Neuron

Review

Role of Dopamine Neurons in Reward and Aversion:

A Synaptic Plasticity Perspective
Marco Pignatelli1 and Antonello Bonci1,2,3,*
1Intramural Research Program, Synaptic Plasticity Section, National Institute on Drug Abuse, Baltimore, MD 21224, USA
2Solomon H. Snyder Neuroscience Institute
3Department of Psychiatry

Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

*Correspondence: antonello.bonci@nih.gov
http://dx.doi.org/10.1016/j.neuron.2015.04.015

The brain is wired to predict future outcomes. Experience-dependent plasticity at excitatory synapses within
dopamine neurons of the ventral tegmental area, a key region for a broad range of motivated behaviors, is
thought to be a fundamental cellular mechanism that enables adaptation to a dynamic environment. Thus,
depending on the circumstances, dopamine neurons are capable of processing both positive and negative
reinforcement learning strategies. In this review, we will discuss how changes in synaptic plasticity of dopa-
mine neurons may affect dopamine release, as well as behavioral adaptations to different environmental con-
ditions falling at opposite ends of a saliency spectrum ranging from reward to aversion.

The ventral tegmental area (VTA) is a heterogeneous midbrain
structure that plays a major role in regulating different adaptive
brain functions related to reward and motivation processing.
It is predominantly composed of dopaminergic neurons (55%–
65%), while the rest are mainly GABAergic (30%) and a small
portion are glutamatergic cells (5%) (Hnasko et al., 2012; Stef-
fensen et al., 1998). Here, we will focus on the main neuronal
population of the VTA: dopamine neurons.
Dopamine (DA) release from the VTA efferent projections takes
place in a broad range of structures such as prefrontal cortex
(PFC), nucleus accumbens (NAc), amygdala, and hippocampus
(Barrot, 2014).
One key feature of this dopaminergic pathway, known as the
meso-cortico-limbic circuit, is its ability to reinforce natural
rewarding behavior and attribute motivational salience to other-
wise neutral environmental stimuli (Berridge and Robinson,
1998; Smith et al., 2011). Here, we propose that two forms of
synaptic plasticity, known as long-term potentiation (LTP) and
long-term depression (LTD), occurring onto DA neurons, repre-
sent a key fundamental mechanism capable of affecting reward
and aversion processes, as well as changes in motivational
salience accomplished via effects on VTA DA release exerted
in the target areas.
LTP and LTD are widely recognized as cellular substrates
for learning and memory in the brain (Anggono and Huganir,
2012; Bliss and Collingridge, 1993; Collingridge et al., 2010).
Since the discovery of synaptic plasticity, these forms of
cellular memory have been the subject of intensive investi-
gation in several brain regions that support cognitive pro-
cesses, such as hippocampus and cortex. The functional
significance of synaptic plasticity in the aforementioned struc-
tures has been extensively characterized (Bliss et al., 2014).
In contrast, the cellular events underlying synaptic plasticity
in DA neurons of the VTA, and the role of LTP and
LTD in shaping DA-dependent behaviors, are still poorly
understood.
In this review, we will focus on the significance of LTP and LTD
within DA neurons of the VTA, with respect to neural processing
and coding of both rewarding and aversive stimuli. First, we will
provide an overview of the role of DA in learning and memory
processes that occur when organisms adapt their behavior on
the basis of associations with reward and aversion. Next, we
will present recent findings that shed light on the circuit connec-
tivity and functional heterogeneity of the VTA, highlighting the
complexity and the diversity of a myriad of cellular regulators
of reward and aversion. Finally, we will review the general rules
governing synaptic plasticity of VTA DA neurons and the poten-
tial impact of a defined synaptic state in terms of DA release, or
co-release capability and behavioral flexibility.
Encoding and Modulation of Appetitive and Aversive
Learning in VTA Dopamine Neurons
Dopamine and Goal-Directed Behaviors
DA is implicated in the execution of goal-directed behaviors
and in the regulation of reward-related vigor (Beierholm et al.,
2013; Ranaldi, 2014). These concepts have emerged mostly
from behavioral studies showing that DA antagonists are
capable of attenuating motivation to perform an action, even
before motor responses occur (Wise, 2004). Interestingly, condi-
tioned learning precedes and guides the performance of an
instrumental act, as well as being DA-dependent (Darvas et al.,
2014). In particular, fundamental goal-directed behaviors such
as seeking food or water are not innate, but learned (Changizi
et al., 2002). It is widely believed that stimuli provided by the sur-
rounding environment can be selectively reinforced and thus
guide the proper execution of directed and motivated behavior,
even for a naive organism (Hall and Mayer, 1975; Johanson and
Hall, 1979). Once stimulus-reward associations are formed, they
can last long after the appropriate motivational drive states are
present (Balleine and Dickinson, 1992; Mendelson, 1966; Mor-
gan, 1974). Nevertheless, behavioral effects to conditioned re-
sponses are flexible and subject to extinction if paired with

