Download Effects of the Abused Inhalant Toluene on the

Ashdin Publishing
Journal of Drug and Alcohol Research
Vol. 3 (2014), Article ID 235838, 8 pages
doi:10.4303/jdar/235838
ASHDIN
publishing
Review Article
Effects of the Abused Inhalant Toluene on the Mesolimbic Dopamine
System
John J. Woodward1 and Jacob Beckley1,2
1 Department
of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
of Neurology, University of California, San Francisco (UCSF), San Francisco, CA 94117, USA
Address correspondence to John J. Woodward, [email protected]
2 Department
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 Commons
Attribution 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 inhaled
solvents that are voluntarily used by adolescents and adults for their
euphorigenic effects. Research into the mechanisms of action of
inhaled solvents has lagged behind that of other drugs of abuse despite
mounting evidence that these compounds exert profound neurobehavioral and neurotoxicological effects. Results from studies carried out
by the authors and others suggest that the neural effects of inhalants
arise from their interaction with a discrete set of ion channels that
regulate brain activity. Of particular interest is how these interactions
allow toluene and other solvents to engage portions of an addiction
neurocircuitry that includes midbrain and cortical structures. In this
review, we focus on the current state of knowledge regarding toluene’s
action on midbrain dopamine neurons, a key brain region involved in
the initial assessment of natural and drug-induced rewards. Findings
from recent studies in the authors’ laboratory show that brief exposures
of adolescent rats to toluene vapor induce profound changes in markers
of glutamatergic plasticity in ventral tegmental area (VTA) dopamine
(DA) neurons. These changes are restricted to VTA DA neurons that
project to limbic structures and are prevented by transient activation
of the medial prefrontal cortex prior to toluene exposure. Together,
these data provide the first evidence linking the voluntary inhalation
of solvents to changes in reward-sensitive dopamine neurons.
Keywords synaptic plasticity; AMPA/NMDA ratio; solvents; addiction
1. Abused inhalants as drugs of abuse
The term, abused inhalant, is used to denote a volatile
solvent or gas that is voluntarily used to produce intoxication
and feelings of reward [2]. Many abused inhalants are
industrial solvents or volatile organic solvents and have
important uses in industry and commercial business
applications. Their widespread use and legal status makes
them easily accessible to individuals seeking a cheap
intoxicating substance. Abused inhalants are organized
This article is a part of a Special Issue on “Advances in the
Neurobiological Basis of Inhalant Abuse.” Preliminary versions of the
papers featuring this special issue were originally presented at the 4th
Meeting of the International Drug Abuse Research Society (IDARS)
held in Mexico City, April 15–19, 2013.
into three large classes based largely upon chemical and
structural similarity: (1) volatile alkyl nitrites such as amyl
nitrite, (2) anesthetic gas nitrous oxide, and (3) volatile
solvents, fuels, and anesthetics [1]. Volatile solvents and
fuels in the last category represent the largest class of
abused inhalants and include compounds such as toluene
and similar alkylbenzenes, trichloroethane, butane, and
propane; and even gasoline that is a complex mixture of
volatile hydrocarbons. Although anesthetic gases such as
nitrous oxide and isoflurane are also used as drugs of
abuse, their use is more restricted due to licensing and
regulatory standards designed to limit their availability. It is
clear from this classification scheme that abused inhalants
represent a diverse set of chemical structures that share the
ability to induce actions that some individuals “like” or find
rewarding. In this regard, abused inhalants are similar to the
more classical drugs of abuse such as cocaine, heroin or
marijuana. However, in contrast to drugs of abuse that have
high affinity for known protein targets (e.g., DAT, mu-opiate
receptor, and CB1 receptor), abused inhalants have been
thought of as relatively nonselective due to their relatively
simple nonpolar chemical structure. However, as reviewed
below, results from a series of studies show that solvents
such as toluene have a surprising degree of molecular and
brain region selectivity.
