Lavin, A. et al. Mesocortical dopamine neurons operate in distinct temporal domains using multimodal signaling. J. Neurosci. 25, 5013-5023

Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2005; 25(20):5013-23. DOI: 10.1523/JNEUROSCI.0557-05.2005
Source: PubMed


In vivo extracellular recording studies have traditionally shown that dopamine (DA) transiently inhibits prefrontal cortex (PFC) neurons, yet recent biophysical measurements in vitro indicate that DA enhances the evoked excitability of PFC neurons for prolonged periods. Moreover, although DA neurons apparently encode stimulus salience by transient alterations in firing, the temporal properties of the PFC DA signal associated with various behaviors is often extraordinarily prolonged. The present study used in vivo electrophysiological and electrochemical measures to show that the mesocortical system produces a fast non-DA-mediated postsynaptic response in the PFC that appears to be initiated by glutamate. In contrast, short burst stimulation of mesocortical DA neurons that produced transient (<4 s) DA release in the PFC caused a simultaneous reduction in spontaneous firing (consistent with extracellular in vivo recordings) and a form of DA-induced potentiation in which evoked firing was increased for tens of minutes (consistent with in vitro measurements). We suggest that the mesocortical system might transmit fast signals about reward or salience via corelease of glutamate, whereas the simultaneous prolonged DA-mediated modulation of firing biases the long-term processing dynamics of PFC networks.


Available from: Antonieta Lavin, Mar 04, 2015
The ability of the mesocortical dopamine system to operate
in distinct temporal modes
Christopher C. Lapish & Sven Kroener &
Daniel Durstewitz & Antonieta Lavin &
Jeremy K. Seamans
Received: 1 May 2006 / Accepted: 16 July 2006 / Published online: 4 November 2006
Springer-Verlag 2006
Background This review discusses evidence that cells in
the mesocortical dopamine (DA) system influence infor-
mation processin g in target areas across three distinct
temporal domains.
Discussions Phasic bursting of midbrain DA neurons may
provide temporally precise information about the mismatch
between expected and actual rewards (predicti on errors)
that has been hypothesized to serve as a learning signal in
efferent regions. However, because DA acts as a relatively
slow modulator of cortical neurotransmission, it is unclear
whether DA can indeed act to precisely transmit prediction
errors to prefrontal cortex (PFC). In light of recent physio-
logical and anatomical evidence, we propose that corelease
of glutamate from DA and/or non-DA neurons in the VTA
could serve to transmit this temporally precise signal. In
contrast, DA acts in a protracted manner to provide spatially
and temporally diffuse modulation of PFC pyramidal
neurons and interneurons. This modulation occurs first via
a relatively rapid depolarization of fast-spiking interneurons
that acts on the order of seconds. This is followed by a more
protracted modulation of a variety of other ionic currents on
timescales of minutes to hours, which may bias the manner
in which cortical networks process information. However,
the prolonged actions of DA may be curtailed by counter-
acting influences, which likely include opposing actions at
D1 and D2-like receptors that have been shown to be time-
and concentration-dependent . In this way, the mesocortical
DA system optimizes the characteristics of glutamate,
GABA, and DA neurotransmission both within the midbrain
and cortex to communicate temporally precise information
and to modulate network activity patterns on prolonged
Keywords Prefrontal cortex
Midbrain dopamine (DA) neurons send projections to a
variety of forebrain structures, forming a complex neuro-
modulatory system crucial for many cognitive processes
and motor functions. Dysfunctions of this system underlie
aspects of drug abuse and neuropsychiatric disorders, in-
cluding schizophrenia and addiction (Phillips et al. 2003;
Rompre and Wise 1989 ; Volkow et al. 2005; Winterer and
Weinberger 2004). Often, pathologies that are associated
with these disease states are manifested in aberrations of
normal functions of the system such as working memory
and reward processing (Winterer and Weinberger 2004;
Abi-Dargham et al. 2002; Wise 2005; Ungless 2004). To
combat these disorders, we need an understanding of the
intricacies of the networks involved. Our current under-
standing of these processes are certain to change as we
uncover the variety of signaling modalities that the meso-
cortical DA system may be able to employ. Likewise, our
Psychopharmacology (2007) 191:609625
DOI 10.1007/s00213-006-0527-8
C. C. Lapish (*)
S. Kroener
A. Lavin
Department of Neurosciences,
Medical University of South Carolina,
Suite 430 BSB 173 Ashley,
Charleston, SC, USA
D. Durstewitz
Centre for Theoretical and Computational Neuroscience,
University of Plymouth,
Plymouth, United Kingdom
J. K. Seamans
Brain Research Centre, University of British Columbia,
Vancouver, British Columbia, Canada
Page 1
understanding of the inputs that activate the DA system has
developed significantly in recent years. The present article
will review aspects of DA signaling in PFC and highlight
how the mesocortical DA system may affect information
processing over various time scales in this area.
The most influenti al interpretation of the function of the
DA system is the idea that the phasic activation/inactivation
of DA neurons encodes a prediction error signal which is
crucial for reinf orcement learning. This theory suggests that
DA neurons transmit information to efferent regions about
discrepancies between predicted and actual reward magni-
tude, as well as the probability of forthcoming rewards
(Schultz 1998a,b; Tobler et al. 2005). This theory highlights
the precise temporal signaling demands placed on the DA
system to effectively transmit these prediction error signals
to target regions.
The PFC is postulated to be instrumental for a variety of
temporally delimited executive functions such as trial-unique
working memory and error detection (Goldman-Rakic 1995;
Miller and Cohen 2001; VanVeen and Carter 2002). Many of
these processes also require temporal precision in neural
mappings of stimuli and rewards. For instance, working
memory requires the active maintenance of a subset of stimuli
that will be used to guide a correct forthcoming response.