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unrewarded trials (Wise et al., 1978) or if the experimental setting
occurs without a supportive drive state (Mendelson, 1966;
Morgan, 1974). In general terms, consumption of reward (food,
mating, and drugs of abuse) produces a hedonic state that is
thought to initiate learning processes devoted to consolidate
specific goals or cues that predict availability of a reward or
actions that permit its consumption (Wise and Kiyatkin, 2011).
The overall concept is to promote a motivational state to allow
an organism to purposely select the best way to achieve the
successful procurement of its essential needs. Based on this
assumption, the brain seems to store and estimate the value of
certain actions based on prior experience. In other words, an
animal uses stored values to predict and plan actions, based
on past events that involved a wide range of variables, including
reward and aversion (Montague et al., 2004).
Dopamine Neuron Activity and Prediction Error
The brain is wired to predict future outcomes. This fundamental
extraordinary feature occurs in response to a myriad of discrete
stimuli or situations, and it is mainly based on prior experience
and specific patterns of response. However, when the outcome
differs from what is expected, a ‘‘prediction error’’ occurs. Such
prediction error, mainly supported by dopaminergic activity, is
generally used by the brain to refine and optimize its future re-
sponses, as well as learn new behavioral strategies for all needs
that are essential to ensure survival (Cohen et al., 2012; Holler-
man and Schultz, 1998; Schultz, 2006; Schultz et al., 1993,
1997, 1998).
The neural language of DA neurons at resting condition ex-
hibits a consistent tonic pattern of firing. On top of this tonic ac-
tivity, a brief phasic burst of spike activity can appear and be
superimposed based on prior history of reward experience. De-
pending on the circumstances, these neurons are capable of
coding three different functional states: a reward that is ‘‘as
expected,’’ ‘‘better than expected,’’ or ‘‘worse than expected.’’
Reward falling in the category of ‘‘as expected’’ produce tonic
activity, reward that are ‘‘better than expected’’ result in phasic
bursts signal, and a pause in firing parallels reward that are
‘‘worse than expected.’’ Interestingly, a burst of action potentials
is capable of releasing more DA in specific projection areas
than the same number of spikes organized in spaced action
potentials do (Schultz, 1986). These cellular phenotypes recapit-
ulate the classic concept that, in mammals, single spikes
firing in DA neurons are thought to play a permissive role in
initiating movements (Romo and Schultz, 1990), while burst
firing is correlated with arousal states and motivation.
More importantly, mimicking a ‘‘better than expected’’ reward
prediction error signal by optogenetic activation of DA neurons
during the occurrence of reward delivery was sufficient to estab-
lish a long-lasting increase in reward-seeking behavior caused
by cue-reward learned associations (Steinberg et al., 2013).
Many studies have shown that burst firing activity is highly regu-
lated by glutamatergic afferent inputs (Grace and Bunney,
1984a, 1984b; Grace et al., 2007). Not surprisingly, another
substantial body of evidence supports a role for glutamate
in learning mechanisms related to reward adaptive behaviors
(Kauer, 2004; Lüscher and Malenka, 2011; Schultz, 2011).
In fact, glutamatergic afferents reaching the VTA are suscep-
tible to plasticity during reward and drug-associated learning
1146 Neuron 86, June 3, 2015 ª2015 Elsevier Inc.
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(Chen et al., 2008; Stuber et al., 2008; Ungless et al., 2001). Using
behavioral sensitization, a phenomenon that is based on esca-
lating behavioral responses to repeated exposure to a drug, it
was discovered that N-methyl-D-aspartate receptor (NMDAR)
antagonists delivered into the VTA prevented the development
of this behavioral phenomenon. In addition, alpha-amino-3-hy-
droxy-5-methyl-4-isoxazolepropionate receptor (AMPAR)
blockade is capable of affecting the maintenance of behavioral
sensitization (Jackson et al., 2000; Wolf, 1998). Therefore, phar-
macological compounds administered within the VTA that
antagonize the activity of AMPARs and NMDARs severely
disrupt classical Pavlovian associative learning (Harris and As-
ton-Jones, 2003; Kelley et al., 2003; Stuber et al., 2008).
The functional interpretation of these findings opens up several
possible cellular scenarios, including disruption of cellular pro-
cesses related to synaptic plasticity, intrinsic properties, or burst
firing modalities of DA neurons. In fact, both LTP and the ability to
generate burst firing rely on the integrity of NMDAR activity in
DA neurons of the VTA. It is tempting to speculate that in these
experimental settings a glutamatergic antagonist could affect
both processes. Moreover, burst firing of DA neurons in the sub-
stantia nigra can play a permissive role in the proper occurrence
of NMDA synaptic plasticity (Harnett et al., 2009). Presumably,
this phenomenon might happen also for DA neurons of the VTA,
thus engaging the first fundamental step toward the expression
of the AMPAR mediated LTP during cocaine exposure (Argilli
et al., 2008), or potentially during the occurrence of natural
reward-related association.
Aversion: The Other Face of Dopamine
DA neurons are capable of encoding both reward and aversion.
There is solid evidence that several types of rewarding stimuli,
like food (McCutcheon et al., 2012; Roitman et al., 2004), intrao-
ral infusion of a sucrose based solution (Roitman et al., 2008),
drugs of abuse (Aragona et al., 2009; Stuber et al., 2005a,
2005b) and cues predicting their delivery (Daberkow et al.,
2013; Phillips et al., 2003), all strongly, albeit transiently, increase
the probability of DA release events. Given that animals are
willing to perform tasks that lead to the consumption of
reward, but are generally reluctant to deal with aversive stimuli
(Miller and Hunt, 1944), it will be crucial to unequivocally differen-
tiate between opposite hedonic evaluations, like reward and
aversion, as a direct effect of selective coding occurring in
DA neurons.
There are several approaches that can be used to mimic aver-
sive situations in experimental animal models. The methodolo-
gies involve a variety of conditions ranging from acute or chronic
exposure to aversive stimuli (foot shocks, forced swimming test,
hind paw injection of formalin, social defeat stress, fear condi-
tioning) to stereotypical orofacial responses evoked by intraor-
ally delivered solutions (Berridge, 2000; Chaudhury et al., 2013;
Fadok et al., 2009; Friedman et al., 2014; Lammel et al., 2012;
Tye et al., 2013). From these studies, a role for DA and DA neu-
rons, in the modulation and coding of aversive life experiences
clearly emerges. Importantly, DA neurons are active players dur-
ing fear-related experiences (Fadok et al., 2010), facilitating the
early stabilization of the memory trace of fear-related learning.
Additionally, VTA DA neurons undergo activity-dependent plas-
ticity mechanisms (Gore et al., 2014) and actively participate in
Neuron
Review
the modulation of amygdala action potentials during Pavlovian
fear conditioning and stress (Inglis and Moghaddam, 1999;
Rosenkranz and Grace, 2002).
Along these lines, a mouse model carrying a genetic inactiva-
tion of functional NMDA receptors on DA neurons displays a mal-