2. Who uses abused inhalants?
The use and abuse of volatile solvents and gases is
widespread and ranges from young children to licensed
and practicing physicians. The use of these compounds by
children and adolescents are of particular concern to health
professionals and parents due to their effects on cognition
and brain maturation and their toxicity following acute or
chronic use. National surveys of drug use reveal that up
to 20% of adolescents and teenagers have used or tried
inhalants at least once although the percent of regular users
2
Journal of Drug and Alcohol Research
of inhalants is much lower. In addition, there is an agedependence in the reported use of inhalants with individuals
from 13 to 20 years old showing similar rates of use that
drops markedly in persons older than 22–23 [16]. The
reason for this age-dependency of inhalant use is currently
unknown and may involve economic and social reasons
as well as neurobiological factors that make inhalants
especially rewarding in children and adolescents.
3. Adverse consequences of abused inhalants
Significant health concerns related to the use of inhalants
as drugs of abuse are many and include a sudden sniffing
death that is associated with cardiac arrhythmia. Motor
incoordination and other signs of intoxication following
acute solvent inhalation may also contribute to injury or
death in motor vehicle accidents. Chronic use of abused
inhalants can lead to a variety of disorders including
hearing loss, peripheral neuropathies, kidney damage, and
loss of white matter in various brain regions [9]. The
neurobehavioral consequences of chronic inhalant abuse are
consistent with actions on the central nervous system [5]
and include dementia, loss of memory and significant
impairments in hippocampal-dependent maze learning [14]
as well as deficits in PFC-dependent abilities such as
executive function and working memory [22]. In addition,
exposure to abused inhalants during the prenatal period can
produce changes in the developing fetus that, like those
associated with prenatal alcohol exposure, involve both
anatomical and cognitive changes [17, 25].
Together, the serious health effects of abused inhalants
combined with their use among a highly vulnerable
adolescent population underscores the significance of
defining the actions of inhalants on brain function. However,
despite their importance as drugs of abuse, it is clear that
funding for research on abused inhalants is below that for
other drugs. Figure 1 shows a graph comparing the 30-day
prevalence for use of various drugs among American 8th,
10th, and 12th graders versus the number of investigatorinitiated R01 grants per drug of abuse that are funded by
the U.S. National Institute on Drug Abuse (NIDA, collected
from http://projectreporter.nih.gov/). As of March 2013, the
number of NIDA funded inhalants grants found in the NIH
database is 10, as determined by the presence of at least one
of five keywords in the title or abstract (inhalant, volatile
solvent, alkyl nitrite, or nitrous oxide). In contrast, the number of NIH research grants involving cocaine, a drug with a
comparable prevalence of use among adolescents, is 410.
4. Sites of action for toluene
The molecular and cellular targets for abused inhalants
including toluene are discussed in more detail in another
paper of this issue [8]. In summary, a wide variety of
voltage-gated and ligand-gated ion channels are affected
Figure 1: Trends in drug prevalence and funding from
the National Institute of Drug Abuse (NIDA). The graph
depicts a relationship between a 30-day prevalence of drug
use by a class and the number of R01s currently funded
by NIDA for that drug class. Data for volatile solvents
are indicated by a gold encircled triangle. Prevalence
data are from the work of Johnston et al. [16]. Funding
data are obtained from NIH Project Reporter for fiscal
year 2013. Keywords are marijuana: marijuana, cannabis,
THC, cannabidiol; inhalants: inhalant, volatile solvent, alkyl
nitrite, nitrous oxide; cocaine: cocaine, crack; amphetamine:
amphetamine, Adderall; methamphetamine; heroin; tranquilizers: benzodiazepine, Xanax, valium, klonopin, tranquilizer; hallucinogen: hallucinogen, psilocybin, LSD, PCP,
ketamine; MDMA: MDMA, ecstasy.
by toluene with both inhibition and potentiation being
reported. These actions are similar to those produced by
some volatile anesthetics and ethanol although in some
cases, toluene’s effects appear to be more selective than
these agents. In addition to these effects, toluene has actions
on intracellular signaling pathways including those linked
to generation of retrograde signaling molecules such as
endocannabinoids [4, 24].
5. Mesolimbic dopamine neurons
Dopamine (DA) neurons are expressed in a variety of brain
areas with two major nuclei being located in the substantia
nigra (SN; A9) and the ventral tegmental area (VTA; A10).
