Ashdin PublishingJournal of Drug and Alcohol ResearchVol. 3 (2014), Article ID 235838, 8 pagesdoi:10.4303/jdar/235838

ASHDINpublishing

Review Article

Effects of the Abused Inhalant Toluene on the Mesolimbic DopamineSystem�

John J. Woodward1 and Jacob Beckley1,2

1Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA2Department of Neurology, University of California, San Francisco (UCSF), San Francisco, CA 94117, USAAddress correspondence to John J. Woodward, woodward@musc.edu

Received 10 December 2013; Revised 3 January 2014; Accepted 27 January 2014

Copyright © 2014 John J. Woodward and Jacob Beckley. This is an open access article distributed under the terms of the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract Toluene is a representative member of a class of inhaledsolvents that are voluntarily used by adolescents and adults for theireuphorigenic effects. Research into the mechanisms of action ofinhaled solvents has lagged behind that of other drugs of abuse despitemounting evidence that these compounds exert profound neurobehav-ioral and neurotoxicological effects. Results from studies carried outby the authors and others suggest that the neural effects of inhalantsarise from their interaction with a discrete set of ion channels thatregulate brain activity. Of particular interest is how these interactionsallow toluene and other solvents to engage portions of an addictionneurocircuitry that includes midbrain and cortical structures. In thisreview, we focus on the current state of knowledge regarding toluene’saction on midbrain dopamine neurons, a key brain region involved inthe initial assessment of natural and drug-induced rewards. Findingsfrom recent studies in the authors’ laboratory show that brief exposuresof adolescent rats to toluene vapor induce profound changes in markersof glutamatergic plasticity in ventral tegmental area (VTA) dopamine(DA) neurons. These changes are restricted to VTA DA neurons thatproject to limbic structures and are prevented by transient activationof the medial prefrontal cortex prior to toluene exposure. Together,these data provide the first evidence linking the voluntary inhalationof solvents to changes in reward-sensitive dopamine neurons.

Keywords synaptic plasticity; AMPA/NMDA ratio; solvents; addic-tion

1. Abused inhalants as drugs of abuse

The term, abused inhalant, is used to denote a volatilesolvent or gas that is voluntarily used to produce intoxicationand feelings of reward [2]. Many abused inhalants areindustrial solvents or volatile organic solvents and haveimportant uses in industry and commercial businessapplications. Their widespread use and legal status makesthem easily accessible to individuals seeking a cheapintoxicating substance. Abused inhalants are organized

�This article is a part of a Special Issue on “Advances in theNeurobiological Basis of Inhalant Abuse.” Preliminary versions of thepapers featuring this special issue were originally presented at the 4thMeeting of the International Drug Abuse Research Society (IDARS)held in Mexico City, April 15–19, 2013.

into three large classes based largely upon chemical andstructural similarity: (1) volatile alkyl nitrites such as amylnitrite, (2) anesthetic gas nitrous oxide, and (3) volatilesolvents, fuels, and anesthetics [1]. Volatile solvents andfuels in the last category represent the largest class ofabused inhalants and include compounds such as tolueneand similar alkylbenzenes, trichloroethane, butane, andpropane; and even gasoline that is a complex mixture ofvolatile hydrocarbons. Although anesthetic gases such asnitrous oxide and isoflurane are also used as drugs ofabuse, their use is more restricted due to licensing andregulatory standards designed to limit their availability. It isclear from this classification scheme that abused inhalantsrepresent a diverse set of chemical structures that share theability to induce actions that some individuals “like” or findrewarding. In this regard, abused inhalants are similar to themore classical drugs of abuse such as cocaine, heroin ormarijuana. However, in contrast to drugs of abuse that havehigh affinity for known protein targets (e.g., DAT, mu-opiatereceptor, and CB1 receptor), abused inhalants have beenthought of as relatively nonselective due to their relativelysimple nonpolar chemical structure. However, as reviewedbelow, results from a series of studies show that solventssuch as toluene have a surprising degree of molecular andbrain region selectivity.