adaptive conditioning to a cue predicting an aversive outcome,
and concurrently this impairment in contingency alertness is
associated with the development of a generalized anxiety-like
phenotype (Zweifel et al., 2011). Consistent with a direct involve-
ment of DA neurons in the coding and modulation of emotional
memory formation and adaptive behavior, bidirectional control
(via optogenetic inhibition or excitation) of genetically targeted
midbrain DA neurons rapidly modulates prototypical symptoms
caused by chronic stress (Chaudhury et al., 2013; Friedman
et al., 2014; Tye et al., 2013). The latter approaches can directly
test the involvement of the DA system in the behavioral control
of aversion. However, optogenetic manipulations, like the ones
performed in the previous studies, can indeed rescue pheno-
typic alterations in animals that underwent behavioral manipula-
tion, such as depressive-like phenotypes, but such rescue first
requires the induction of a non-physiological behavior (Friedman
et al., 2014; Tye et al., 2013).
In summary, to gain full knowledge about the exquisitely intri-
cate physiology of DA neurons, it will be important in the future
to compare reward and aversive responses within an ‘‘intact’’
mesolimbic system. Furthermore, the many groundbreaking
contributions, briefly discussed in this review, shed light toward
a better understanding of how, and where, reward and aversion
processing takes place within the CNS. Scientists are not far
from giving a precise identity and role to the various neuronal
sub-populations located within the VTA, that are engaged in
the coding of reward, aversion, or in facilitating contingency
awareness, with the ultimate goal to identify potential targets
for therapeutic intervention.
Cracking the Dopamine Code with New Approaches to
Understand Neuronal Heterogeneity
DA neurons located within the VTA are clustered into specific
anatomical niches and project to a single target region such as
nucleus accumbens, prefrontal cortex, hypothalamus, basolat-
eral amygdala, lateral habenula, pallidum, and bed nucleus
of stria terminalis (Haber, 2014). The VTA is a very heteroge-
neous region in which dopaminergic, GABAergic and gluta-
matergic neurons intermingle. As previously mentioned in the
introduction, dopaminergic neurons are the most abundant
population (65%), followed by GABA neurons (30%), while gluta-
matergic neurons (5%) are the most underrepresented popula-
tion (Morales and Root, 2014; Yamaguchi et al., 2007, 2011).
Such anatomical complexity is paralleled by a functional and,
perhaps, vesicular promiscuity, since dopaminergic neurons
can co-release glutamate or GABA.
The most powerful approaches used to disentangle the
anatomical and physiological intricacies of the VTA are derived
from the proper combination of transgenic technologies, opto-
genetics, electrophysiology, and immunocytochemistry. For
example, the use of retrograde tracing allowed for a detailed
functional identification of DA neurons residing within the VTA
and projecting to NAc, PFC and basolateral amygdala (BLA)
(Lammel et al., 2011; Margolis et al., 2008). Using this approach,
it has been shown that VTA neurons projecting to the lateral shell
of NAc reside within the lateral portion of the VTA and exhibit
large Ih currents, a hyperpolarization-activated cationic current,
which represents an electrophysiological feature traditionally
used to identify DA neurons. In addition, a recent study found
that glutamatergic synapses display a low AMPAR/NMDAR ratio
at resting state. Conversely, DA neurons projecting to the baso-
lateral amygdala, PFC, and core of the NAc originate from the
medial portion of the VTA. Moreover, these neurons do not
show Ih currents, and the glutamatergic synaptic configuration
displayed a high AMPAR/NMDAR ratio at resting conditions.
Interestingly, salient appetitive events, like a passive exposure
to cocaine, induced synaptic potentiation mostly within DA neu-
rons projecting to the lateral shell, while an aversive event (hind
paw injection of formalin) was capable of inducing synaptic
potentiation, mostly within PFC projecting neurons (Lammel
et al., 2011) (Figure 1).
These distinct subsets of neurons receive different afferent
synapses. NAc shell projection neurons receive excitatory affer-
ents, both glutamatergic and cholinergic inputs, from the latero-
dorsal tegmentum (LDTg) and inhibitory afferents from the rostro-
medial tegmental nucleus (RMTg). In the case of dopaminergic
neurons projecting to the PFC, the excitatory afferents are pro-
vided by glutamatergic input emanating from the lateral habe-
nula. The lateral habenula also sends glutamatergic synapses
onto GABAergic neurons of the RMTg that project back to NAc
shell-projecting neurons. The behavioral implication of this intri-
cate circuit has been determined in vivo by using optogenetic
stimulation of specific presynaptic terminals, allowing an exami-
nation of the functional significance of input specificity, relative to
the VTA. Optical stimulation of channelrhodopsin-2 expressing
terminals in the VTA produced a robust conditioned place prefer-
ence (CPP), a form of Pavlovian conditioning used to measure the
motivational effects of experiences. On the other hand, light stim-
ulation of the lateral habenula and RMTg terminals in the VTA pro-
duced conditioned place aversion (Lammel et al., 2012).
Providing proper control of DA neuron firing rates in VTA is
essential for the physiological expression of reward processing
and motivational salience. The balance between excitatory and
inhibitory drive has emerged as a fundamental mechanism for
the control of firing rates and activity patterns of DA neurons.
Glutamatergic input via AMPA and NMDA receptors expressed
on DA neurons can shape DA release events. GABAergic synap-
ses are also capable of regulating firing activity via activation of
GABAA receptors located on DA neurons, thereby profoundly
reducing their firing rate. Interestingly, there are several glutama-
tergic and GABAegic inputs, in addition to those already
mentioned, orchestrating the activity of dopaminergic neurons
of the VTA.
Activation of pyramidal neurons of the PFC in vivo can induce
bursting of VTA DA neurons (Tong et al., 1996). Lateral hy-
pothalamus (Kempadoo et al., 2013) and BNST (Jennings et al.,
2013) can also provide glutamatergic inputs. GABA neurons are
located within the VTA, as well. Coordinated activity of these
GABA cells, via selective optogenetic stimulation, can support
conditioned place aversion and disrupt reward consumption
(Tan et al., 2012; van Zessen et al., 2012). Surprisingly, this
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Figure 1. Synaptic Plasticity and Dopaminergic Activity in Response to Rewarding or Aversive Processes
Rewarding experiences like a passive exposure to cocaine are capable of producing synaptic potentiation mostly within VTA DA neurons projecting to NAc lateral
shell (left) while aversive events, hind paw injection of formalin, cause synaptic potentiation mostly within PFC projecting neurons (right). These distinct subsets of
DA neurons receive different afferents. NAc shell projection neurons receive afferents from LDTg and RMTg and modulate reward processing, while PFC
projecting neurons receive excitatory afferents provided by LHb and they are implicated in aversion. The observed enhanced expression of AMPA receptors
occurring onto specific subsets of DA neurons, respectively supporting reward and aversion, might be a cellular mechanism for burst generation and concurrent
increased DA release.