DA neurons in the SN project massively to the dorsal
striatum and are most well known for their involvement in
sensorimotor function while VTA DA neurons project to
limbic and cortical structures. The dopaminergic projection
to the ventral striatum or nucleus accumbens (NAc) is
particularly important in signaling rewarding aspects of
environmental stimuli as well as to drugs of abuse. A
prevailing theory of drug use suggests that continued use
of drugs of abuse may shift behavior from goal-directed
responses involving reward-sensitive mesolimbic circuitry
to that characterized by stimulus-response or habitual
responding driven by nigrostriatal circuits.
Journal of the International Drug Abuse Research Society
Electrophysiological studies reveal that most midbrain
DA neurons display low tonic rates of firing (1–5 Hz)
interspersed with bursts of firing (20–80 Hz) that are
associated with novel or rewarding stimuli [31]. The
mechanisms that underlie the transition between tonic
and burst modes of VTA DA neuron firing are still being
elucidated but involve activation of synaptic N-methyl-Daspartate (NMDA) glutamate receptors and modulation of
potassium channels including SK and KCNQ subtypes.
Firing of VTA DA neurons is strongly suppressed via
activation of D2 dopamine receptors and this feature is
often used to identify putative DA neurons during in vitro
and in vivo recordings. However, there is now a convincing
evidence that D2 modulation of firing is produced in
only a subpopulation of DA neurons and that the VTA
expresses an array of dopamine neurons with divergent
electrophysiological properties [29]. Classic DA neurons are
defined by a set of functional criteria including broad action
potentials with prominent afterhyperpolarization (AHP),
a low firing frequency, a large hyperpolarization-induced
inward current (IH ), and a strong D2-mediated inhibition
of firing [15]. Within the VTA, these classic DA neurons
occupy a more lateral position and project to the lateral shell
of the nucleus accumbens. VTA DA neurons that project
to the core or more medial aspects of the NAc and those
that project to the PFC show smaller amplitude AHPs, less
regular firing patterns, and often no evidence of the inward
IH current. While electrophysiological criteria are by
themselves often insufficient to unequivocally identify VTA
DA neuron subtypes, combining recordings with retrograde
labeling can identify projection specific populations of DA
neurons. Using these techniques, Lammel et al. revealed that
mesolimbic and mesocortical projecting VTA DA neurons
display cell-type specific alterations in glutamatergic
signaling in response to drugs of abuse or stress [20].
6. Toluene and VTA DA neurons
Work by Riegel, French, and colleagues first established that
toluene could alter the firing rate of VTA DA neurons. Single unit recordings of classic DA neurons (see Section 5
above) in ketamine anesthetized rats showed that toluene,
administered via a tracheal breathing tube at a concentration of 11,500 ppm, either enhanced or inhibited the firing
of VTA DA neurons [27]. Each neuron showed either an
increase or a decrease with no evidence of a single neuron
showing both patterns of response. Recordings performed in
midbrain slices of rat brain also showed that toluene could
affect cell firing with differences noted depending on the
subregion examined. For example, toluene enhanced the firing rate of classic DA neurons within the VTA and also
increased firing of putative non-DA neurons [28]. Interestingly, in other midbrain areas, toluene inhibited the firing of
neurons in the interpeduncular nucleus but had no effect on
3
neurons in the retrorubral field. The increase in firing of DA
neurons in the presence of toluene persisted when synaptic transmission was inhibited suggesting that toluene may
act on intrinsic mechanisms that regulate firing. Data from
preliminary studies in the author’s laboratory suggest that
toluene may interact with ion channels on VTA DA neurons
that regulate firing as toluene-induced increases in firing are
blocked in the presence of quinine, a compound that blocks
various gap junction and potassium channels [10, 32].
As expected from results of the electrophysiological
studies, toluene exposure in animals leads to increases
in extracellular dopamine in areas such as striatum [33],
nucleus accumbens [18, 28], VTA [28], and prefrontal
cortex [13, 18]. In addition, toluene infused directly into
the posterior but not anterior VTA increased extracellular
dopamine levels in the NAc [28]. The behavioral consequences of toluene exposure have also been investigated
and reveal that, in rodents, solvent inhalation enhances
locomotor activity [19, 26], produces a conditioned place
preference [11, 21], and produces anxiolytic effects in the
elevated plus maze [6].
