván). https://doi.org/10.1016/j.ntt.2019.02.002 Received 1 December 2018; Received in revised form 26 February 2019; Accepted 27 February 2019 Available online 28 February 2019 0892-0362/ © 2019 Elsevier Inc. All rights reserved. S.L. Cruz, et al. Neurotoxicology and Teratology 73 (2019) 9–14 whether synaptic transmission alterations exist in the mPFC of adoles- responses were amplified with an Axopatch 200B; the analog signals cent animals repeatedly exposed to toluene. Here, we show that re- were sampled by a Digidata 1440A interface coupled to pCLAMP 10 peated exposure to toluene increases the mPFC synaptic strength and software (Molecular Devices, Foster City, CA). The fEPSP latency was reduces the inhibitory transmission impinging on prelimbic mPFC layer calculated from the end of the electrical stimulus to the beginning of the 5 pyramidal in adolescent rats. We also show that toluene blocked the fEPSP sink. Paired-pulse inhibition was expressed as the ratio between ability of exogenous dopamine to induce synaptic potentiation. the second and the first fEPSP of the pair (S2/S1). To corroborate the participation of the GABAergic inhibition, picrotoxin (50 μM; see 2. Materials and methods Fig. 1C) was perfused at the end of the PPI protocol. Dopamine (DA) perfusion (100 μM, 10 min) was performed in the presence of 0.4 mM of 2.1. Animals ascorbic acid to avoid fast oxidation of DA; NMDA (20 μM) was bath perfused for 3 min. A total of 47 male Wistar rats (postnatal days 30–37) provided form our vivarium were used. Our procedures complied with the Mexican Official Norm for utilization and care of laboratory animals “NOM-062- 2.6. Statistical and data analysis ZOO-1999”, the local Ethics Committee of our Institution (authoriza- tions: 0101-14 and 0090-14), the National Institutes of Health guide- A two-way ANOVA test was used to analyze data obtained from I-O lines (NIH, 2011) and ARRIVE guidelines. curves, FV-fEPSP curves and the effects of different ISIs on fEPSP and PPI ratios. One-Way ANOVA followed by Student-Newman-Keuls post- 2.2. Drugs hoc was used to compare the effect of toluene on the fEPSP slope during perfusion of DA. For further comparisons, we analyzed an early and late Toluene (99.8% HPLC grade), dopamine, L-ascorbic acid, S(−)-ra- effect of DA at minute 10th of DA perfusion and min 40th after DA clopride (+)-tartrate salt, R(+)-SCH-23390 hydrochloride, N-methyl-D- washout. Student's t-test was used for comparison of NMDA effects. All aspartate (NMDA), Kynurenic acid, and picrotoxin were purchased hypotheses were tested when α = 0.05. from Sigma-Aldrich Chemicals Co. (St. Louis, MO, USA). Tetrodotoxin (TTX) was from Alomone Labs (Jerusalem, Israel). 3. Results 2.3. Toluene exposure 3.1. Repeated toluene exposure alters the synaptic efficacy of layer 5 mPFC The exposure method has been described in detail elsewhere (Armenta-Resendiz et al., 2018). Briefly, independent groups of rats Two evoked responses were evaluated, extracellular field potentials were exposed to air or 8000 ppm toluene for five consecutive days, left (fEPSP) and population spikes (PS). Whereas the fEPSP was sensitive to untreated during the weekend, and re-exposed to air or toluene for five the non-specific blocker of glutamate receptors, Kynurenic acid (Kyn additional days. Each session lasted 30 min, was conducted in 27-l static 2 mM), the inward deflection of the PS was abolished with the perfusion exposure chambers and was repeated twice daily (6 h apart). The of the sodium channel blocker TTX (0.5 μM; Fig. 1B). Next, we eval- amount of toluene injected into the chamber was calculated using the uated the input-output (I-O) relationship of the fEPSP (stimulation ideal gas equation for closed systems (Nelson, 1971). The nominal current vs. evoked fEPSP). In control, the maximal amplitude was concentration was confirmed with a photoionization detector (Pho- 1.3 ± 0.09 mV. The mPFC slices from animals repeatedly exposed to Check Tiger, Ion Science, LTD, Cambs, UK). Toluene concentration was toluene (hereafter referred as experimental group) reached a maximal chosen based on previous reports of its effect on animal behavior and value of 1.62 ± 0.1 mV (Fig. 1D). In both groups, the latency to the relevance to solvent intoxication (Armenta-Resendiz et al., 2018; evoked responses was constant at all the stimuli tested Bowen et al., 2006). (2.66 ± 0.03 ms). Computing the average rate of change of I-O curves (Villanueva-Castillo et al., 2017) showed that toluene exposure in- 2.4. Brain slice preparation creased the I-O relationship in 31.5%. Two-way ANOVA found changes