population of cells can also innervate NAc. In addition, it has been
recently demonstrated that these cells synapse onto accumbal
cholinergic interneurons (CINs). More importantly, optogenetic
manipulation of these terminals can induce a pause in the firing
pattern of CINs in behaving mice and enhanced discrimination
of stimulus previously paired with an aversive outcome (Brown
et al., 2012). Thus, these data support the intriguing idea that
GABA neurons within the VTA can ‘‘teach’’ NAc how to respond
and promote actions, in regard to salient events.
Given the functional importance of GABAergic neurons
located within the VTA, it is important to note that they receive
inhibitory input from medium spiny neurons of the NAc
(Bocklisch et al., 2013), BNST (Jennings et al., 2013), and ventral
pallidum (Hjelmstad et al., 2013). Interestingly, it has been
discovered that synapses between medium spiny neurons ex-
pressing DA receptor type 1 of the NAc projecting to GABA
neurons of the VTA can undergo synaptic plasticity, namely
potentiation, after repeated in vivo experiences with cocaine.
This synaptic potentiation is also capable of occluding the
occurrence of homosynaptic, inhibitory long-term potentiation
(Bocklisch et al., 2013). At the circuit level, this plastic adaptation
induced a reduction in the activity of GABAergic neurons, thus
causing a subsequent disinhibition of DA neurons. The circuits
and neuronal population described above belong to anatomi-
cally and molecularly defined neurons.
It is important to emphasize that beside the biological com-
plexity conferred by the promiscuous release of neurotrans-
mitter, the existence of a ‘‘hybrid’’ population of neurons within
the VTA emerges as a very prominent reality that strongly deter-
mines the intrinsic circuitry of this system. These populations of
cells reside within the VTA and project to the lateral habenula, ex-
pressing the prototypical markers of DA neurons, but are unable
to release detectable levels of DA in the target region. Surpris-
ingly, they can release GABA in the LH and, accordingly, pro-
mote reward-seeking behaviors (Stamatakis et al., 2013).
It is remarkable to point out that, during the last few years, sci-
entists have been able to add several fundamental anatomical
and functional details to an already complicated and heteroge-
neous region. We are now facing a fascinating era in which we
are combining together all these pieces of information, with the
aim of clarifying and understanding the rules governing the
reward circuits in physiological and pathological states.