7. Toluene effects on VTA DA neuron plasticity
As discussed above, VTA DA neurons are critical elements
of the brain’s reward circuitry and brief exposures to
toluene alter DA neuron firing and release of DA in rewardassociated areas. Results from previous studies show that a
single in vivo exposure to a drug of abuse such as cocaine or
ethanol induces a change in glutamatergic signaling of VTA
DA neurons [30, 34]. This is reflected in an increase in the
ratio of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) to NMDA excitatory postsynaptic currents
(EPSCs) that is thought to reflect an initiation of long-term
potentiation of synaptic glutamatergic transmission [23].
Anecdotal evidence suggests that volatile solvents are
abused for their intoxicating effects and as discussed above,
toluene has been shown to directly enhance VTA DA neuron
firing. Despite these findings, prior to a recent publication
from the authors’ laboratory [3], no previous studies had
examined whether in vivo exposure to toluene induces
a change in VTA DA neuron plasticity that is similar to
that produced by other drugs of abuse. A challenge in
these studies was the knowledge that there are different
subpopulations of DA neurons in the VTA that have
different signaling properties and projection targets [20].
In the standard acute slice preparation, it is not possible
to determine the efferent projection of the DA neuron
being recorded from or to verify that the recorded neuron
is in fact dopaminergic. To circumvent this limitation,
we microinjected fluorescent retrobeads into selective
projection regions of VTA DA neurons. Once injected, these
beads are taken up by presynaptic terminals in the target
area and transported back to the cell body where they can be
4
Journal of Drug and Alcohol Research
concentration-dependent as exposure to 5,700 ppm toluene
(equivalent to that used by human solvent abusers) increased
the AMPA/NMDA ratio while 2,850 ppm had no effect. The
altered ratio in mesolimbic core neurons persisted for at least
3 days after exposure and returned to baseline values within
1 week (Figure 3(d)). Remarkably, the AMPA/NMDA ratio
of mesolimbic shell neurons was still significantly enhanced
3 weeks following the brief exposure to toluene vapor
(Figure 3(e)). In contrast, exposure to 5,700 ppm toluene
vapor had no effect on the AMPA/NMDA ratio of VTA DA
neurons that project to the mPFC (Figure 4). These results
demonstrate that a brief exposure to toluene vapor induces
highly selective and long-lasting effects on VTA DA neuron
excitability and show that these compounds, like other drugs
of abuse, impact dopaminergic neurons involved in reward.
Figure 2: Identification of VTA neurons by immunohistochemistry. (a) Examples of tyrosine hydroxylase (TH)
positive (left) and negative (right) VTA neurons. Red
indicates the biocytin label in a recorded neuron and green
represents the presence of TH, while yellow indicates
both. (b) Proportion of TH+ recorded neurons from each
retrobead-labeled region. Blue is TH positive; red is TH
negative. Derived from the work of Beckley et al. [3].
To determine a mechanism for the change in the
AMPA/NMDA ratio following toluene exposure, we
measured spontaneous AMPA EPSCs in core-projecting
VTA DA neurons in control and toluene exposed animals.
These data revealed an increase in the amplitude but not
frequency of AMPA EPSCs suggesting that the enhanced
AMPA/NMDA ratio was due to an increase in the postsynaptic expression of AMPA receptors (Figure 5). This was
confirmed by experiments showing that following toluene
exposure, the rectification index of electrically evoked
AMPA EPSCs was significantly increased, consistent with
an upregulation of calcium-permeable, GluA2 lacking
AMPA receptors in VTA DA neurons following toluene
exposure (Figure 5, bottom panels).
visualized in living cells under epifluorescence microscopy.