Upon completion of the response, the reward contingencies
may change and their representations in working memory
would have to be remapped. Accordingly, neurons in the PFC
show sustained elevations in firing during delay periods that
are specific for the previously encoded stimulus and its
relationship to reward and when the location of the to-be-
remembered stimulus changes, so does the delay-period
activity of a given PFC neuron (Funahashi et al. 1989).
Moreover , in humans, the error-related negativity (ERN) often
observed on tasks involving conflict is an approximately 100
250 ms negativity in the event-related potential centered on
the anterior cingulate region of the medial frontal cortex that
reflects detection that an error was made based on a mismatch
between the actual and intended movement (VanVeen and
Carter 2002). The ERN serves as an extremely fast internal
signal of conflict that is present during situations when a
perceived conflict arises immediately surrounding an incorrect
response. Both working memory-related activity (Suri and
Schultz 1999) and the ERN (Holroyd and Coles 2002)have
been proposed to be influenced by phasic DA signaling. In
fact, the ERN itself may be generated by phasic DA release
associated with reward prediction errors (Holroyd and Coles
2002; Holroyd et al. 2003). If this is the case, then it is vital
for DA release and its effects in PFC be temporally precise in
onset and offset because if the DA signal is slow in onset and
protracted, then it would be impossible for PFC neurons to
accurately map the constantly changing associations between
stimuli, reward, and responses (both intended and committed)
to guide accurate responding in a trial unique manner.
However, when taking into account the physiological and
biochemical properties of the mesocortical DA system, it
becomes difficult to reconcile current theory with data that
suggests that DA acts as a slow modulator of cellular and
synaptic properties. While the firing patterns of DA neurons
fit perfectly with the requirements of a prediction error
signal, the duration and peak of DAs effects in PFC alone
appear too protracted to provide a relevant and timely bias on
PFC networks to efficiently fill such a role, as will be
discussed in detail later. On the other hand, recent evidence
suggesting that DA neurons may corelease glutamate could
reconcile many of the problems associated with the ability of
mesocortical DA neurons to provide temporally precise
information (Seamans a nd Yang 2004). In this review, we
will focus on two main topics: (1) how DA modulates neu-
rotransmission in the PFC to bias information processing in
the network, and (2) how the mesocortical DA system is
able to communicate temporally precise information. To
this end, we will discuss evidence from the anatomy and
physiology of the mesocortical DA system.
Basic anatomy of the DA system: volume transmission
and extrasynaptic signaling
The dopaminergic innervation of the forebrain of mam-
mals is constituted by a small number (15,00020,000
neurons on each side of the rat brain) of highly
collateralized neurons residing in the ventral mesencepha-
lon (Fallon and Loughlin 1995;Lindvalletal.1984;
W illiams and Goldman-Rakic 1998). These mesencephalic
cell groups are designated as A8, A9, and A10, according to
the nomenclature of Dahlstrom and F uxe (1964 ), and they
generally correspond to the DA cells of the substantia nigra
(SN, A9), ventral tegmental area (VTA, A10), and the retro-
rubral area (A8) (Berger et al. 1991; Porrino and Goldman-
Rakic 1982; Williams and Goldman-Rakic 1998).
DA neurons show two predominant patterns of firing ac-
tivity termed tonic and phasic (Grace 1991, 2000). Tonic
activity consists of a regular spike firing pattern of 16Hz
that DA neurons usually exhibit in the absence of salient
stimuli (Grace and Bunney 1984b; Schultz et al. 1997).
Tonic firing patterns maintain basal extracellular levels of
DA in afferent regions, and can be affected by visceral
stimuli that can moderately increase or decrease efferent DA
levels to provide a tone on DA receptors (Grace 1991).
These levels recorded using in vivo microdialysis are on
the order of 0.3 to 15 nM in the striatum and PFC (Devoto
et al. 2001; Garris et al. 1993; Garris and Wightman 1994;
Hernandez and Hoebel 1995;Hildebrandetal.1998;
Ihalainen et al. 1999; Izaki et al. 1998; Shoblock et al.
2003). Phasic activation of DA neurons increases their firing
rates to 20 Hz (Grace and Bunney 1984a; Kiyatkin and
610 Psychopharmacology (2007) 191:609625
Page 2
Zhukov 1988; Kiyatkin and Stein 1995), which results in
significant and long-lasting increases in extracellular DA con-
centrations (Phillips et al. 2003; Williams and Millar 1990;
Lavin et al. 2005). Changes in the firing rate of DA neurons
can evoke a wide range of effects on efferent neurons by
increasing or decreasing levels of DA (Phillips et al. 2003;
Williams and Millar 1990; Lavin et al. 2005). We will
examine the time course of DA modulation in PFC and
attempt to reconcile this with changes in firing rates of DA
neurons evoked by behaviorally salient stimuli.