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General Rules Governing Synaptic Plasticity in DA
Neurons
In vitro brain slice electrophysiology has been an invaluable tool
to address synaptic level changes in the function of glutamater-
gic synapses occurring in the brain, following different circum-
stances. Several electrophysiological studies have revealed
that learning induces long-lasting changes in the synaptic
strength of central glutamatergic synapses. As discussed earlier,
this activity-dependent modification of the efficacy of synaptic
transmission is generally termed synaptic plasticity. It is widely
recognized that this plasticity mechanism is a fundamental
cellular candidate for the acquisition and maintenance of
learning and memory traces in the brain. In the mammalian
brain, given the diversity of the properties and functions of
each region, several different forms of synaptic plasticity have
been described. In this section, we attempt to provide a broad
overview of the mechanisms of synaptic plasticity that have
been described at excitatory synapses in the VTA. Glutamatergic
synapses reaching the VTA are capable of expressing plasticity
properties. Indeed, several studies have found that both LTP and
LTD caused by evoked AMPAR currents can be induced in the
VTA (Bonci and Malenka, 1999; Thomas et al., 2000). Older in-
duction protocols, adapted from the hippocampus literature,
held DA neurons at a depolarized potential for a long period of
time, while stimulating afferents at high or low frequencies.
Despite the fact that the older induction protocols were capable
of producing plasticity, they were unable to recapitulate biolog-
ically relevant patterns of synaptic activity.
Theoretically speaking, perhaps a more physiologically rele-
vant induction protocol is represented by spike-timing–depen-
dent plasticity (STDP). In STDP, the induction of plasticity is
governed by specific rules that organize the order and precise
temporal interval between pre and post-synaptic spikes, resem-
bling the physiological activity of the neuron (Feldman, 2012).
Based on these assumptions, the use of STDP has emerged in
the VTA plasticity field over the last decade. Interestingly, both
classical and STDP induction protocols are capable of producing
LTP and, similarly to what has been reported in other brain re-
gions (i.e., hippocampus), rely on NMDAR activation, as well as
a subsequent increase in postsynaptic calcium. Conversely,
LTD in the VTA is NMDAR independent. In fact, bath application
of APV, the NMDA receptor antagonist, is not able to prevent low-
frequency stimulation-induced LTD (LFS-LTD). Surprisingly,
however, Ca2+ signaling in the postsynaptic compartment is
essential for the proper expression of LFS-LTD; in fact having
the Ca2+ chelator BAPTA in the recording pipette prevents LFS-
LTD. Furthermore, bath application of DA or the D2 receptor
agonist quinpirole blocks LFS-LTD (Thomas et al., 2000). The mo-
lecular mechanisms underlying this synaptic process are still
poorly understood. Certainly, the functional recruitment of den-
dritic potassium channels by DA, or by quinpirole, is unlikely since
these experiments were performed with TEA and cesium in the
whole cell pipette, both potassium channel blockers.
It is very intriguing that activation of mGlu1 (Group I metabo-
tropic glutamate receptors) is also capable of producing LTD in
the VTA and, more importantly, mGlu and LFS-LTD coexist
and do not occlude each other, thus supporting the idea that
they are mechanistically distinct (Bellone and Lüscher, 2005).
mGlu1-mediated LTD is also supported by elevation of intracel-
lular Ca2+ levels, since having BAPTA in the pipette completely
prevents LTD (Bellone and Lüscher, 2005). The expression
mechanism of mGlu1-LTD in the VTA is quite peculiar. In fact,
instead of relying on a reduced number of postsynaptic AMPA
receptors, it relies on an exchange of AMPA receptors with a
lower conductance, those that contain the GluA2 subunit (Bel-
lone and Lüscher, 2005). We will discuss the importance of
AMPAR composition in further detail below. Ultimately, the mo-
lecular players regulating the increase or decrease in synaptic
strengths observed in LTP and LTD, respectively, are the
AMPARs. This class of receptors can undergo differential traf-
ficking or a change in subunit composition at the cell surface,
depending on the type of synaptic plasticity occurring. In
fact, depending on the synaptic mechanism engaged for the
synaptic potentiation or depression of AMPAR-mediated excit-
atory synaptic transmission, we could imagine the following
molecular scenarios: an increase or decrease in sensitivity,
number of receptors, or changes in the expression of AMPAR
subunits.
AMPARs are fundamental ionotropic transmembrane recep-
tors mediating fast excitatory synaptic transmission in the
CNS. Assembly of these receptors requires four subunits
(GluA1–GluA4), which can form hetero- or homomeric com-
plexes (Gan et al., 2015). AMPARs are thought to exist as hetero-
meric complexes containing both GluA2/3 and GluA1 subunits.
At resting state, the vast majority of AMPARs contain the
GluA2 subunit, forming heteromeric receptors with GluA1 or
GluA3. However, GluA2-lacking AMPARs can form, in which
the tetrameters are composed of GluA1/1 or GluA1/3 AMPARs,
in other words ‘‘GluA1-type.’’ GluA1-type AMPARs are perme-
able to calcium, which can be a permissive signaling event for
the establishment of plasticity, while GluA2 containing receptors
are Ca2+ impermeable (Isaac et al., 2007). Our understanding of
how AMPAR subunit composition is regulated has been aided by
both biochemical (crosslinking methods) and electrophysiolog-
ical techniques. The use of crosslinking assays allowed the res-
olution of AMPAR subunit type present on the cell surface and
also revealed the phosphorylation state of specific sets of AM-
PARs subunits.
Importantly, depending on their phosphorylation state, AMPARs
can increase or decrease channel conductance. Electrophysiolog-
ical techniques have also taken advantage of a specific feature
of GluA2-lacking AMPARs: that functional block occurs when
intracellular polyamines are applied at a positive potential. This
biophysical feature parallels a very unique inward rectifying
current-voltage relationship that can be used to determine the
presence or absence of GluA2-lacking AMPARs. Biochemical
and electrophysiological approaches can then be used in combi-
nation, via the use of specific subunit-selective peptide antago-
nists. The elegance of the use of the latter approach resides
in the possibility to dissect out the relative contribution of GluA1
and GluA2 AMPAR subunits in both in vitro and in vivo experi-
mental conditions.
A powerful and convenient behavioral framework for studying
synaptic plasticity and the electrophysiological impact, in terms
of behavioral adaptation, has been offered by the drug addiction
field. Evidence that drugs of abuse are capable of producing
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plasticity within DA neurons of the VTA was shown with a single
non-contingent injection of cocaine. Our group discovered an
increased AMPAR/NMDAR ratio, a ‘‘surrogate’’ measure of
LTP, 24 hr after the treatment (Ungless et al., 2001). Additionally,
it was demonstrated that excitatory synapses were not further
strengthened, supporting the idea that the potentiation, and
the subsequent occlusion phenomena, was due to the fact that
cocaine-induced LTP shared the same mechanism as physio-
logical LTP. This plastic neuroadaptation was observed 24h after
the injection and persists for up to 5 days.
Interestingly, several other salient events like food and sucrose,
delivered after self-administration procedures, are capable of
producing the same neuroadaptation (Chen et al., 2008). The
fundamental difference is revealed by the duration of the synaptic
potentiation. Plasticity triggered by sucrose, food, or pure appe-
titive Pavlovian learning and memory mechanisms is a very tran-
sient phenomenon that decays rapidly over time. In the case of
cocaine, and particularly in animals trained to self-administer
the drug, this LTP-like state persists for several weeks. Interest-
ingly, cocaine-induced synaptic potentiation of AMPARs is
mediated by prior recruitment of NMDA receptors. In fact, in vivo
treatment with MK-801, the noncompetitive antagonist of the
NMDARs, prevented the occurrence of synaptic plasticity.
Notably, the increase in AMPAR/NMDAR ratio parallels an
increased sensitivity to polyamines, which is indicative of
the presence of GluA2-lacking AMPARs (Argilli et al., 2008;
Bellone and Luscher, 2006). In addition, both in vitro and in vivo
activation of mGlu1 are capable of reversing the early synaptic
effects triggered by cocaine exposure, namely GluA2-lacking
AMPARs, via de novo synthesis and synaptic incorporation
of GluA2 containing receptors (Bellone and Luscher, 2006; Ma-
meli et al., 2007) (Figure 2).
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Figure 2. Cocaine Exposure ‘‘Hijacks’’
Synaptic Plasticity Rules of VTA Dopamine
Neurons
Synaptic plasticity involves several orchestrated
changes of synaptic efficacy supporting experi-
ence-dependent modifications of brain function.
The increased efficacy of glutamatergic synapses
onto DA neurons observed after cocaine exposure
is supported by a redistribution of AMPA (GluR2
Lacking) and NMDA receptors (GluN2B and
GluN3A containing). The observed changes in
AMPA and NMDA subunit composition lead to