In our VTA studies, we microinjected retrobeads into either
the NAc core or shell or the medial prefrontal cortex (mPFC)
of adolescent male rats. Each animal received an injection in
only one area in order to label a specific pathway. Based on
the injection site, these beads will label either mesolimbic
or mesocortical DA neurons that are known to be involved
in different aspects of reward processing [29]. Animals were
returned to their home cage to allow for retrograde transport
of beads and then animals were exposed to two brief
(10 min each separated by 10 min of air) sessions of toluene
vapor to mimic that experienced by human solvent abusers
(high vapor concentration; short duration). At different
times following exposure (1 day to 3 weeks), animals were
sacrificed and whole-cell patch-clamp electrophysiology
was used to determine the AMPA/NMDA ratio in beadlabeled DA neurons. Post-hoc immunohistochemistry with
an antibody to tyrosine hydroxylase was used to confirm
that bead-labeled neurons were dopaminergic (Figure 2). As
shown in Figure 3, the brief exposure to toluene vapor
induced a highly significant two-fold increase in the
AMPA/NMDA ratio of mesolimbic core and shell VTA
DA neurons when measured 24 h later [3]. This effect was
In a final set of studies, we determined whether in
vivo manipulation of the mPFC could influence toluene’s
ability to induce changes in VTA DA neuron plasticity.
To do this, we microinjected pharmacological modulators
of GABA receptors into the mPFC of the rat just prior
to vapor exposure and then examined changes in the
AMPA/NMDA ratio of bead-labeled DA neurons 24 h later.
In animals pretreated with the GABAA receptor blocker
picrotoxin that enhances mPFC neuronal firing, 5,700 ppm
toluene no longer increased the AMPA/NMDA ratio of
mesolimbic core VTA DA neurons (Figure 6(b)). In contrast,
in animals injected with a cocktail of the GABAA/B receptor
agonists muscimol/baclofen to reduce mPFC neuronal
firing, 2,850 ppm toluene, a concentration that had no effect
in control animals, now produced a significant increase
in the AMPA/NMDA ratio of mesolimbic DA neurons
(Figure 6(c)). These results are the first to demonstrate that
the PFC can modulate the response of VTA DA neurons
to a drug of abuse. They suggest that output from the
prefrontal cortex critically determines whether abused
solvents and likely other drugs of abuse will induce longlasting changes in glutamatergic signaling in brain reward
areas such as the VTA. The mechanisms underlying the
PFC modulation of VTA DA neuron excitability are not yet
Journal of the International Drug Abuse Research Society
5
Figure 3: Toluene vapor enhances the AMPA/NMDA ratio of mesoaccumbens DA neurons. Top panels show the location
of retrobead injections in the NAc core (a) and shell (b) and examples of bead-labeled neurons in VTA. Values represent the
distance in mm from bregma. Middle panels show the effects of toluene on the AMPA/NMDA ratio of VTA DA neurons in
the 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 tolueneexposed animals. Derived from the work of Beckley et al. [3].
known. Detailed tracing and electron microscopy studies by
Carr and Sesack show that mPFC neurons make excitatory
synapses on mesocortical but not mesoaccumbens VTA DA
neurons [7]. In addition, a recent study using a modified
rabies virus to transynaptically label VTA DA neuron
inputs showed that mesolimbic DA neurons receive few
if any direct connections from mPFC neurons while those
from orbitofrontal cortex and other areas are relatively
robust [35]. Carr and Sesack also showed that medial
prefrontal neurons make excitatory synapses onto local
interneurons in the VTA and those that project to the NAc.
This arrangement would allow mPFC neurons to regulate
mesolimbic DA neuron activity via activation of GABA
neurons that inhibit VTA DA neurons and NAc medium
spiny neurons (MSNs). Such circuitry could explain how
pharmacological manipulation of mPFC activity in the
study of Beckley et al. [16] could bidirectionally alter the
response of VTA DA neurons to toluene vapor exposure.
Studies are currently underway in the author’s laboratory to
test this hypothesis.
6
Journal of Drug and Alcohol Research
Figure 4: Toluene vapor has no effect on AMPA/NMDA ratio in mesocortical DA neurons. (a) Location of retrobead
injections into medial prefrontal cortex and an example of bead-labeled VTA DA neurons. Values represent the distance in
mm from bregma. (b) The graph shows a lack of change in ratio between air- and toluene-exposed animals. (c) Representative
traces 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 AMPA
EPSC amplitude (±SEM) from air- and toluene-exposed animals (5,750 ppm). Inset shows mean (±SEM) amplitude of
AMPA 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 from
control. 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 traces
were obtained at −70 mV and upward traces are at +40 mV. Note a blunted outward current amplitude in a toluene-treated
neuron. Calibration bar: 25 pA, 5 ms. (c) A summary of the effect of toluene vapor exposure on the rectification index of
evoked 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].