The time course and local specificity of dopaminergic
neurotransmission depends to a large extent on the region-
ally specific properties of uptake/breakdown of DA. In
limbic and cortical regions such as the basolateral amygdala
and PFC, DA clearance rates are slower than in the striatum
(Cass and Gerhardt 1995; Garris et al. 1993; Garris and
Wightman 1994). In the PFC, a 60 Hz/2 s stimulation
evoked a m aximal DA co ncentration of 2.4 μMand
stimulation at lower frequencies (30 Hz/120 pulses) evoked
200 nM (Garris et al. 1993). Decay of DA levels back to
baseline in the PFC typically took longer than 5 s, while
higher concentrations (1.2 μM) of exogenously applied DA
decayed away over tens of seconds (Cass and Gerhardt
1995; Garris et al. 1993). Focal stimulation at 30 Hz/30
pulses evoked DA level s that reached 320 nM in PFC
slices, and this decayed over a period greater than 5 s
(Mundorf et al. 2001). Finally, in vivo we observed that a
20 Hz/2 s stimulation of the VTA evoked a 3040 nM rise
in DA that decayed back to baseline within a few seconds
(Lavin et al. 2005). Because DA varicosities are fairly
sparse in the PFC (10
per mm
; Descarries et al. 1987),
this concentration is rapidly depleted by radial diffusion, to
nanomolar levels in the extrasynaptic space. Unlike in
striatal regions, the PFC shows very low levels of DA
transporter expres sion (Sesack et al. 1998) and the DA
transporter accounts for only 40% of DA uptake in the
PFC, compared with 95% in the striatum (Wayment et al.
2001). Rather, unlike in the striatum, a significant portion
of DA uptake in the PFC is mediated by the norepinephrine
transporter and catabolized enzymatically by catechol-O-
methyltransferase and to a lesser degree monoamine oxi-
dase (Bymaster et al. 20 02 ; Cass and Gerhardt 1995;
Moron et al. 2002; Wayment et al. 2001).
In the PFC of rats and primates, dopaminergic fibers
make between 4090% specialized contacts [ 39% in
the sulcus principalis of primates Smiley and Goldman-
Rakic (1993); 56% in the suprarhinal, and 93% in the
anteromedial PFC of rats, Seguela et al. (1988)]. The
remaining a xonal varicosities constitute unspecialized
synaptic release sites and probably contribute to the
actions of DA v ia volume transmission (Garris and
Wightman 1994; Smiley and Goldman-Rakic 1993;Zoli
et al. 1998).
In general, synapses of the central nervous system are
classified as asymmetric (or type I), or symmetric (or type
II), respectively, and these correspond to functional classes
as well (Colonnier 1968; Gray 1959). Symmetric synapses
are characterized by a darkening of both the pre- and
postsynaptic side of the synapse, while asymmetric synapses
are characterized by an intense darkening of the postsynaptic
density (PSD) only (Colonnier 1968;Gray1959). Asym-
metric synapses are generally associated with glutamate
transmission and excitatory synaptic actions, while synapses
with symmetric densifications of their memb ranes are
implicated in inhibitory synaptic transmission.
Based on its physiological effects, DA is neither a classi-
cal excitatory nor inhibitory transmitter (Seamans and Yang
2004), and DA axons can form both symmetric and asym-
metric synaptic contacts, although the latter ones clearly
represent a minority: Asymmetric synapses have been found
to constitute between as little as 3% and as much as 22% of
the population of DA synapses. Part of this variability may
stem from differences in methodology [see Smiley and
Goldman-Rakic (1993) for a discussion of technical con-
siderations], while other differences may depend on the area
investigated. For example, in the rat medial PFC 84% of DA,
synapses were characterized as symmetric and 16% as asym-
metric, whi le in the ventro-orbital PFC 78% were found to be
asymmetric and 22% asymmetric (Descarries et al. 1987;
Seguela et al. 1988). For rat medial PFC, where much of
the electrophys iological data has been collected character-
izing the PFC DA system, an estimate of 16% (Seguela
et al. 1988) would translate into
of asym-
metric DA synapses out of 1315×10
DA varicosities/mm
reported for layer V (Descarries et al. 1987).
An important findi ng is that, in the striatum including
the nucleus accumbens, most DA receptors can be found in
the vici nity of glutamatergic asymmetric synapses, but are
located at distant sites from a tyrosine-hydroxylase labeled
DA synapse, further supporting the notion of volume trans-
mission (Caille et al. 1996; Hara and Pickel 2005). A
similar situation exists in PFC. Using mono and polyclonal
antibodies directed at the C-terminal of the human D1
receptor, Smiley et al. ( 1994) found that D1 immunoreac-
tivity was usually displaced to the side of the postsynaptic
density of large asymmetric synapses that showed profiles
not indicative of DA synapses. In fact, they report that none
of the 21 synapses formed by tyrosine hydroxylase axons
were labeled for D1 receptors. They conclude that some or
all cortical DA synapses do not utilize D1 receptors and that
a substantial portion of D1 effects occur at sites other than
synaptic specializations. Likewise, Bergson et al. (1995)
reported that D1 and D5 receptors are usually found on
asymmetric synapses and not at DA synapses. As in the
striatum, most D1 labeling was observed in spines and was
typically displaced from the asymmetrical synapse. Most of
Psychopharmacology (2007) 191:609625 611
Page 3
the signal was observ ed in dendritic shafts, while only 5%
of D5 labeling was found in spine heads. Likewise, most
D2 immunogold labeling in dendrites and spines is associ-
ated with asymmetric synapses, but is found also outside the
PSD at extrasynaptic and perisynaptic sites (Negyessy and
Goldman-Rakic 2005). Collectively, these data indicate that
D1 and D2 receptors are most often associated with asym-
metric terminals, which are typically displaced from the
PSD in the peri- or extrasynaptic space. In this way, DA is
suited to modulate glutamate and GABA neurotransmission
in a manner consistent with volume transmission.