2. Who uses abused inhalants?

The use and abuse of volatile solvents and gases iswidespread and ranges from young children to licensedand practicing physicians. The use of these compounds bychildren and adolescents are of particular concern to healthprofessionals and parents due to their effects on cognitionand brain maturation and their toxicity following acute orchronic use. National surveys of drug use reveal that upto 20% of adolescents and teenagers have used or triedinhalants at least once although the percent of regular users

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of inhalants is much lower. In addition, there is an age-dependence in the reported use of inhalants with individualsfrom 13 to 20 years old showing similar rates of use thatdrops markedly in persons older than 22–23 [16]. Thereason for this age-dependency of inhalant use is currentlyunknown and may involve economic and social reasonsas well as neurobiological factors that make inhalantsespecially rewarding in children and adolescents.

3. Adverse consequences of abused inhalants

Significant health concerns related to the use of inhalantsas drugs of abuse are many and include a sudden sniffingdeath that is associated with cardiac arrhythmia. Motorincoordination and other signs of intoxication followingacute solvent inhalation may also contribute to injury ordeath in motor vehicle accidents. Chronic use of abusedinhalants can lead to a variety of disorders includinghearing loss, peripheral neuropathies, kidney damage, andloss of white matter in various brain regions [9]. Theneurobehavioral consequences of chronic inhalant abuse areconsistent with actions on the central nervous system [5]and include dementia, loss of memory and significantimpairments in hippocampal-dependent maze learning [14]as well as deficits in PFC-dependent abilities such asexecutive function and working memory [22]. In addition,exposure to abused inhalants during the prenatal period canproduce changes in the developing fetus that, like thoseassociated with prenatal alcohol exposure, involve bothanatomical and cognitive changes [17,25].

Together, the serious health effects of abused inhalantscombined with their use among a highly vulnerableadolescent population underscores the significance ofdefining the actions of inhalants on brain function. However,despite their importance as drugs of abuse, it is clear thatfunding for research on abused inhalants is below that forother drugs. Figure 1 shows a graph comparing the 30-dayprevalence for use of various drugs among American 8th,10th, and 12th graders versus the number of investigator-initiated R01 grants per drug of abuse that are funded bythe U.S. National Institute on Drug Abuse (NIDA, collectedfrom http://projectreporter.nih.gov/). As of March 2013, thenumber of NIDA funded inhalants grants found in the NIHdatabase is 10, as determined by the presence of at least oneof five keywords in the title or abstract (inhalant, volatilesolvent, alkyl nitrite, or nitrous oxide). In contrast, the num-ber of NIH research grants involving cocaine, a drug with acomparable prevalence of use among adolescents, is 410.

4. Sites of action for toluene

The molecular and cellular targets for abused inhalantsincluding toluene are discussed in more detail in anotherpaper of this issue [8]. In summary, a wide variety ofvoltage-gated and ligand-gated ion channels are affected

Figure 1: Trends in drug prevalence and funding fromthe National Institute of Drug Abuse (NIDA). The graphdepicts a relationship between a 30-day prevalence of druguse by a class and the number of R01s currently fundedby NIDA for that drug class. Data for volatile solventsare indicated by a gold encircled triangle. Prevalencedata are from the work of Johnston et al. [16]. Fundingdata are obtained from NIH Project Reporter for fiscalyear 2013. Keywords are marijuana: marijuana, cannabis,THC, cannabidiol; inhalants: inhalant, volatile solvent, alkylnitrite, nitrous oxide; cocaine: cocaine, crack; amphetamine:amphetamine, Adderall; methamphetamine; heroin; tran-quilizers: benzodiazepine, Xanax, valium, klonopin, tran-quilizer; hallucinogen: hallucinogen, psilocybin, LSD, PCP,ketamine; MDMA: MDMA, ecstasy.

by toluene with both inhibition and potentiation beingreported. These actions are similar to those produced bysome volatile anesthetics and ethanol although in somecases, toluene’s effects appear to be more selective thanthese agents. In addition to these effects, toluene has actionson intracellular signaling pathways including those linkedto generation of retrograde signaling molecules such asendocannabinoids [4,24].