in the I-O curve of control slices vs. the experimental group (F(1, Eighteen hours after the last solvent exposure, mPFC slices were 233) = 83.819; p = 0.001) and current intensity (F(12, 233) = 33.01; prepared, as described in detail elsewhere (Armenta-Resendiz et al., p < 0.001). Slices in which a presynaptic fiber volley (FV) preceded 2018). Briefly, after decapitation the brain was placed in frozen sucrose the postsynaptic response were independently analyzed to establish the solution consisting of (in mM): 210 sucrose, 25 NaHCO3, 2.8 KCl, 2 FV–fEPSP relationship. For a given FV, the evoked fEPSP response MgSO4, 1.25 NaH2PO4, 10 glucose, 4 MgCl2, and 1 CaCl2, bubbled with augmented 32.8% in the experimental group (F(12, 233) = 18.939; 95%:5% O2:CO2. The mPFC was dissected, and coronal slices (385 μm) p < 0.001; Fig. 1E). However, a two-way ANOVA found no statistically were obtained using a vibratome slicer. Slices were used after 1.5 h of significant differences between both curves (F(1, 233) = 3.093; recovery in a solution consisting of (in mM): 125 NaCl, 2.5 KCl, 1.2 p = 0.080). Representative traces showing the fEPSP and FV for both

NaH2PO4, 25 NaHCO3, 10 glucose, 4 MgCl2, and 1 CaCl; bubbled with experimental conditions are depicted in Fig. 1F. Next, we evaluated 95%:5% CO2:O2. For the experiments, slices were superfused with ar- synaptic inhibition mediated by GABAergic interneurons using a tiﬁcial cerebrospinal ﬂuid composed of (in mM): 125 NaCl, 3.0 KCl, paired-pulse inhibition (PPI; see Fig. 1C) protocol. Stimulation in layer

1.25 NaH2PO4, 25 NaHCO3, 10 glucose, 2.5 CaCl2, and 1.5 MgCl2. 1–2 evoked an orthodromic fEPSP. Two-way ANOVA found no changes in the PPI curve of the dendritic-evoked fEPSPs in control vs. the ex-

2.5. Extracellular recordings and stimulation protocols perimental group (F(1, 118) = 0.0902; p = 0.765; Fig. 1G), although there was a significant effect for ISI (F(6, 118) = 49.56; p < 0.001). In The extracellular field excitatory potentials (fEPSP) were recorded another group of slices, the antidromic population spike was obtained in layer 5 with borosilicate pipettes filled with 3 M NaCl solution stimulating mPFC layer 6 (see Fig. 1A for electrode arrangement). The (1–2MΩ resistance). The test stimuli (0.06 Hz; 100 μs) were delivered PPI curve of the PS showed a reduced inhibition of 37.2% in the ex- via a nichrome electrode (38 μM bare diameter) positioned on layer 1–2 perimental group. Two-way ANOVA showed significant effects for

(to evoke an orthodromic fEPSP) or layer 6 (to evoke antidromic po- treatment (F(1, 125) = 40.49; p < 0.001) and ISI (F(6, 125) = 13.43; pulation spike; see Fig. 1A for details). The stimulation and recording p < 0.001; Fig. 1H). electrodes followed the columnar arrangement of the mPFC. The

10 S.L. Cruz, et al. Neurotoxicology and Teratology 73 (2019) 9–14

Fig. 1. Input-output and paired-pulse inhibition curves of mPFC layer 5 prelimbic neurons. A) Schematic representation of mPFC layers and the position of the stimulation (stim) and recording (rec) electrodes. B) Stimulation of layer I/II evoked an orthodromic fEPSP sensitive to Kynurenic acid; blockade of the synaptic response uncovered the presynaptic fiber volley (FV, see arrowheads). Stimulation of layer VI evoked an antidromic population spike. The population spike was sensitive to TTX but not Kynurenic acid. C) Representative trace of paired-pulse inhibition and the effect of the blockade of GABAA receptors with picrotoxin. D) Input-output curve. The scatter plot was constructed by averaging five consecutive sweeps, applying current pulses (5 μA step increase). The experimental group