Journal of the International Drug Abuse Research Society
7
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 VTA
DA neurons. (c) Intra-PFC injection of muscimol/baclofen allows a previously inactive dose of toluene vapor to enhance the
AMPA/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 toluene
has important actions on midbrain dopamine neurons and
higher cortical areas that regulate reward-based brain areas.
Repeated use of toluene and other abused inhalants would
be expected to profoundly alter the reward circuitry and may
predispose individuals to further use of these compounds
as well as other abused substances. The use of inhalants
by children and adolescents is particularly troubling as a
persistent use of these agents may lead to deficits in normal
brain development especially in the frontal cortical areas
that do not fully mature until young adulthood. Despite these
adverse consequences, treatment of individuals who abuse
inhalants is not well developed and there are relatively few
reports of effective pharmacotherapies for inhalant abuse.
A recent review of volatile solvent misuse and its treatment
described the use of either lamotrigine, an anticonvulsant, or
aripiprazole, a dopamine D2 partial agonist, to treat ongoing
inhalant abuse. These compounds appeared to reduce the
number of days of inhalant use by adolescents and prevented
relapse in an adult patient for the 6-month study period [12].
Lamotrigine and aripiprazole have been used to treat
other addictive disorders and may target dysfunctional
glutamatergic and dopaminergic signaling pathways in
mesolimbic and mesolimbic-reward sensitive brain areas.
Other agents may be used to treat the acute signs of
withdrawal from inhalant use that resemble those associated
with alcohol withdrawal. These compounds include
GABAergic agents including baclofen and benzodiazepines
that reduce excitability and antiseizure medications that
may target hyperactive glutamatergic signaling pathways.
A difficulty in treating inhalant abuse is that it is often
accompanied by neuropsychiatric symptoms associated with
mood and conduct disorders. Thus, successful diagnosis and
treatment of the underlying psychiatric disorder with wellestablished pharmacotherapies may alleviate the misuse
of solvents. Finally, there are likely long-term effects
of inhalant abuse on cortical-based processes including
memory, attention, and self-control that contribute to
the likelihood of relapse to solvent use. Treatment of these
deficits by agents or approaches that enhance cognition (e.g.,
Ampakines, nicotinic agonists, etc.) or improve cognitive
control over impulsive behaviors (cognitive behavioral
therapy; coping strategies) may be particularly beneficial in
regaining control over inhalant use. In conclusion, as with
many other aspects of inhalant research, the treatment of
inhalant abuse lags behind that of other addictive substances
and more effort is needed to develop rationale and effective
treatments of inhalant abuse.
Acknowledgments This work was supported by NIH Grants R01
DA013951 (JJW) and F31 DA030891 (JTB).
References
[1] R. L. Balster, Neural basis of inhalant abuse, Drug Alcohol
Depend, 51 (1998), 207–214.
[2] R. L. Balster, The pharmacology of inhalants, in Principles of
Addiction Medicine, R. K. Ries, D. A. Fiellin, S. A. Miller, and
R. 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 tolueneinduced changes in markers of synaptic plasticity of mesolimbic
dopamine neurons, J Neurosci, 33 (2013), 804–813.
[4] J. T. Beckley and J. J. Woodward, The abused inhalant toluene
differentially modulates excitatory and inhibitory synaptic transmission in deep-layer neurons of the medial prefrontal cortex,
Neuropsychopharmacology, 36 (2011), 1531–1542.
8
[5] S. E. Bowen, J. C. Batis, N. Páez-Martı́nez, 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 abused
inhalants on mouse behavior in an elevated plus-maze, Eur J
Pharmacol, 312 (1996), 131–136.
[7] D. B. Carr and S. R. Sesack, Projections from the rat prefrontal
cortex to the ventral tegmental area: target specificity in the
synaptic associations with mesoaccumbens and mesocortical
neurons, J Neurosci, 20 (2000), 3864–3873.
[8] S. L. Cruz, M. T. Rivera-Garcı́a, and J. J. Woodward, Review of
toluene actions: clinical evidence, animal studies, and molecular
targets, 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 Neuropathol Exp Neurol, 63 (2004), 1–12.