5. Mesolimbic dopamine neurons

Dopamine (DA) neurons are expressed in a variety of brainareas with two major nuclei being located in the substantianigra (SN; A9) and the ventral tegmental area (VTA; A10).DA neurons in the SN project massively to the dorsalstriatum and are most well known for their involvement insensorimotor function while VTA DA neurons project tolimbic and cortical structures. The dopaminergic projectionto the ventral striatum or nucleus accumbens (NAc) isparticularly important in signaling rewarding aspects ofenvironmental stimuli as well as to drugs of abuse. Aprevailing theory of drug use suggests that continued useof drugs of abuse may shift behavior from goal-directedresponses involving reward-sensitive mesolimbic circuitryto that characterized by stimulus-response or habitualresponding driven by nigrostriatal circuits.

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Electrophysiological studies reveal that most midbrainDA neurons display low tonic rates of firing (1–5 Hz)interspersed with bursts of firing (20–80 Hz) that areassociated with novel or rewarding stimuli [31]. Themechanisms that underlie the transition between tonicand burst modes of VTA DA neuron firing are still beingelucidated but involve activation of synaptic N-methyl-D-aspartate (NMDA) glutamate receptors and modulation ofpotassium channels including SK and KCNQ subtypes.Firing of VTA DA neurons is strongly suppressed viaactivation of D2 dopamine receptors and this feature isoften used to identify putative DA neurons during in vitroand in vivo recordings. However, there is now a convincingevidence that D2 modulation of firing is produced inonly a subpopulation of DA neurons and that the VTAexpresses an array of dopamine neurons with divergentelectrophysiological properties [29]. Classic DA neurons aredefined by a set of functional criteria including broad actionpotentials with prominent afterhyperpolarization (AHP),a low firing frequency, a large hyperpolarization-inducedinward current (IH ), and a strong D2-mediated inhibitionof firing [15]. Within the VTA, these classic DA neuronsoccupy a more lateral position and project to the lateral shellof the nucleus accumbens. VTA DA neurons that projectto the core or more medial aspects of the NAc and thosethat project to the PFC show smaller amplitude AHPs, lessregular firing patterns, and often no evidence of the inwardIH current. While electrophysiological criteria are bythemselves often insufficient to unequivocally identify VTADA neuron subtypes, combining recordings with retrogradelabeling can identify projection specific populations of DAneurons. Using these techniques, Lammel et al. revealed thatmesolimbic and mesocortical projecting VTA DA neuronsdisplay cell-type specific alterations in glutamatergicsignaling in response to drugs of abuse or stress [20].

6. Toluene and VTA DA neurons

Work by Riegel, French, and colleagues first established thattoluene could alter the firing rate of VTA DA neurons. Sin-gle unit recordings of classic DA neurons (see Section 5above) in ketamine anesthetized rats showed that toluene,administered via a tracheal breathing tube at a concentra-tion of 11,500 ppm, either enhanced or inhibited the firingof VTA DA neurons [27]. Each neuron showed either anincrease or a decrease with no evidence of a single neuronshowing both patterns of response. Recordings performed inmidbrain slices of rat brain also showed that toluene couldaffect cell firing with differences noted depending on thesubregion examined. For example, toluene enhanced the fir-ing rate of classic DA neurons within the VTA and alsoincreased firing of putative non-DA neurons [28]. Interest-ingly, in other midbrain areas, toluene inhibited the firing ofneurons in the interpeduncular nucleus but had no effect on

neurons in the retrorubral field. The increase in firing of DAneurons in the presence of toluene persisted when synap-tic transmission was inhibited suggesting that toluene mayact on intrinsic mechanisms that regulate firing. Data frompreliminary studies in the author’s laboratory suggest thattoluene may interact with ion channels on VTA DA neuronsthat regulate firing as toluene-induced increases in firing areblocked in the presence of quinine, a compound that blocksvarious gap junction and potassium channels [10,32].

As expected from results of the electrophysiologicalstudies, toluene exposure in animals leads to increasesin extracellular dopamine in areas such as striatum [33],nucleus accumbens [18,28], VTA [28], and prefrontalcortex [13,18]. In addition, toluene infused directly intothe posterior but not anterior VTA increased extracellulardopamine levels in the NAc [28]. The behavioral conse-quences of toluene exposure have also been investigatedand reveal that, in rodents, solvent inhalation enhanceslocomotor activity [19,26], produces a conditioned placepreference [11,21], and produces anxiolytic effects in theelevated plus maze [6].