(8000 ppm; nslices/animals = 9/9) exhibited an increase in the fEPSP (red symbols) amplitude compared to control animals (empty symbols nslices/animals = 9/9). E)

Fiber volley vs. fEPSP response curve. The plot was constructed from slices in which a volley preceded the actual fEPSP. Compared to control (nslices/animals = 9/7), the experimental group (nslices/animals = 9/5) exhibited a larger fEPSP in response to a presynaptic volley. F) Representative traces in control and the experimental group showing composite FV-fEPSPs responses. G) Dendritic-evoked paired-pulse inhibition curve. No diﬀerence was found in the inhibition curve of control vs. the experimental group (nslices/animals = 9/9 for each condition) Right panel, representative traces for both conditions. H) Antidromic-evoked paired-pulse inhibition curve. Compared to control, slices from the experimental group exhibited reduced inhibition (nslices/animals = 9/9 for each condition) Right panel, representative population spikes at the time indicated by arrowheads. (For interpretation of the references to colour in this ﬁgure legend, the reader is referred to the web version of this article.)

3.2. Toluene alters the dopamine-mediated modulation of the glutamatergic eﬀect =18.7 ± 4.2% depression; F(2, 45) = 86.819; p < 0.001). transmission of the mPFC Next, we determined the contribution of DA receptors on the DA-

evoked biphasic response. DA was perfused in combination with the D2 After acquiring a stable baseline of fEPSPs, DA was bath perfused for receptor antagonist raclopride (5 μM) or the D1 receptor antagonist 10 min and then washout for 40 min. DA caused a biphasic effect on the SCH-23390 (3 μM). DA + raclopride blocked the initial depression glutamatergic response. An initial depression of the fEPSP slope, fol- caused by DA (fEPSP slope during DA + raclopride = 97 ± 07% of lowed by potentiation during washout (maximal DA-induced depres- baseline response; F(2, 25) = 49.567; p < 0.05), but did not alter late sion =22.9 ± 6.2%; F(2, 45) = 105.527; p < 0.001; late DA effect potentiation (fEPSP slope at 40 min washout = 137.7 ± 5.6%; F(2, =168.9 ± 16.1%. F(2, 45) = 105.527; p < 0.001). In contrast, the 25) = 49.567; p < 0.001, one-way ANOVA). Perfusion of DA + SCH- slices from the experimental group exhibited a sustained depression of 23390 did not interfere with the initial depression caused by DA (fEPSP the fEPSP slope during and after DA washout (initial DA effect slope = 33.7 ± 11.2% of depression; F(2, 25) = 18.282; p < 0.001, =35.3 ± 5.7% depression; F(2, 45) = 86.819; p < 0.001, late DA one-way ANOVA) but, similarly to toluene, suppressed the late DA-

11 S.L. Cruz, et al. Neurotoxicology and Teratology 73 (2019) 9–14

Fig. 2. Dopamine eﬀects on the glutamatergic-evoked response of the mPFC. A) Time course of normalized fEPSP slope, during and after a 10 min application of 100 μMDA (indicated by ﬁlled bar), as recorded in control (open cir-

cles, nslices/animals = 9/9) and experimental group (red cir-

cles, nslices/animals = 9/9). B) Bar graphs summarizing the individual eﬀect of DA per experiment (symbols) and the average response (bars) at the indicated points of the time- course graph. C) Representative traces (averaged from 5 sweeps) obtained at the indicated time. D) Average time- course graph of the normalized fEPSP slope, during and after a 10 min application of 100 μM DA in combination

with the D2 receptor antagonist raclopride (5 μM; gray tri-

angles, nslices/animals = 5/3), or the D1 receptor antagonist SCH-23390 (3 μM; open triangles, nslices/animals = 5/3). (For interpretation of the references to colour in this ﬁgure legend, the reader is referred to the web version of this article.)