Electrophysiological properties of PFC DA:
understanding the classical inhibitory
and excitatory effect s of DA
There is a long history of studies showing that VTA ac-
tivation or DA exert a predominately inhibitory effect on
spontaneous firing of single pyramidal cells recorded extra-
cellularly in vivo (Bunney and Aghajanian 1976; Ferron
et al. 1984; Godbout et al. 1991; Mantz et al. 1992; Mora
et al. 1976; Pirot et al. 1992; Sesack and Bunney 1989;
Tseng et al. 2006). Specifically, VTA stimulation tends to
inhibit spont aneous firing o f PFC neurons for a period of
about 100200 ms. Local iontophoretic application of DA
also decreased the spontaneous firing of PFC neurons re-
corded extracellularly in vivo and this spike suppression
was reduced by a D2, but generally not by a D1 antagonist
(Parfitt et al. 1990; Pirot et al. 1992). Accordingly, D2
agonists were more effective than D1 agonists in replicating
the DA-mediated inhibition of spont aneous firing (Thierry
et al. 1998). However, Sesack and Bunney (1989) found
that iontophoretic application of a D2 agonist directly
onto single PFC neurons in vivo failed to mimic the DA-
mediated firing suppression . Taken together, VTA stimu-
lation or local DA application are capable of transiently
inhibiting the spontaneous firing of PFC neurons although
the DA receptor subtype involved is disputed.
In contrast to the effects on spontaneous firing recorded
extracellularly, DA robustly increases the firing of PFC
neurons evoked by intracellular current pulses both in vitro
(Ceci et al. 1999; Henze et al. 2000; Lavin and Grace 2001;
Penit-Soria et al. 1987; Yang and Seamans 1996; Shi et al.
1997; Wang and ODonnell 2001), and in vivo (Lavin et al.
2005). Indeed, PFC neurons recorded intracellularly in vivo,
VTA stimulation could both suppress spontaneous firing and
enhance evoked firing (Lavin et al. 2005). The mechanisms
underlying DA modulation of spontaneous firing in vivo and
evoked firing by intracellular current pulses are somewhat
different. Spontaneous firing in vivo involves a complex
interplay of ionic currents. Computational models suggest
that at low (spontaneous) levels of network activity, the
DA-mediated increase in firing of interneurons (Gorelova
et al. 2002; Kroener et al. 2006
; Zhou and Hablitz 1999)
and decreased glutamate release probability (Gao et al.
2001; Seamans et al. 2001a; Zhou and Hablit z 1999) domi-
nate the D1-mediated effects, and cause a decrease of spon-
taneous firing in pyramidal cells. In contrast, firing evoked
by somatic current injection (Lavin et al. 2005) is likely to
depend to a larger degree on persistent Na
and slowly
inactivating K
currents. By enhancing the former and di-
minishing the latter, D1 receptor activation increases firing
evoked by intracellular current pulses (Dong et al. 2004;
Dong and White 2003; Gorelova and Yang 2000 ; Henze
et al. 2000; Yang and Seaman s 1996). In addition, strong
synaptic inputs driving PFC neurons to more depolarized
levels will remove the voltage-dependent Mg
block of
NMDA channels, amplifying the D1-mediated enhance-
ment of NMDA receptors, establishing a positive feedback
situation. Thus, the net enhancing effect of DA would be
much more dramatic in strong activity situations such as
persistent activity states (Goldman-Rakic 1995; Durstewitz
et al. 2000a; Wang and ODonnell 2001; Durstewitz and
Seamans 2002). D1-mediated effects lead to an enhance-
ment of sustained recurrent network inputs, while the
effects of weaker or brief inputs are usually diminished
(Seamans et al. 2001a; Durstewitz and Seamans 2002). The
DA modulation of the currents involved in these effects is
very protracted but collectively their combined effect can
be thought of as a form of increased signal-to-noise ratio
(Winterer and Weinberger 2004), favoring sustained and
high-rate at the expense of transient or low-rate inputs.
Unlike the protracted effects of DA on NMDA, Na
, and
currents in pyramidal neurons that lead to the effects
described above, DA appears to quickly and transiently
depolarize interneurons. DA has been shown to selectively
depolarize fast-spiking interneurons, yet has little effect
on other subtypes of interneurons (Gorelova et al. 2002;
Kroener et al. 2006). The depolarization and increased ex-
citability of fast-spiking interneurons is mediated solely
by D1 receptors in some studies (Gorelova et al. 2002;
Kroener et al. 2006) but also includes D2 receptors in
others (Tseng and ODonnell 2004). Surprisingly, the de-
polarization of FS interneurons and the simultaneous
increase in interneuronal excitability by DA occur on dif-
ferent time scales. For the same application of DA and in
the same interneuro n, the depolarization lasted for less than
10 min, while the increase in evoked firing lasted >40 min
(Gorelova et al. 2002; Seamans and Yang 2004; Kroener
et al. 2006). Because these two actions depend on DA modu-
lation of different K
currents in interneurons (Gorelova
et al. 2002; Wu and Hablitz 2005), these data raise the
interesting possibility that DA can act through the same
receptor to modulate different ionic currents on different
time scales to produce the different du ratio ns of changes in
612 Psychopharmacology (2007) 191:609625
Page 4
neuronal excitability vs membrane depolarization. Unlike
the slower changes in evo ked excitability, the depolar iza-
tion of interneurons that can be observed with the focal
pressure application of DA occurs within seconds of DA
application (Fig. 1). However, the exact time frame of this
depolarization is not clear due to technical constraints when
using focal pressure application, such as the d iffusional
properties of the brain slice and variability in the placement
of the pressure application pipette relative to the cell being
recorded. However, at least in the brain slice preparation,
this potent and relatively short-lived effect of DA on fast
spiking interneurons is not observed for the DA m odulation
of a variety of intrinsic and synaptic currents in PFC pyra-
midal and interneurons (Gorelova et al. 2002; Gonzalez-
Burgos e t al. 2005; Gulledge and Jaffe 2001; Henze et al.
2000; Seamans et al. 2001a,b ;Yang and Seamans 1996).