7. Toluene effects on VTA DA neuron plasticity

As discussed above, VTA DA neurons are critical elementsof the brain’s reward circuitry and brief exposures totoluene alter DA neuron firing and release of DA in reward-associated areas. Results from previous studies show that asingle in vivo exposure to a drug of abuse such as cocaine orethanol induces a change in glutamatergic signaling of VTADA neurons [30,34]. This is reflected in an increase in theratio of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid (AMPA) to NMDA excitatory postsynaptic currents(EPSCs) that is thought to reflect an initiation of long-termpotentiation of synaptic glutamatergic transmission [23].Anecdotal evidence suggests that volatile solvents areabused for their intoxicating effects and as discussed above,toluene has been shown to directly enhance VTA DA neuronfiring. Despite these findings, prior to a recent publicationfrom the authors’ laboratory [3], no previous studies hadexamined whether in vivo exposure to toluene inducesa change in VTA DA neuron plasticity that is similar tothat produced by other drugs of abuse. A challenge inthese studies was the knowledge that there are differentsubpopulations of DA neurons in the VTA that havedifferent signaling properties and projection targets [20].In the standard acute slice preparation, it is not possibleto determine the efferent projection of the DA neuronbeing recorded from or to verify that the recorded neuronis in fact dopaminergic. To circumvent this limitation,we microinjected fluorescent retrobeads into selectiveprojection regions of VTA DA neurons. Once injected, thesebeads are taken up by presynaptic terminals in the targetarea and transported back to the cell body where they can be

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Figure 2: Identification of VTA neurons by immunohis-tochemistry. (a) Examples of tyrosine hydroxylase (TH)positive (left) and negative (right) VTA neurons. Redindicates the biocytin label in a recorded neuron and greenrepresents the presence of TH, while yellow indicatesboth. (b) Proportion of TH+ recorded neurons from eachretrobead-labeled region. Blue is TH positive; red is THnegative. Derived from the work of Beckley et al. [3].

visualized in living cells under epifluorescence microscopy.In our VTA studies, we microinjected retrobeads into eitherthe NAc core or shell or the medial prefrontal cortex (mPFC)of adolescent male rats. Each animal received an injection inonly one area in order to label a specific pathway. Based onthe injection site, these beads will label either mesolimbicor mesocortical DA neurons that are known to be involvedin different aspects of reward processing [29]. Animals werereturned to their home cage to allow for retrograde transportof beads and then animals were exposed to two brief(10 min each separated by 10 min of air) sessions of toluenevapor to mimic that experienced by human solvent abusers(high vapor concentration; short duration). At differenttimes following exposure (1 day to 3 weeks), animals weresacrificed and whole-cell patch-clamp electrophysiologywas used to determine the AMPA/NMDA ratio in bead-labeled DA neurons. Post-hoc immunohistochemistry withan antibody to tyrosine hydroxylase was used to confirmthat bead-labeled neurons were dopaminergic (Figure 2). Asshown in Figure 3, the brief exposure to toluene vaporinduced a highly significant two-fold increase in theAMPA/NMDA ratio of mesolimbic core and shell VTADA neurons when measured 24 h later [3]. This effect was

concentration-dependent as exposure to 5,700 ppm toluene(equivalent to that used by human solvent abusers) increasedthe AMPA/NMDA ratio while 2,850 ppm had no effect. Thealtered ratio in mesolimbic core neurons persisted for at least3 days after exposure and returned to baseline values within1 week (Figure 3(d)). Remarkably, the AMPA/NMDA ratioof mesolimbic shell neurons was still significantly enhanced3 weeks following the brief exposure to toluene vapor(Figure 3(e)). In contrast, exposure to 5,700 ppm toluenevapor had no effect on the AMPA/NMDA ratio of VTA DAneurons that project to the mPFC (Figure 4). These resultsdemonstrate that a brief exposure to toluene vapor induceshighly selective and long-lasting effects on VTA DA neuronexcitability and show that these compounds, like other drugsof abuse, impact dopaminergic neurons involved in reward.

To determine a mechanism for the change in theAMPA/NMDA ratio following toluene exposure, wemeasured spontaneous AMPA EPSCs in core-projectingVTA DA neurons in control and toluene exposed animals.These data revealed an increase in the amplitude but notfrequency of AMPA EPSCs suggesting that the enhancedAMPA/NMDA ratio was due to an increase in the postsy-naptic expression of AMPA receptors (Figure 5). This wasconfirmed by experiments showing that following tolueneexposure, the rectification index of electrically evokedAMPA EPSCs was significantly increased, consistent withan upregulation of calcium-permeable, GluA2 lackingAMPA receptors in VTA DA neurons following tolueneexposure (Figure 5, bottom panels).