changes in Ca2+ permeability that are capable of
affecting synaptic rules governing activity-
dependent plasticity. As a consequence, anti-
Hebbian pairing protocols, not sufficient to induce
LTP in naive conditions, can produce LTP after
cocaine exposure. Interestingly, both in vitro and
in vivo activation of mGluR1 can reverse cocaine-
induced synaptic adaptation via synaptic incor-
poration of GluR2 containing AMPA receptors.
Whether activation of mGluR1 is also capable of
reversing NMDA receptors redistribution is still
unknown.
Another level of complexity has been
revealed by photo-uncaging glutamate
at single synapses of DA neurons in ani-
mals that underwent in vivo cocaine
exposure. The experiments showed reduced NMDAR-mediated
currents (Mameli et al., 2011). Reduction in NMDAR-mediated
currents can concurrently support and greatly amplify the
observed increased in AMPA/NMDA ratio. It is important to point
out that NMDARs are fundamental players in the induction phase
of LTP and in several other integrative cellular processes. Thus,
their expression or subunit composition can be a crucial
component for the proper tuning of synaptic plasticity. DA
neurons of animals exposed to cocaine display a larger sensi-
tivity to the selective GluN2B inhibitor ifenprodil, compared to
the selective GluN2A inhibitor zinc (Yuan et al., 2013). The
latter discovery leads to the consideration of the ratio of
GluN2A/GluN2B receptors at synapses. It is important to
appreciate that switches in NMDAR subunit composition can
potently regulate Ca2+ entry into the post-synaptic compart-
ment and, more importantly, can affect the thresholds required
for inducing synaptic plasticity (Kopp et al., 2007). Yuan et al.
(2013) discovered that the observed change in subunit
composition was strictly dependent on the insertion of GluN3A
receptors, shown via a combination of GluN3A knockout ani-
mals and short hairpin RNA approaches. Synaptic insertion
of GluN3A receptors lead to reduced Ca2+ permeability and
magnesium sensitivity and is required for the development of
a cocaine-induced increase in AMPAR/NMDAR ratio. The
observed changes in AMPA and NMDA subunit composition,
in terms of Ca2+ permeability, can reconcile the observation
that after cocaine exposure, anti-Hebbian pairing protocols,
not sufficient to induce LTP in naive conditions, are capable
of inducing LTP (Mameli et al., 2011).
Thanks to the advent of optogenetics, circuit level analysis has
become a very fruitful and important way to investigate how
neuroadaptations caused by appetitive events, like cocaine
Neuron
Review
experience, occur within DA neurons. DA neurons can be classi-
fied depending on their different projection targets. While VTA DA
neurons projecting to NAc medial shell display a robust increased
AMPAR/NMDAR ratio 24 hr after cocaine injection, VTA DA neu-
rons projecting to a lateral shell show only a subtle change in the
AMPA/NMDA ratio. Surprisingly, VTA DA neurons projecting to
the prefrontal cortex are insensitive to cocaine exposure and
have unchanged AMPAR/NMDAR ratio 24h after cocaine treat-
ment. Instead, they respond vigorously to an aversive experience
(hind paw injection of formalin) with a remarkable increase in
AMPAR/NMDAR ratio (Lammel et al., 2011). The functional
segregation of DA neurons based on the projection targets
is also supported by behavioral optogenetic manipulations.
In fact, optogenetic stimulation of accumbens-projecting DA
neurons support conditioned place preference, while optoge-
netic stimulation of prefrontal cortex-projecting DA neurons sup-
ports a vigorous conditioned place aversion (Lammel et al.,
2012). Establishment of a maladaptive process of reward-related
learning has been suggested as a core feature of drug addiction.
Therefore, the ability of drugs of abuse to forge synaptic plasticity
and ‘‘hijack’’ the natural reward process is an appealing reason
for the development and, more importantly, for the persistence
of behavioral responses associated with drugs of abuse.
However, to date, there is no clear evidence that the observed
initial synaptic plasticity changes triggered by substances of
abuse represent a hallmark of addiction, but rather an initial
step that will eventually lead to the induction of the disorder later
on. Moreover, it has been shown that the persistence of synaptic
plasticity occurring in the VTA is a requirement for the expression
of a later synaptic adaptation that takes place in the NAc (Mameli
et al., 2009). Potentially, synaptic adaptation in the ventral stria-
tum might represent a gate for a later establishment of stimulus-
response habit formation occurring in the dorsal striatum (Belin
and Everitt, 2008).
Together, these observations raise the question of whether
this cocaine-induced long-lasting potentiation may also reflect
a disruption in the ability of DA neurons to code for reward and
aversion during the occurrence of naturalistic behavior.
Synaptic Plasticity and Dopaminergic Activity: Shaping
DA Release Events
The majority of information related to DA function in the brain
has been provided by a combination of behavioral, pharmaco-
logical, genetic, and electrophysiological approaches. Surpris-
ingly, none of the cited approaches can selectively provide
subsecond, temporal resolution information related to DA
release happening within ‘‘intact’’ forebrain terminal regions.
The relatively recent introduction of voltammetric approaches,
like fast scan cyclic voltammetry (FSCV), has radically changed
the way we approach DA release in the brain, especially in
regards to appetitive and aversive experiences. The power
of this methodology is mostly represented by a capacity to
quantitate phasic changes in DA concentration, within given
target regions, occurring on a physiological timescale.
Detecting DA concentration by using FSCV within the NAc of
animals that are experiencing opposite hedonic valence re-
vealed an opposite pattern of DA release. While the appetitive
sucrose-based oral solution evoked a robust increase in DA
transients, the aversive quinine-based oral solution induced a
reduction in DA release (Roitman et al., 2008). Interestingly, DA
release does not only depend on the hedonic or the motivational
states engaged by the behavioral framework used, but it is highly
regulated by learned associations (Roitman et al., 2004). When
animals received extensive Pavlovian conditioning training,
where a conditioned stimulus (CS+) predicts the delivery of a
reinforcer-unconditioned stimulus (US), phasic DA release within
the NAc, that early in training appears to be primarily associated
to the delivery of the reward, moves to the onset of the CS.
The idea that learned associations can affect the occurrence
of DA release within the NAc has also been shown for aversive
experiences. In fact, phasic DA release events are suppressed
by stimuli that have been associated with an aversive outcome.
Conversely, phasic DA release events are increased by stimuli
that precede the successful avoidance of an aversive event
(Oleson et al., 2012). The lessons that we have learned so far
account for an active interplay between learning and memory
mechanisms and the regulation of specific patterns of DA
release. The question left is how learning and memory mecha-
nisms are connected with the occurrence of DA release. Interest-
ingly, during reward-learned associations, DA release to reward
predictive cues parallel an enhanced synaptic strength onto DA
neurons (Stuber et al., 2008). Moreover, the observed synaptic
potentiation develops over the course of cue-reward learning.
It is worth mentioning that in conditioned appetitive learning,
where environmental cues are associated with the receipt of a
reward, food restriction can strongly increase the acquisition
rate with which the animals learn how to perform the task.
Notably, restriction of food intake is also a well-known strategy
to enhance the reinforcing efficacy of drugs of abuse in experi-
mental animal models (Carroll et al., 1979). The overall idea is
that food restriction can enhance motivational or hedonic states
that are important for learning and acquisition of behavioral
tasks. Surprisingly, animals under food restriction protocols
display not just an increase in behavioral responses to drugs of
abuse, but also enhanced burst firing of DA neurons, increased
AMPA/NMDA ratio and D2 autoreceptor-mediated desensitiza-
tion in DA neurons (Branch et al., 2013).
The timing in which synaptic plasticity occurs, and the fact that
glutamatergic plasticity might affect the cellular mechanisms by
which DA neurons produce DA release, is of great interest to the
scientific community. In fact, the enhanced synaptic strength
observed in the aforementioned conditions might be the cellular
mechanism lying at the core of the transformation of neutral
environmental stimuli to salient reward-predictive cues and
potentially supports the establishment of specific hedonic and
motivational states that are involved in learning processes.
The Dual Role of Glutamatergic Input onto Dopamine
Neurons
Glutamatergic inputs are not just required for the induction of
synaptic plasticity but they are also a fundamental player in
the induction of burst firing of DA neurons. In particular, activa-
tion of NMDARs induces burst firing by regulating calcium
transients that initiate and terminate bursts via Ca2+-activated
potassium channels (Paladini and Roeper, 2014). Functional
alterations, in the previously cited cellular mechanisms, can
Neuron 86, June 3, 2015 ª2015 Elsevier Inc. 1151