Fast-spiking interneurons that are the targets of this DA
modulation synapse near the spike initiation zone of
pyramidal neurons and directly regulate their spike initia-
tion and timing (Szabadics et al. 2006; Tamas et al. 2000).
Thus, a synchronous DA-mediated depolarization of fast-
spiking interneurons might be a highly effective way to
quickly shut off pyramidal neuron activity, and this could
contribute to the transient inhibition in spontaneous firing
after VTA stimulation or DA iontophoresis discussed above.
Accordingly, Pirot et al. (1992) showed that the GABA
antagonist bicuculline blocked the iontophoretic DA and
VTA-mediated inhibition of spontaneous firing in 57 and
51% of cells, respectively. Moreover, a D2 antagonist re-
duced the DA-mediated and VTA stimulation induced in-
hibition of spontaneous firing in PFC in 89 and 54% of
cells, respectively. Furthermore, depleting DA stores by
pretreatment with α-methly-p-tyrosine reduced the number
of cells inhibited by VTA stimulation to 39% and in this
subset of cells the VTA-induced inhibition was no longer
influenced by sulpiride (a D2 antagonist), but was blocked
by bicuculline (Pirot et al. 1992). Thus, there is both a DA-
dependent activation of local GABAergic interneurons and
direct inhibition of PFC neurons through GABAergic
The direct effect of GABAergic interneurons by VTA
stimulation may relate to potentially unique properties of
Fig. 1 Orders of magnitude in the observed time course following
dopamine (DA) application or VTA stimulation. a A very fast EPSP
IPSP sequence can be recorded in prefrontal cortical cells after
stimulation of the VTA in-vivo. The EPSP is evoked with a latency on
the order of milliseconds and is thought to be the result of corelease of
glutamate from dopamine cells in the VTA. b Depolarization of a fast-
spiking interneuron by DA in the prefrontal cortex in vitro. Local
pressure application of DA leads to depolarization and repolarization
of the membrane potential that seems to follow the diffusion of the
drug in the slice on the timescale of seconds (Kroener and Seamans,
unpublished observations). c Modulation of a variety of intrinsic and
synaptic currents by DA has been shown to occur over minutes and
hours both in vivo and in vitro. Activation of D1- and D2-type
receptors occurs in both pyramidal cells and interneurons, adding to
DAs ability to modulate network behavior. The time course and
direction of some of the effects indicated in the diagram have been
shown to be concentration- and receptor-specific. It is assumed that in
vivo the very long lasting effects that have been reported in
experimental s ettings can be curtailed by fluctuating levels of
extracellular DA and opposing effects at the different DA receptors
that result from it. See text for details
Psychopharmacology (2007) 191:609625 613
Page 5
the DA system. The feed-forward activation of PFC inter-
neurons by DA neurons is reflected in the EPSPIPSP
sequences evoked by VTA stimulation in PFC pyramidal
neurons recorded intracellularly in vivo (Fig. 1; Lavin et al.
2005; Lewis and ODonnell 2000; Mercuri et al. 1985;
Seamans et al. 2003; Tseng et al. 2006). The EPSPIPSP
sequence potently inhibits PFC firing for the duration of the
IPSP (200 ms) and likely accounts for much of the de-
scribed fast inhibition of spontaneous firing of PFC neurons
after VTA stimulation in in vivo single unit recordings
(Bunney and Aghajanian 1976; Ferron et al. 1984; Godbout
et al. 1991; Mora et al. 1976; Pirot et al. 1992). The mech-
anisms responsible for generating this EPSPIPSP se-
quence will be discussed in more detail below.
Collectively, these data suggest that the fast excitation of
local interneurons and a VTA-induced IPSP contribut e to
the classic observation of a brief reduction in spontaneous
firing of PFC neurons. On the other hand, modulation of
intrinsic and NMDA synaptic currents by DA contribute to
the enhancement in currentpulse evoked excitability as
well as the amplification of sustained recurrent or particu-
larly strong depolarizing inputs. In this way, diverse effects
of the DA system act through a variety of seemingly
unrelated mechanisms and on multiple time scales to both
transiently inhibit spontaneous firing, while enhancing the
efficacy of depolarizing inputs over prolonged time scales.
Beyond DA: the nature of the EPSPIPSP
in the VTA-PFC pathway
As noted above, stimulation of the VTA evokes an EPSP
IPSP sequence in PFC neurons recorded intracellularly in
vivo, or in field recordings from the PFC (Fig. 1; Lavin
et al. 2005). One of the first reports of VTA-induced EPSPs
in PFC was given by Mercuri et al. (1985 ). In this study, a
fast monosynaptic EPSP was record ed in the PFC of rats
when the medial forebrain bundle was stimulated. Similar
studies have observed evoked EPSPs in the striatum after
electrical stimulation of the substantia nigra (Guyenet and
Aghajanian 1978; Hull et al. 1973; Kocsis and Kitai 1977;
Preston et al. 1981). Kocsis and Kitai (1977) observed a
fast EPSP evoked in the caudate nucleus when the SN was
stimulated. In addition to the fast-evoked EPSP, the authors
also reported the presence of a slower EPSP. This slow
EPSP was blocked by simultaneous orthodromic stimula-
tion (collision), thus suggesting that it was an antidromic
response. However, the fas t excitatory response was
maintained and may have been carried by DAergic fibers.
Thus, these studies were instrumental in suggesting an
excitatory role for DA neurons.