In a final set of studies, we determined whether invivo manipulation of the mPFC could influence toluene’sability to induce changes in VTA DA neuron plasticity.To do this, we microinjected pharmacological modulatorsof GABA receptors into the mPFC of the rat just priorto vapor exposure and then examined changes in theAMPA/NMDA ratio of bead-labeled DA neurons 24 h later.In animals pretreated with the GABAA receptor blockerpicrotoxin that enhances mPFC neuronal firing, 5,700 ppmtoluene no longer increased the AMPA/NMDA ratio ofmesolimbic core VTA DA neurons (Figure 6(b)). In contrast,in animals injected with a cocktail of the GABAA/B receptoragonists muscimol/baclofen to reduce mPFC neuronalfiring, 2,850 ppm toluene, a concentration that had no effectin control animals, now produced a significant increasein the AMPA/NMDA ratio of mesolimbic DA neurons(Figure 6(c)). These results are the first to demonstrate thatthe PFC can modulate the response of VTA DA neuronsto a drug of abuse. They suggest that output from theprefrontal cortex critically determines whether abusedsolvents and likely other drugs of abuse will induce long-lasting changes in glutamatergic signaling in brain rewardareas such as the VTA. The mechanisms underlying thePFC modulation of VTA DA neuron excitability are not yet

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Figure 3: Toluene vapor enhances the AMPA/NMDA ratio of mesoaccumbens DA neurons. Top panels show the locationof retrobead injections in the NAc core (a) and shell (b) and examples of bead-labeled neurons in VTA. Values represent thedistance in mm from bregma. Middle panels show the effects of toluene on the AMPA/NMDA ratio of VTA DA neurons inthe NAc core (c), (d) and shell (e). Panels (f) and (g) show representative traces from control and toluene exposed animals.Calibration bar: 20 pA, 10 ms. Symbol (∗) indicates a significant difference (P < .05) in ratio between air- and toluene-exposed animals. Derived from the work of Beckley et al. [3].

known. Detailed tracing and electron microscopy studies byCarr and Sesack show that mPFC neurons make excitatorysynapses on mesocortical but not mesoaccumbens VTA DAneurons [7]. In addition, a recent study using a modifiedrabies virus to transynaptically label VTA DA neuroninputs showed that mesolimbic DA neurons receive fewif any direct connections from mPFC neurons while thosefrom orbitofrontal cortex and other areas are relativelyrobust [35]. Carr and Sesack also showed that medialprefrontal neurons make excitatory synapses onto local

interneurons in the VTA and those that project to the NAc.This arrangement would allow mPFC neurons to regulatemesolimbic DA neuron activity via activation of GABAneurons that inhibit VTA DA neurons and NAc mediumspiny neurons (MSNs). Such circuitry could explain howpharmacological manipulation of mPFC activity in thestudy of Beckley et al. [16] could bidirectionally alter theresponse of VTA DA neurons to toluene vapor exposure.Studies are currently underway in the author’s laboratory totest this hypothesis.

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Figure 4: Toluene vapor has no effect on AMPA/NMDA ratio in mesocortical DA neurons. (a) Location of retrobeadinjections into medial prefrontal cortex and an example of bead-labeled VTA DA neurons. Values represent the distance inmm from bregma. (b) The graph shows a lack of change in ratio between air- and toluene-exposed animals. (c) Representativetraces from PFC projecting VTA DA neurons. Calibration bar: 20 pA, 10 ms. Derived from the work of Beckley et al. [3].