affect the way DA neurons produce burst firing during motiva-
tionally relevant conditions. Plasticity mechanisms occurring in
response to aversive, appetitive, and associative learning condi-
tions develop via a selective recruitment of synaptic AMPARs
(Lammel et al., 2011; Saal et al., 2003; Ungless et al., 2001).
Thus, it is likely that enhanced expression of AMPARs in DA neu-
rons represents an additional cellular mechanism for promoting
burst generation (Canavier and Landry, 2006; Komendantov
et al., 2004). It is therefore plausible to hypothesize that a poten-
tiated synaptic state onto DA neurons may allow the generation
of a more depolarized membrane potential under specific cir-
cumstances and subsequently allow fast Mg2+ unbinding ki-
netics of NMDARs, thus increasing channel open probability
and burst firing generation. The latter functional state may allow
several behavioral conditions to generate uncontrolled burst
firing, representing an unchecked route to specific forebrain ef-
fectors capable of supporting different psychiatric conditions.
In support of this prediction is the demonstration that burst firing
of DA neurons is elevated in awake rats that are experiencing
passive exposure to cocaine (Koulchitsky et al., 2012).
Unexpectedly, in a social defeat stress model, a behavioral
condition with presumably an opposite hedonic valence in res-
pect to cocaine exposure, susceptible mice showed a robust
hyperactivity of VTA DA neurons. This cellular phenotype was
caused by the upregulation of the hyperpolarization-activated
cyclic nucleotide-gated type 2 (HCN2) channels (Ih), a protein
regulating intrinsic excitability onto DA neurons. On the other
hand, mice expressing a resilient phenotype displayed an even
larger Ih and also increased potassium (K+) channel-mediated
currents. Pharmacological treatment with the Ih potentiator la-
motrigine, or increasing activity of DA VTA neurons via optoge-
netic manipulation in susceptible mice, is capable of reversing
depression-related traits (Friedman et al., 2014). Interestingly,
optogenetic stimulation occurring within DA neurons of the
VTA mediates behavioral rescue via a homeostatic plasticity
mechanism occurring between VTA-NAc projecting neurons
(Friedman et al., 2014). Future studies will likely solve the ques-
tion of how synaptic plasticity and intrinsic mechanisms regu-
lating cellular excitability can affect, in a cooperative fashion,
phasic DA release in a population of DA-projecting neurons.
A glutamatergic regulation of DA release has been also sug-
gested at the level of nerve terminals for PFC and NAc (Floresco
et al., 1998; Jones et al., 2010; Takahata and Moghaddam,
1998). For example, dopaminergic and excitatory terminals are
localized in close apposition both in the PFC and NAc. Anatom-
ical studies identified that glutamatergic afferents from the
BLA terminate in close apposition to DA terminals in the NAc
(Johnson et al., 1994). On the other hand, DA terminals and excit-
atory afferents from the hippocampal formation are localized
in close apposition in the PFC (Carr and Sesack, 1996; Smiley
and Goldman-Rakic, 1993). DA release within NAc and PFC is
highly sensitive to AMPARs blockade, suggesting that AMPARs
are regulating DA release in a tonic fashion. This experimental
data raise the possibility that AMPA receptors do not only reside
within the somatic or dendritic shaft compartments of VTA DA
neurons (Paquet et al., 1997), but could also be potentially ex-
pressed on DA terminals, where they might exert a control over
DA release. However, electron microscopy studies were not
1152 Neuron 86, June 3, 2015 ª2015 Elsevier Inc.
Neuron
Review
able to identify AMPA receptors in striatal DA terminals (Bernard
and Bolam, 1998; Bernard et al., 1997).
How can it be possible that AMPA receptors are capable of
modulating DA release in the striatum via action onto dopami-
nergic terminals if there is no evidence for expression? It has
been suggested that H2O2 can act as a key regulator of this local
AMPAR-mediated DA release (Avshalumov et al., 2000, 2008;
Avshalumov and Rice, 2003). In this model, glutamatergic activ-
ity occurring onto AMPARs expressed in medium spiny neurons
(MSNs) could lead to the production of H2O2, which could then
diffuse to adjacent DA terminals, open KATP channels and regu-
late DA release. While there is no clear evidence for the existence
of AMPARs in dopaminergic terminals in the NAc, there is solid
evidence for the existence of mGlu receptors (mGluRs) (Paquet
and Smith, 2003). mGluRs, mostly located at the perisynaptic
sites, are engaged in the regulation of DA release in the striatum,
where they are recruited in the case of glutamate spillover. Once
functionally recruited, they could activate Ca2+-activated K+
channels and thus affect DA release (Zhang and Sulzer, 2003).
All of these studies however only partially account for a local
glutamatergic regulation of DA release into the NAc, at the level
of dopaminergic terminals, under physiological conditions.
In fact, little is known about the presence and the function
of AMPARs onto dopaminergic terminals after exposure to
reward-related stimuli, drugs of abuse, or aversive stimuli. Addi-
tionally, there seems to be no evidence about the presence of
AMPA receptors on DA terminals located in the PFC, even
though it is known that AMPA receptors blockade in the PFC
significantly reduced cortical DA release (Takahata and Moghad-
dam, 2000).
It is plausible to speculate that AMPA receptors may be
actively transported to axonal terminals or incorporated there,
after in loco de novo synthesis from preexisting mRNA, when
the dopaminergic system is expressing synaptic plasticity pro-
cesses triggered by salient conditions (Figure 3). The expression
and synaptic recruitment of these AMPA receptors would be
potentially regulated depending on the biological identity of
each individual DA neuron, projection target, specific glutama-
tergic afferent, or, more importantly, by the emotional nature of
the experience an animal faces. Cross talk between AMPARs
and mGluRs at the axonal terminals can then shape DA release
events within a given terminal region in a multifaceted way,
thereby adding another level of complexity to the excitatory
events happening at the somatic level.
Moreover, neuronal inputs arising from multiple sites of the
brain, and converging at the axonal level, might differentially
impact DA release and ensure appropriate behavioral response
to the information provided by an ever-changing environment
in both physiological and pathological states (Floresco et al.,
1998; Jones et al., 2010; Takahata and Moghaddam, 1998).
Thus, mesocortical DA neurons may be engaged in cognitive
processing underlying working memory or extinction process-
ing, as well as acute stress reaction occurring during aversive ex-
periences and so modulate alertness (Abraham et al., 2014).
Meanwhile, mesoaccumbal DA neurons might be engaged in
motivational functions like proper orientation of goal directed be-
haviors, in the emotional valence and attribution of saliency to
the experience (Ungless, 2004).
Neuron