Recent studies have sought to elucidate the mechanisms
that mediate these fast excitatory responses using in vivo
recordings. Lavin et al. (2005) found that when the VTA
was stimulated pharmacologically or elect rically, an excit-
atory event was recorded using both field potential record-
ings and intracellular recordings in PFC. These responses
were blocked by a glutamate antagonists, but not by DA
antagonists. However, when the VTA was unilaterally le-
sioned with 6-hydroxydopamine, the fast-response evoked
by the VTA stimulation was abolished in the hemisphere
ipsilateral to the lesion, while excitatory responses in the
contralateral hemisphere rema ined intact, collectively sug-
gesting that it was mediated by release of glutamate from
DA neurons and not antidromic activation of descending
PFC-VTA fibers or fibers passing by the VTA. However, a
surprising result from our characterization of the fast EPSP
evoked by VTA stimulation was that the onset latency of
the response seemed to be faster than what is commonly
reported for DA axons (Lavin et al. 2005). DA axons in the
rat are unmyelinated; thus, implying that propagation of
action potentials through the axon will be rather slow com-
pared to a myelinated axon (Siggins 1978; Chang et al.
1981). Based on antidromic activation, the conduction ve-
locity reported for VTA-cortical fibers ranges between 0.55
and 11.5 m/s (Deniau et al. 1980; Thierry et al. 1980). The
fast conduction (11.5 m/s) fibers are unaffected by 6OHDA
lesions and are likely myelinated non-DA fibers (Glowinski
et al. 1984; Thierry et al. 1980). The lower conduction
value of 0.55 m/s for unmyelinated mesolimbic DA fibers
is similar to the 0.58 m/s reported for nigrostriatal DA
fibers (Guyenet and Aghajanian 1978). The predicted onset
latency for a pathway of this length from the VTA to PFC
(not accounting for synaptic delays) is expected to be
between 9.5 and 18 ms. However, VTA stimulation often
evoked a field or intracellular EPSP with onset latencies
faster than these values (Lavin et al. 2005; Fig. 1). There-
fore, such fast conduction velocities continue to represent a
potential problem for the idea that the EPSP is generated by
DA neurons.
Because conduction velocities are usually calculated
based on antidromic activation, EPSP latency estimates are
only correct if one assumes that conduction velocities are
equivalent in both the ortho- and antidromic direction. DA
neurons have atypical morphological features that may
influence their assumed conduction velocities (Gauthier
et al. 1999; Hausser et al. 1995; Prensa and Parent 2001;
Preston et al. 1981; Tepper et al. 1987). One feature of the
DA neuron is that often the axon of the DA neuron orig-
inates from the apical dendrite (Prensa and Parent 2001;
Tepper et al. 1987). The somata of DA n eurons are
typically 2030 μm in diameter with three to six primary
dendrites emanating from it. The primary dendrites extend
for about 2040 μm before bifurcating into secondary
dendrites (Prens a and Parent 2001). Often, the axon
branches from a primary dendrite within 40 μm of the
614 Psychopharmacology (2007) 191:609625
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soma (Gauthier et al. 1999; Prensa and Parent 2001;
Tepper et al. 1987). However, it has been observed that the
axon can be as far as 250 μm from the soma (Ha usser et al.
1995; Fig. 2). Furthermore, in DA neurons there seems to
be heterogeneity within the make-up of the axon itself, with
at least two different types of axons being evident in single-
neuron tracings (Prensa and Parent 2001). These two types
of DA axons project to different postsynaptic targets and
they are characterized by different apparent diameters and
properties, and presumably different conduction velocities
(Prensa and Parent 2001).
In DA neurons, where the axon arises from the dendrite,
it could be that action potentials are initiated first in the
dendrites (or axon initial segment located on the dendrite)
from where they pass directly into the small diameter, low
capacitance, high input resistance axon, bypassing the
soma. It has been shown in motorneurons that axons can
be fired independently of the soma or initial segment
(Gogan et al. 1983), and in pyramidal cells spike initiation
most often occurs in the axon initial segment (Colbert and
Johnston 1996). However, with antidromic spike initiation,
the spikes would have to propagate from low (axon) to high
(dendritic stem, soma) capacitance/low input resistance
regions, resulting in a higher likelihood of failures and
potential delays. Hence, the dynamic of the action potential
propagation may differ for antidromic and orthodromic
propagation, thus leading to different transmission delays
for the two directions. Indirect support for this hypothesis
was found in an elegan t study performed by Hausser et al.
(1995) that suggests that the flow of current to initiate an
action potential in DA neurons may go from the dendrites
to the axon and then to the soma, rather than from the
dendrites to the soma, and then finally the axon. Given that
the site of action potential initiation is in the axon just
beyond the initial segment (Colbert and Johnston 1996), a
dendrite that gives rise to an axon may be in a position to
bring the axon to threshold and circumvent the soma
altogether, a possibility that Hausser and coworkers termed
the privileged dendrite (Hausser et al. 1995). In the case
of a DA neuron, antidromic activation would involve the
soma because this is the site sampled in extracellular single
unit recordings. In contrast, a stimulating electrode need not
activate the soma orthodromically. Therefore, conduction
velocity asymmetries may be pronounced in the case of DA
neurons, making it difficult to compare conduction veloc-
ities using different techniques. A resolution of this issue
awaits future investigations.
Assuming that it is actually DA neurons that are re-
sponsible for the fast EPSPs then it supports the idea of
glutamate corelease by DA neurons (Sulzer et al. 1998).
DA neurons in culture are capable of making excitatory
synapses utilizing glutamate as a cotransmitter (Dal Bo et al.
2004; Sulzer et al. 1998). Because neurons grown in culture
often lack their usual postsynaptic targets, they frequently
form synaptic connections with themselves, at a rate much
higher than what occurs in the intact brain (Bekkers 1998).
These autapses allow for the study of pre- and postsynap-
tic mechanisms that govern neurotransmitter release in the
same cell. In this preparation, it was found that DA neurons
form excitator y autapses that release glutamate (Sulzer et al.