evoked potentiation (fEPSP slope at 40 min washout = 98.8 ± 21.4% NR2B NMDA receptor subunits (Williams et al., 2005); an effect that of baseline response; F(2, 25) = 49.567; p < 0.05, Fig. 2D). has been associated with drug reinforcement and dependence (Liu et al., 2006). In line with this, we found a leftward shift of the I-O curve 3.3. Toluene reduces the NMDA-mediated synaptic depression of the mPFC in the experimental group, which indicates increased excitability of glutamatergic neurons. The increased excitatory response might be a A stable baseline was acquired for 20 min, followed by NMDA consequence of altered NMDA receptor subunit composition expressed perfusion (3-min) and washout. NMDA suppressed the fEPSP in control by prelimbic neurons in response to the repeated exposure to toluene or condition, and this depression lasted up to 70 min (NMDA-mediated altered levels of extracellular glutamate, as previous reports have also depression at 70 min washout = 45.09 ± 29.7%; t(40) = 2402.0; found that toluene alters glutamate levels following acute or chronic p < 0.001). By contrast, the fEPSP from the experimental group exposure (O'Leary-Moore et al., 2007; Perrine et al., 2011). showed reduced sensitivity to NMDA and returned to baseline level at On the other hand, the fiber volley vs. fEPSP relationship (Fig. 1E, F) the end of the recording (NMDA-mediated depression at 70 min was increased in the experimental group; indicating increased excit- fi washout = 6.5 ± 6.3%; t(40) = 1777.02; p = 0.132; Fig. 3A and B). ability of individual bers or larger synaptic responses converging on Representative traces of this experimental manipulation are shown in prelimbic neurons (see, for example, Villanueva-Castillo et al., 2017). Fig. 3C. The latter suggests that inputs from other brain regions converging onto mPFC also exhibit increased excitability after repeated toluene ex- 4. Discussion posure. In support of this idea, a report by Beckley et al. (2013) demonstrated that toluene exposure increases the glutamatergic strength Recently, we reported that repeated toluene exposure increases the of dopamine neurons projecting to the nucleus accumbens core and intrinsic excitability and the spontaneous glutamatergic activity of medial shell. mPFC neurons (Armenta-Resendiz et al., 2018). Here, we show that the Our paired-pulse curves showed a selective loss of inhibition. same exposure paradigm alters the strength of the synaptic transmis- Although no changes were detected in the PPI when layer 1/2 was sion, reduces the inhibitory transmission and impairs the synaptic stimulated, antidromic PPI (evoked in layer 6) was accompanied with plasticity of mPFC neurons. Our data are consistent with the idea that reduced inhibition in the experimental group. The loss of inhibition at NMDA receptor-mediated transmission of the adolescent brain exhibits the somatic, but not at the dendritic level, strongly suggests that in- altered functionality after a repeated solvent exposure paradigm that terneurons targeting somata, axons and apical dendrites of mPFC neu- mimics a binge pattern of intoxication (Bukowski, 2001). rons are more vulnerable to repeated toluene exposure than inter- Repeated exposure to toluene alters the expression of NR1 and neurons targeting apical or dendritic tufts of prelimbic neurons.