Figure 5: Toluene exposure increases AMPA EPSC amplitude but not frequency and enhances AMPA current rectification.Top panels: (a) Averaged EPSCs from air-exposed (gray) and toluene-exposed (black) animals (calibration bar: 5 pA, 5 ms)and examples of spontaneous AMPA EPSCs (calibration bar: 25 pA, 500 ms). (b) Cumulative probably chart of AMPAEPSC amplitude (±SEM) from air- and toluene-exposed animals (5,750 ppm). Inset shows mean (±SEM) amplitude ofAMPA EPSCs from air- and toluene-exposed animals. (c) A cumulative probability chart of AMPA EPSC interevent interval(±SEM). Inset shows mean (±SEM) for air- and toluene-exposed animals. Symbol (∗∗∗) indicates a significant (P < .001;mixed ANOVA) amplitude x treatment interaction; symbol (∗) indicates a value significantly (P < .05; t-test) different fromcontrol. Bottom panels: (a) A current-voltage relationship for evoked AMPA EPSCs from air- and toluene-exposed animals.(b) Representative examples of AMPA EPSCs evoked from air (left) and toluene (right) exposed animals. Downward traceswere obtained at −70 mV and upward traces are at +40 mV. Note a blunted outward current amplitude in a toluene-treatedneuron. Calibration bar: 25 pA, 5 ms. (c) A summary of the effect of toluene vapor exposure on the rectification index ofevoked AMPA EPSCs. Symbol (∗∗∗) indicates a significant (P < .001; mixed ANOVA, Bonferroni multiple comparison test)difference in current at +40 mV between toluene-treated and air-treated animals; symbol (∗) indicates a value significantly(P < .05; t-test) different from control. Derived from the work of Beckley et al. [3].

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Figure 6: PFC output regulates the toluene’s effect on AMPA/NMDA ratio in mesoaccumbens core DA neurons. (a)Placement of microinjection cannula in the medial prefrontal cortex. Values represent the distance (mm) from bregma.(b) Intra-PFC injection of picrotoxin blocks the toluene-induced increase in AMPA/NMDA ratio in mesoaccumbens VTADA neurons. (c) Intra-PFC injection of muscimol/baclofen allows a previously inactive dose of toluene vapor to enhance theAMPA/NMDA ratio of mesoaccumbens VTA DA neurons. (∗∗) indicates a value significantly (P < .01; two-way ANOVA,Bonferroni post-hoc test) different from all other groups; (∗) indicates a value significantly (P < .05; two-way ANOVA,Bonferroni post-hoc test) different from all other groups. Derived from the work of Beckley et al. [3].

8. Summary and implications for treatment

The studies outlined above clearly indicate that toluenehas important actions on midbrain dopamine neurons andhigher cortical areas that regulate reward-based brain areas.Repeated use of toluene and other abused inhalants wouldbe expected to profoundly alter the reward circuitry and maypredispose individuals to further use of these compoundsas well as other abused substances. The use of inhalantsby children and adolescents is particularly troubling as apersistent use of these agents may lead to deficits in normalbrain development especially in the frontal cortical areasthat do not fully mature until young adulthood. Despite theseadverse consequences, treatment of individuals who abuseinhalants is not well developed and there are relatively fewreports of effective pharmacotherapies for inhalant abuse.A recent review of volatile solvent misuse and its treatmentdescribed the use of either lamotrigine, an anticonvulsant, oraripiprazole, a dopamine D2 partial agonist, to treat ongoinginhalant abuse. These compounds appeared to reduce thenumber of days of inhalant use by adolescents and preventedrelapse in an adult patient for the 6-month study period [12].Lamotrigine and aripiprazole have been used to treatother addictive disorders and may target dysfunctionalglutamatergic and dopaminergic signaling pathways inmesolimbic and mesolimbic-reward sensitive brain areas.Other agents may be used to treat the acute signs ofwithdrawal from inhalant use that resemble those associatedwith alcohol withdrawal. These compounds includeGABAergic agents including baclofen and benzodiazepinesthat reduce excitability and antiseizure medications thatmay target hyperactive glutamatergic signaling pathways.A difficulty in treating inhalant abuse is that it is often

accompanied by neuropsychiatric symptoms associated withmood and conduct disorders. Thus, successful diagnosis andtreatment of the underlying psychiatric disorder with well-established pharmacotherapies may alleviate the misuseof solvents. Finally, there are likely long-term effectsof inhalant abuse on cortical-based processes includingmemory, attention, and self-control that contribute tothe likelihood of relapse to solvent use. Treatment of thesedeficits by agents or approaches that enhance cognition (e.g.,Ampakines, nicotinic agonists, etc.) or improve cognitivecontrol over impulsive behaviors (cognitive behavioraltherapy; coping strategies) may be particularly beneficial inregaining control over inhalant use. In conclusion, as withmany other aspects of inhalant research, the treatment ofinhalant abuse lags behind that of other addictive substancesand more effort is needed to develop rationale and effectivetreatments of inhalant abuse.