1998). Furthermore, it was shown that DA neurons in cul-
ture and in vivo also contain vesicular glutamate transporter
2 (VGluT 2), a protein that is responsible for packaging
glutamate into vesicles (Dal Bo et al. 2004 ). A possible
confound of these studies are dedifferentiation processes
known to occur in culture that potentially could lead to an
aberrant release phenotype, which may not truly represent a
process found in vivo. However, evidence for VGluT2
Fig. 2 Anatomy of a dopaminergic VTA neuron, illustrating the distal
dendritic location from which the axon can originate. Composite
confocal images of a VTA neuron recorded in a coronal brain slice of
a transgenic mouse expressing green fluorescent protein under the
control of the TH gene promoter (TH-GFP+). The green cell was filled
with a red dye (Alexa 594) during the recording, resulting in a yellow
signal in the merged image. The insert represents a magnified view of
the white square in the main picture. The arrow points where the axon
(on the right) branches off the dendrite
Psychopharmacology (2007) 191:609625 615
Page 7
expression has also been found in acute midbrain prepara-
tions as well (Hur and Zaborszky 2005).
In a quantitative analysis of VGluT2 expression in VTA
(A10), Kaw ano et al. (2006) reported that 19% of the total
TH-labeled neurons also expressed mRNA for VGLUT2,
yet, remarkably, such signal was largely absent in A8 and
A9. The percentage was as high as 52.7% in the rostral
linear nucleus (RLi) of the VTA which is a rostral midline
nuclei projecting preferentially to PFC and limbic regions
(Swanson 1982). Accordingly, VTA neurons expressing
VGluT2 mRNA were retrogradely labeled from PFC (Hur
& Zaborszky 2005). However, almost half of the neurons in
VGluT2-rich areas of VTA expressed mRNA for VGluT2
but were TH-. It was suggested that these glutamatergic
non-DA VTA neurons may be the myelinated high
conduction velocity fibers originally described by Thierry
et al. (1980) (Kawano et al. 2006). Therefore, this
represents another possible explanation for the observed
fast onset latencies we observed (Lavin et al. 2005). These
fast EPSPs may then merge with slower onset EPSPs
arising from corelease of glutamate from nonmyelinated
DA neurons. It is likely that both DA and non-DA subtypes
of VTA neurons were recorded in behavioral physiology
experiments because they cannot be dissociated electro-
physiologically (Margolis et al. 2006 ).
Using a unique brain slice preparation that left the VTA-
NAcc projection intact, Chuhma et al. (2004) found that
electrical or pharmacological stimulation of the VTA could
evoke a fast glut amate-mediated response in the NAcc. Fur-
thermore, this study showed that the fast response after VTA
activation was modulated by the D2 agonist quinpirole. This
indicates that D2 receptors, which are located presynaptic in
the SN/VTA, are able to modulate the release of glutamate
from DA neurons (Meador-Woodruff et al. 1989; Sesack
et al. 1994). Taken together, these data support the notion
that DA neurons can provide a fast excitatory signal via
corelease of glutamate, and that DA itself is acting as a
neuromodulatory influence.
However, several issues with this interpretation remain.
One of them, discussed above, relates to the fast onset la-
tencies of EPSPs from putatively unmyelinated DA axons.
Furthermore, several studies found evidence for a third
population of neurons in the VTA, which are not consi dered
to be GABA or DA cells, and that in theory could mediate
these excitatory events (Margolis et al. 2006; Ungless et al.
2004). Another issue is the fact that only a small portion of
DA positive fibers to the PFC makes asymmetric synapses
indicative of glutamate (see above). However, because in the
EM studies discussed above DA immunoreactivity was used
to detect DA axons, these data may underestimate the
number of asymmetric synapses, if some axon terminals
from DA neurons contain glutamate, while others only
contain DA (Sulzer et al. 1998). A much high proportion of
VGLUT2/TH+ terminals exhibit synaptic specializations
than for singly labeled TH+ terminals (Berube-Carriere et
al. 2006). Furthermore, asymmetrical synapse profiles may
not always reflect an accurate assessmen t of glutamatergic
release sites (Kaneko and Fujiyama 2002) as suggested by
recent findings based on the location of VGluTs (Fremeau
et al. 2002, 2004; Gras et al. 2002; Schafer et al. 2002).
Surprisingly, several studies have shown that synapses that
express VGluT3 often h ave symmetric profiles (Fremeau et
al. 2002; Gras et al. 2002; Herzog et al. 2004). Furthermore,
VGluT3 has been isolated in neurons that also expressed
other neurotransmitters tradi tionally not thought to partic-
ipate in excitatory neurotransmission, such as serotonin,
GABA, and acetylcholine (Hioki et al. 2004; Schafer et al.
2002). Yet, data that supports the expression of VGluT3 in
DA neurons is tenuous, with studies finding that VGluT3
and Tyrosine Hydroxylase (TH) do not show clear colo-
calization (Fremeau et al. 2002; Gras et al. 2002). However,
there have been reports of colocalization of VGluT3 and the
vesicular monoamine transporter-2 (VMAT2). Furthermore,
it appears that the VGluT3 protein is expressed in the VTA;
however, reports are still conflicting concerning the ex-
pression of VGluT3 mRNA in the VTA (Fremeau et al.
2002; Herzog et al. 2004 ). Thus, although the fine details of
VGluT3 expression are pending, these data indicate that we
must reevaluate what we consider a unique marker of glu-
tamatergic synapses. Therefore, while certain issues related
to DA/glutamate corelease persist, it remains a viable option
for fast neurotransmission in the mesocortical system.