12 S.L. Cruz, et al. Neurotoxicology and Teratology 73 (2019) 9–14

Fig. 3. N-methyl D-aspartate effects on the glutamatergic transmission of the mPFC. A) Averaged time-course of control and experimental group (empty and red symbols, respectively; nslices/animals = 8/8 for control slices and 8/6 for the experimental group). Perfusion of NMDA (20 μM for 3 min) induced long-lasting depression of the fEPSP slope. In slices from the experimental group, NMDA caused a less pronounced depression of the fEPSP slope that returned to baseline levels. B) Graphs summarizing the individual effect (circles) of NMDA and the average response (bars) at the indicated time points. C) Representative traces (averaged from 5 sweeps) obtained at the indicated time. D) Graphical representation of the toluene effects on synaptic activity in the mPFC. The repeated exposure to toluene increases the excitatory activity impinging on mPFC prelimbic neurons at both dendritic and somatic level. This phenomenon is accompanied by a dysregulation of the dopaminergic modulation that alters the DA-modulated glutamatergic plasticity. Lastly, the repeated exposure to toluene reduces the inhibitory tone of the prefrontal cortex of adolescent rats, suggesting a dysregulation of subpopulations of cortical interneurons. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Consistently, other misused substances, including alcohol and cocaine, 5. Conclusions reduce the total number of parvalbumin-positive cells in the cortex (Moore et al., 1998; Morrow et al., 2003), a group of inhibitory cells Repeated toluene exposure alters the synaptic strength of mPFC. that release GABA and innervate the perisomatic region and axons of Such modifications alter the synaptic balance of prelimbic neurons and pyramidal neurons (Markram et al., 2004). It is reasonable to assume impair several forms of NMDA-receptor mediated plasticity in the that toluene affects the functionality of this specific subgroup of inter- adolescent rat brain. neurons. We are currently investigating this possibility. The role of DA in controlling the glutamatergic transmission on Transparency document mPFC neurons is well established. However, the effects of DA and selective activation of the different DA receptor in the mPFC are diverse The Transparency document associated with this article can be and often contradictory. Some authors reported that exogenous DA found, in online version. causes transient depression of the glutamatergic transmission that re- quires activation of D1-like or D2-like receptors (Law-Tho et al., 1994; Acknowledgments Otani et al., 1998). Other reports indicate that DA causes potentiation of the NMDA component and depression of the non-NMDA response, Funding was provided by CONACYT grants CB-239192 (SLC) and and both effects are ascribed to activation of D1-like receptors CB-2016-281617 (EJG). The present data are part of Maira I. Torres (Seamans, 2000). One possibility to explain the biphasic effect here Flores' MS dissertation thesis (fellowship-Conacyt 338374). The authors observed is that DA-induced an early synaptic depression overridden wish to thank Dr. Isabel Sollozo-Dupont and Melissa Hernandez-Frausto during washout, which allowed synaptic potentiation. Consistent with for additional experiments. this possibility, additional explorations performed in our study showed that D2 receptor activation is necessary for synaptic depression and D1 References receptor activation, for glutamatergic potentiation. Therefore, it is likely that DA caused early activation of D2 receptors that triggered Armenta-Resendiz, M., Cruz, S.L., Galvan, E.J., 2018. Repeated toluene exposure increases the excitability of layer 5 pyramidal neurons in the prefrontal cortex of synaptic depression followed by late activation of D1 receptors, re- adolescent rats. Neurotoxicol. Teratol. 68, 27–35. sponsible for the enhancement of the excitatory response. Bale, A.S., Tu, Y., Carpenter-Hyland, E.P., Chandler, L.J., Woodward, J.J., 2005. Lastly, it is well established that NMDA perfusion causes synaptic Alterations in glutamatergic and gabaergic ion channel activity in hippocampal depression (Lee et al., 1998) that correlates with dendritic spine head neurons following exposure to the abused inhalant toluene. Neuroscience 130, 197–206. shrinkage (He et al., 2011). The reduced depression observed in the Balster, R.L., Cruz, S.L., Howard, M.O., Dell, C.A., Cottler, L.B., 2009. Classification of experimental group suggests dysregulation of the intracellular me- abused inhalants. Addiction 104, 878–882. chanisms associated with the plasticity capabilities of dendritic spines. Beckley, J.T., Evins, C.E., Fedarovich, H., Gilstrap, M.J., Woodward, J.J., 2013. Medial Consistently, a previous report demonstrated a reduction in both den- prefrontal cortex inversely regulates toluene-induced changes in markers of synaptic plasticity of mesolimbic dopamine neurons. J. Neurosci. 33, 804–813. dritic branching and total neuronal size of cortical neurons repeatedly Beckstead, M.J., Weiner, J.L., Eger, E.I., Gong, D.H., Mihic, S.J., 2000. Glycine and exposed to toluene during the brain growth spurt (Pascual et al., 2010). gamma-aminobutyric acid(A) receptor function is enhanced by inhaled drugs of