[10] J. E. Freedman and F. F. Weight, Quinine potently blocks single
K+ channels activated by dopamine D-2 receptors in rat corpus
striatum neurons, Eur J Pharmacol, 164 (1989), 341–346.
[11] M. Funada, M. Sato, Y. Makino, and K. Wada, Evaluation of
rewarding effect of toluene by the conditioned place preference
procedure in mice, Brain Res Protoc, 10 (2002), 47–54.
[12] E. L. Garland and M. O. Howard, Volatile substance misuse:
clinical considerations, neuropsychopharmacology and potential
role 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 produces
regionally specific changes in extracellular dopamine, Drug
Alcohol Depend, 65 (2002), 243–251.
[14] J. M. Gmaz, L. Yang, A. Ahrari, and B. E. McKay, Binge
inhalation of toluene vapor produces dissociable motor and
cognitive dysfunction in water maze tasks, Behav Pharmacol, 23
(2012), 669–677.
[15] A. A. Grace and B. S. Bunney, The control of firing pattern
in 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. Schulenberg, Monitoring the Future—National results on adolescent
drug use: Overview of key findings, 2012. Institute for Social
Research, 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, Toluene
inhalation increases extracellular noradrenaline and dopamine
in the medial prefrontal cortex and nucleus accumbens in freelymoving 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 without
affecting striatal dopamine metabolism in the rat: Behavioral
and microdialysis studies, Pharmacol Biochem Behav, 51 (1995),
97–101.
[20] S. Lammel, A. Hetzel, O. Häckel, I. Jones, B. Liss, and J. Roeper,
Unique properties of mesoprefrontal neurons within a dual
mesocorticolimbic 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 preference
to 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 and
cognitive deficits in mice: an animal model of solvent-induced
psychosis, World J Biol Psychiatry, 11 (2010), 792–802.
Journal of Drug and Alcohol Research
[23] C. Luscher and R. C. Malenka, Drug-evoked synaptic plasticity
in addiction: from molecular changes to circuit remodeling,
Neuron, 69 (2011), 650–663.
[24] M. MacIver, Abused inhalants enhance GABA-mediated synaptic
inhibition, Neuropsychopharmacology, 34 (2009), 2296–2304.
[25] M. Pascual, J. Boix, V. Felipo, and C. Guerri, Repeated
alcohol administration during adolescence causes changes in
the mesolimbic dopaminergic and glutamatergic systems and
promotes alcohol intake in the adult rat, J Neurochem, 108
(2009), 920–931.
[26] A. C. Riegel and E. D. French, Acute toluene induces biphasic
changes in rat spontaneous locomotor activity which are blocked
by remoxipride, Pharmacol Biochem Behav, 62 (1999), 399–402.
[27] A. C. Riegel and E. D. French, An electrophysiological analysis
of rat ventral tegmental dopamine neuronal activity during acute
toluene 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 the
nucleus accumbens by directly stimulating ventral tegmental area
neurons, Neuropsychopharmacology, 32 (2007), 1558–1569.
[29] J. Roeper, Dissecting the diversity of midbrain dopamine
neurons, Trends Neurosci, 36 (2013), 336–342.
[30] D. Saal, Y. Dong, A. Bonci, and R. C. Malenka, Drugs of abuse
and stress trigger a common synaptic adaptation in dopamine
neurons, Neuron, 37 (2003), 577–582.
[31] W. Schultz, Reward signaling by dopamine neurons, Neuroscientist, 7 (2001), 293–302.
[32] M. Srinivas, M. G. Hopperstad, and D. C. Spray, Quinine blocks
specific gap junction channel subtypes, Proc Natl Acad Sci U S
A, 98 (2001), 10942–10947.
[33] K. Stengård, G. Höglund, and U. Ungerstedt, Extracellular
dopamine levels within the striatum increase during inhalation
exposure to toluene: A microdialysis study in awake, freely
moving 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 potentiation
in dopamine neurons, Nature, 411 (2001), 583–587.
[35] M. Watabe-Uchida, L. Zhu, S. K. Ogawa, A. Vamanrao, and
N. Uchida, Whole-brain mapping of direct inputs to midbrain
dopamine neurons, Neuron, 74 (2012), 858–873.