Acknowledgments This work was supported by NIH Grants R01DA013951 (JJW) and F31 DA030891 (JTB).

References

[1] R. L. Balster, Neural basis of inhalant abuse, Drug AlcoholDepend, 51 (1998), 207–214.

[2] R. L. Balster, The pharmacology of inhalants, in Principles ofAddiction Medicine, R. K. Ries, D. A. Fiellin, S. A. Miller, andR. Saitz, eds., Lippincott Williams & Wilkins, Philadelphia, PA,4th ed., 2009, 241–250.

[3] J. T. Beckley, C. E. Evins, H. Fedarovich, M. J. Gilstrap, and J. J.Woodward, Medial prefrontal cortex inversely regulates toluene-induced changes in markers of synaptic plasticity of mesolimbicdopamine neurons, J Neurosci, 33 (2013), 804–813.

[4] J. T. Beckley and J. J. Woodward, The abused inhalant toluenedifferentially modulates excitatory and inhibitory synaptic trans-mission in deep-layer neurons of the medial prefrontal cortex,Neuropsychopharmacology, 36 (2011), 1531–1542.

8 Journal of Drug and Alcohol Research

[5] S. E. Bowen, J. C. Batis, N. Paez-Martınez, and S. L. Cruz,The last decade of solvent research in animal models of abuse:Mechanistic and behavioral studies, Neurotoxicol Teratol, 28(2006), 636–647.

[6] S. E. Bowen, J. L. Wiley, and R. L. Balster, The effects of abusedinhalants on mouse behavior in an elevated plus-maze, Eur JPharmacol, 312 (1996), 131–136.

[7] D. B. Carr and S. R. Sesack, Projections from the rat prefrontalcortex to the ventral tegmental area: target specificity in thesynaptic associations with mesoaccumbens and mesocorticalneurons, J Neurosci, 20 (2000), 3864–3873.

[8] S. L. Cruz, M. T. Rivera-Garcıa, and J. J. Woodward, Review oftoluene actions: clinical evidence, animal studies, and moleculartargets, J Drug Alcohol Res, 3 (2014), art235840.

[9] C. M. Filley, W. Halliday, and B. K. Kleinschmidt-DeMasters,The effects of toluene on the central nervous system, J Neu-ropathol Exp Neurol, 63 (2004), 1–12.

[10] J. E. Freedman and F. F. Weight, Quinine potently blocks singleK+ channels activated by dopamine D-2 receptors in rat corpusstriatum neurons, Eur J Pharmacol, 164 (1989), 341–346.

[11] M. Funada, M. Sato, Y. Makino, and K. Wada, Evaluation ofrewarding effect of toluene by the conditioned place preferenceprocedure in mice, Brain Res Protoc, 10 (2002), 47–54.

[12] E. L. Garland and M. O. Howard, Volatile substance misuse:clinical considerations, neuropsychopharmacology and potentialrole of pharmacotherapy in management, CNS Drugs, 26 (2012),927–935.

[13] M. R. Gerasimov, W. K. Schiffer, D. Marstellar, R. Ferrieri,D. Alexoff, and S. L. Dewey, Toluene inhalation producesregionally specific changes in extracellular dopamine, DrugAlcohol Depend, 65 (2002), 243–251.

[14] J. M. Gmaz, L. Yang, A. Ahrari, and B. E. McKay, Bingeinhalation of toluene vapor produces dissociable motor andcognitive dysfunction in water maze tasks, Behav Pharmacol, 23(2012), 669–677.

[15] A. A. Grace and B. S. Bunney, The control of firing patternin nigral dopamine neurons: single spike firing, J Neurosci, 4(1984), 2866–2876.

[16] L. D. Johnston, P. M. O’Malley, J. G. Bachman, and J. E. Schu-lenberg, Monitoring the Future—National results on adolescentdrug use: Overview of key findings, 2012. Institute for SocialResearch, The University of Michigan, Ann Arbor, MI, 2013.