13 S.L. Cruz, et al. Neurotoxicology and Teratology 73 (2019) 9–14

abuse. Mol. Pharmacol. 57, 1199–1205. in the adult rat cingulate cortex. Neurosci. Lett. 249, 25–28. Bowen, S.E., Batis, J.C., Paez-Martinez, N., Cruz, S.L., 2006. The last decade of solvent Morrow, B.A., Elsworth, J.D., Roth, R.H., 2003. Axo-axonic structures in the medial research in animal models of abuse: mechanistic and behavioral studies. prefrontal cortex of the rat: reduction by prenatal exposure to cocaine. J. Neurosci. Neurotoxicol. Teratol. 28, 636–647. 23, 5227–5234. Bukowski, J.A., 2001. Review of the epidemiological evidence relating toluene to re- Nelson, G.O., 1971. Controlled Test Atmospheres. Principles and Techniques. In: Ann productive outcomes. Regul. Toxicol. Pharmacol. 33, 147–156. Arbor Science Publishers. Cruz, S.L., Mirshahi, T., Thomas, B., Balster, R.L., Woodward, J.J., 1998. Effects of the NIH, 2011. Guide for the Care and Use of Laboratory Animals. In: 8th edition. abused solvent toluene on recombinant N-methyl-D-aspartate and non-N-methyl-D- O'Leary-Moore, S.K., Galloway, M.P., McMechan, A.P., Hannigan, J.H., Bowen, S.E., aspartate receptors expressed in Xenopus oocytes. J. Pharmacol. Exp. Ther. 286, 2007. Region-dependent alterations in glutamate and GABA measured by high-re- 334–340. solution magnetic resonance spectroscopy following acute binge inhalation of toluene Gerasimov, M.R., Schiffer, W.K., Marstellar, D., Ferrieri, R., Alexoff, D., Dewey, S.L., in juvenile rats. Neurotoxicol. Teratol. 29, 466–475. 2002. Toluene inhalation produces regionally specific changes in extracellular do- Otani, S., Blond, O., Desce, J.-M., Crépel, F., 1998. Dopamine facilitates long-term de- pamine. Drug Alcohol Depend. 65, 243–251. pression of glutamatergic transmission in rat prefrontal cortex. Neuroscience 85, He, K., Lee, A., Song, L., Kanold, P.O., Lee, H.-K., 2011. AMPA receptor subunit GluR1 669–676. (GluA1) serine-845 site is involved in synaptic depression but not in spine shrinkage Pascual, R., Aedo, L., Meneses, J.C., Vergara, D., Reyes, Á., Bustamante, C., 2010. Solvent associated with chemical long-term depression. J. Neurophysiol. 105, 1897–1907. inhalation (toluene and n-hexane) during the brain growth spurt impairs the ma- Huerta-Rivas, A., López-Rubalcava, C., Sánchez-Serrano, S.L., Valdez-Tapia, M., Lamas, turation of frontal, parietal and occipital cerebrocortical neurons in rats. Int. J. Dev. M., Cruz, S.L., 2012. Toluene impairs learning and memory, has antinociceptive ef- Neurosci. 28, 491–495. fects, and modifies histone acetylation in the dentate gyrus of adolescent and adult Perrine, S.A., O'Leary-Moore, S.K., Galloway, M.P., Hannigan, J.H., Bowen, S.E., 2011. rats. Pharmacol. Biochem. Behav. 102, 48–57. Binge toluene exposure alters glutamate, glutamine and GABA in the adolescent rat Law-Tho, D., Hirsch, J.C., Crepel, F., Law-tho, 1994. Dopamine modulation of synaptic brain as measured by proton magnetic resonance spectroscopy. Drug Alcohol transmission in rat prefrontal cortex: an in vitro electrophysiological study. Neurosci. Depend. 115, 101–106. Res. 21, 151–60. Seamans, J.K., 2000. Dopamine D1/D5 receptor modulation of excitatory synaptic inputs Lee, H.-K., Kameyama, K., Huganir, R.L., Bear, M.F., 1998. NMDA induces long-term to layer V prefrontal cortex neurons. Proc. Natl. Acad. Sci. 98, 301–306. synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors Villanueva-Castillo, C., Tecuatl, C., Herrera-López, G., Galván, E.J., 2017. Aging-related in hippocampus. Neuron 21, 1151–1162. impairments of hippocampal mossy fibers synapses on CA3 pyramidal cells. Liu, X.-Y., Chu, X.-P., Mao, L.-M., Wang, M., Lan, H.-X., Li, M.-H., Zhang, G.-C., Parelkar, Neurobiol. Aging 49, 119–137. N.K., Fibuch, E.E., Haines, M., Neve, K.A., Liu, F., Xiong, Z.-G., Wang, J.Q., 2006. Wayman, W.N., Woodward, J.J., 2018. Exposure to the abused inhalant toluene alters Modulation of D2R-NR2B interactions in response to cocaine. Neuron 52, 897–909. medial prefrontal cortex physiology. Neuropsychopharmacology 43, 912–924. Markram, H., Toledo-Rodriguez, M., Wang, Y., Gupta, A., Silberberg, G., Wu, C., 2004. Williams, J.M., Stafford, D., Steketee, J.D., 2005. Effects of repeated inhalation of toluene Interneurons of the neocortical inhibitory system. Nat. Rev. Neurosci. 5, 793–807. on ionotropic GABA a and glutamate receptor subunit levels in rat brain. Neurochem. Moore, D.B., Quintero, M. a, Ruygrok, A.C., Walker, D.W., Heaton, M.B., 1998. Prenatal Int. 46, 1–10. ethanol exposure reduces parvalbumin-immunoreactive GABAergic neuronal number