Review

Figure 3. Synaptic Plasticity within Specific Cellular Compartments of VTA Dopamine Neurons: Shaping and Tuning Terminal DA Release
within Specific Target Regions in Response to Rewarding or Aversive Events
DA release is regulated at the level of nerve terminals by glutamatergic afferents in the Nucleus accumbens (NAc) and in the medial prefrontal cortex (mPFC).
Glutamatergic afferents arising from the basolateral amygdala (BLA) terminate in close apposition onto DA terminals in the NAc, while afferents emanated by the
hippocampus (Hipp) localized in close apposition to DA terminals in the mPFC. DA release in both terminal regions is sensitive to AMPA receptors blockade,
presumably because AMPA receptors are exerting a tonic control over DA release. We speculate that AMPA receptors may be actively transported to axonal
terminals or incorporated there after de novo synthesis from pre-existing mRNA when DA neurons undergo plasticity processes. The latter condition could
potentially confer a very sophisticated level of control over terminal DA release within specific target regions that are implicated in reward or aversion processing.

Particularly interesting to this matter is the notion that VTA
dopaminergic neurons do not code, per se, for cognitive aspects
of learned associations. As a matter of fact, DA neurons do
not carry detailed aspects about the nature of the stimuli, but
rather they have the ability to add ‘‘color or flavor’’ to experi-
ence-dependent processes implicated in memory formation,
by virtue of their control over ‘‘saliency attribution’’ (Berridge
and Robinson, 1998).
The way DA neurons modulate saliency attribution to
behavioral experiences is by controlling, via DA release, gluta-
matergic synaptic activity within the ventral striatum (O’Donnell
and Grace, 1995; O’Donnell et al., 1999). Glutamatergic inputs
reaching the NAc (from the ventral hippocampus, basolateral
amygdala, PFC, and thalamus) provide information about con-
textual elements, cues, and even subtle descriptive features
that belong to a specific environmental condition (Britt et al.,
2012; Sesack and Grace, 2010). What DA does to these
afferents is to control the signal-to-noise ratio and the resultant
throughput of the ventral striatum, by maintaining a proper
tuning between the drive and resultant behavioral responses
promoted by limbic or cortical inputs, respectively (Goto and
Grace, 2008).
While a lot of work has been done, solving all the biological
questions discussed in this section will provide a much better un-
derstanding of how synaptic plasticity, intrinsic excitability, and
concurrent DA release, occurring in specific circuits engaged
in appetitive or aversive conditions, can produce maladaptive,
pathological behaviors, such as substance use disorders.
Conclusions
In conclusion, we have reviewed recent findings concerning the
effects of both salient appetitive and aversive stimuli in DA neu-
rons of the VTA. Over the past decade, the use of innovative
techniques such as transgenic approaches and optogenetics
has radically changed the view of the midbrain DA system. Sci-
ence has come a long way in the description of the VTA that
is now passing through a novel reclassification based on
neuron subtypes displaying specific features at the molecular,
anatomical, and electrophysiological level (Barrot, 2014; Margo-
lis et al., 2008; Root et al., 2014; Tritsch et al., 2012). These
groundbreaking scientific contributions are reshaping our knowl-
edge about synaptic connectivity and molecular profiling of the
VTA (Ekstrand et al., 2014).

Neuron 86, June 3, 2015 ª2015 Elsevier Inc. 1153


In this review, we speculate that, depending on the emotional
content of the experiences, each individual projection-specific
DA cell might make a unique contribution to inform the brain
how to adapt to behavioral responses. Changes in synaptic
configuration, and the resultant patterns of DA cell activity, might
provide a mechanism by which synaptic neural adaptations
occurring in the reward circuit are transferred to forebrain effec-
tors. DA release, in its ‘‘conventional’’ or promiscuous co-release
with other neurotransmitters, can promote or enhance the occur-
rence of spike-time-dependent plasticity at active cortico-
limbic-striatal synapses (Shiflett and Balleine, 2011). The occur-
rence of synaptic plasticity within the cortico-limbic-striatal
circuits can affect and shape the function of each individual
region that can now take the lead and impose its own specific
function to orchestrate and guide future adaptive behaviors.
Additionally, DA-mediated synaptic plasticity can support the
maintenance and consolidation of learning, presumably by add-
ing specific emotional weight, depending on the functional con-
nectivity of the neural network in which neurons reside.
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