[17] H. E. Jones and R. L. Balster, Inhalant abuse in pregnancy,Obstet Gynecol Clin North Am, 25 (1998), 153–167.

[18] Y. Koga, S. Higashi, H. Kawahara, and T. Ohsumi, Tolueneinhalation increases extracellular noradrenaline and dopaminein the medial prefrontal cortex and nucleus accumbens in freely-moving rats, J Kyushu Dent Soc, 61 (2007), 39–54.

[19] H. Kondo, J. Huang, G. Ichihara, M. Kamijima, I. Saito,E. Shibata, et al., Toluene induces behavioral activation withoutaffecting striatal dopamine metabolism in the rat: Behavioraland microdialysis studies, Pharmacol Biochem Behav, 51 (1995),97–101.

[20] S. Lammel, A. Hetzel, O. Hackel, I. Jones, B. Liss, and J. Roeper,Unique properties of mesoprefrontal neurons within a dualmesocorticolimbic dopamine system, Neuron, 57 (2008), 760–773.

[21] D. E. Lee, M. R. Gerasimov, W. K. Schiffer, and A. N.Gifford, Concentration-dependent conditioned place preferenceto inhaled toluene vapors in rats, Drug Alcohol Depend, 2006(85), 87–90.

[22] B. F. Lin, M. C. Ou, S. S. Chung, C. Y. Pang, and H. H.Chen, Adolescent toluene exposure produces enduring social andcognitive deficits in mice: an animal model of solvent-inducedpsychosis, World J Biol Psychiatry, 11 (2010), 792–802.

[23] C. Luscher and R. C. Malenka, Drug-evoked synaptic plasticityin addiction: from molecular changes to circuit remodeling,Neuron, 69 (2011), 650–663.

[24] M. MacIver, Abused inhalants enhance GABA-mediated synapticinhibition, Neuropsychopharmacology, 34 (2009), 2296–2304.

[25] M. Pascual, J. Boix, V. Felipo, and C. Guerri, Repeatedalcohol administration during adolescence causes changes inthe mesolimbic dopaminergic and glutamatergic systems andpromotes alcohol intake in the adult rat, J Neurochem, 108(2009), 920–931.

[26] A. C. Riegel and E. D. French, Acute toluene induces biphasicchanges in rat spontaneous locomotor activity which are blockedby remoxipride, Pharmacol Biochem Behav, 62 (1999), 399–402.

[27] A. C. Riegel and E. D. French, An electrophysiological analysisof rat ventral tegmental dopamine neuronal activity during acutetoluene exposure, Pharmacol Toxicol, 85 (1999), 37–43.

[28] A. C. Riegel, A. Zapata, T. S. Shippenberg, and E. D. French,The abused inhalant toluene increases dopamine release in thenucleus accumbens by directly stimulating ventral tegmental areaneurons, Neuropsychopharmacology, 32 (2007), 1558–1569.

[29] J. Roeper, Dissecting the diversity of midbrain dopamineneurons, Trends Neurosci, 36 (2013), 336–342.

[30] D. Saal, Y. Dong, A. Bonci, and R. C. Malenka, Drugs of abuseand stress trigger a common synaptic adaptation in dopamineneurons, Neuron, 37 (2003), 577–582.

[31] W. Schultz, Reward signaling by dopamine neurons, Neuroscien-tist, 7 (2001), 293–302.

[32] M. Srinivas, M. G. Hopperstad, and D. C. Spray, Quinine blocksspecific gap junction channel subtypes, Proc Natl Acad Sci U SA, 98 (2001), 10942–10947.

[33] K. Stengard, G. Hoglund, and U. Ungerstedt, Extracellulardopamine levels within the striatum increase during inhalationexposure to toluene: A microdialysis study in awake, freelymoving rats, Toxicol Lett, 71 (1994), 245–255.

[34] M. A. Ungless, J. L. Whistler, R. C. Malenka, and A. Bonci,Single cocaine exposure in vivo induces long-term potentiationin dopamine neurons, Nature, 411 (2001), 583–587.

[35] M. Watabe-Uchida, L. Zhu, S. K. Ogawa, A. Vamanrao, andN. Uchida, Whole-brain mapping of direct inputs to midbraindopamine neurons, Neuron, 74 (2012), 858–873.