Functional signaling in the mesocortical pathway
Midbrain dopaminergic neurons exhibit a phasic burst of
action potentials imme diately after unexpected salient
events, which include sudden novel stimuli (Ljungberg
et al. 1992; Schultz and Romo 1990), and primary rewards
(Ljungberg et al. 1992; Schultz et al. 1993a,b; Ungless
et al. 2004). During the learning phase of a classical con-
ditioning task, reward-related activation of DA neurons first
occurs in response to the (unexpected) primary reward (the
unconditioned stimulus, US). If the US is paired with a con-
ditioned stimulus (CS), activation of DA neurons shifts to
the occurrence of the CS (Ljungberg et al. 1992; Schultz
et al. 1993a,b; Schultz 1998a,b). Both phasic responses to
the CS and US undergo task-dependent modulation in
firing rate (Tobler et al. 2005; Schultz 1998a,b). The initial
response to the CS is graded reflecting the probability and
salience associated with the cue. The more rewarding and
the more probable the delivery of the reward becomes, the
more DA neurons will respond to the CS (Fiorillo et al.
2003; Tobler et al. 2005). In contrast, the later US-asso-
ciated response appears to exhibit phasic activation only for
616 Psychopharmacology (2007) 191:609625
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rewards that are not predicted with high certainty, and the
magnitude of the phasic response incre ases as the pre-
dictability decreases (Fiorillo et al. 2003). Furthermore, if
the value of the US turns out to be less than expected or
aversive, a phasic cessation of tonic firing is observed
(Ljungberg et al. 1992; Schultz et al. 1993a,b; Schultz
1998b, 2002 for review; Ungless et al. 2004). This phasic
suppression may also scale with the reward predictability,
such that when the reward did not occur on trials with high
predictability, a great er suppression can be seen (Fiorillo
et al. 2003). Thus, the CS-associated phasic activation is
directly related to reward predictability, while the US-asso-
ciated phasic activation is inversely related. This suggests
that through phasic modulations in firing rate, DA neurons
initially encode an expectancy of forthcoming rewards
based on how accurate a CS proved to be in predicting the
US. The subsequent phasic US-associated response then
encodes how much better or worse the US turned ou t to be,
relative to what was expected based on precedi ng stimuli,
i.e., it encodes a prediction error. Although it is unclear
whether DA neurons themselves compute explicit reward
expectancies, DA neurons do appear to provide feedback
about such expectations.
The phasic activation of DA neurons could serve as a
teaching signal, instructing target areas to modify their syn-
aptic connections such that predictive links between CS and
US accurately reflect reward value, magnitude, and like li-
hood (Dayan et al. 2000; Fiorillo et al. 2003; Schultz 2002).
Thus, the underlying idea is that surprise (prediction mis-
match) drives the associati ve learning process, and if a
stimulus is no longer surprising (i.e., it is accurately pre-
dicted by a preceding stimulus) then DA is not released
because synaptic connections do not need to be modulated.
Indeed DA neurons fit predictions of formal learning
models as they exhibit the nontrivial blocking phenomenon,
in that they do not show phasic activation in response to a
second CS when it is paired with an established CS that by
itself accurately predicts reward (Waelti et al. 2001). Thus,
in summary, although the DA system may subserve dif-
ferent functions on different time scales (Schultz 2002), the
prediction error theory posits that a critical function of the
phasic DA signal is to create or modify associations of
stimuli according to violations of expectations.
A mino rity of DA neurons also exhibit sustained acti-
vations in the interval between the CS and the US during
trials in which the reward predictability is low. Fiorillo et al.
(2003) have suggested that this sust ained firing pattern
codes reward uncertainty because the sustained response
was largest for (1) stimuli that predicted reward 50% of the
time, or (2) for stimuli that predicted two rewards, which
were most different from each other in valence (i.e., small
to large). Therefore, if a CS tells the animal to expect an
event with an uncertain outcome, sustained DA neuron
activity intervenes between the CS and the outcome. In this
way, DA neurons may provide a sust ained attentional signal
to target areas in situations with uncertain outcomes. These
authors suggest that this type of uncertainty is rewarding in
itself and leads to the learning about stimuli or actions that
are good predictors of reward. In a similar vein, Redgrave
et al. (1999) proposed that DA release is responsible for
reallocating attentional and behavioral resources, alerting
the organism that a new or salient stimul us is present.
Again, both groups (Fiorillo et al. 2003; Schultz 2002;
Redgrave et al. 1999) have highlighted that even in the
context of DA-as sociated attentional processes the ultimate
function of the DA signal is still linked to the formation of
associations. As the consistent interpretation of these data is
that the activity of dopam inergic neurons provides an es-
sential signal for reinforcement learning (Schultz 1998a,b;
c.f. also Montague et al. 1996), the question is then whether
we really need DA to learn reward associations.
DA receptor antagonists have been shown to impair
acquisition of conditioned place preference (Duarte et al.
2003; Spyraki et al. 1982
) and Pavlovian approach behavior
(Di Ciano et al. 2001). However, recent studies employin g
mice genetically engineered to lack DA have greatly refined
the role of DA in reinforcement learning. DA-deficient
mice do not perform a learned task and even stop eating in
the absence of
L-dopa or caffeine, highlighting the
importance of DA in motivation. Yet, when temporarily
taken off
L-dopa, these mice nevertheless prefer a sucrose
solution to water, suggesting that the circuitries, which
mediate food preference, are intact in mice unable to make
DA (Cannon and Palmiter 2003). Similarly, DA-deficient
mice are able to learn reward associations in an appetitive
T-maze task (Robinson et al. 2005) and conditioned place
preference (Cannon and Patel 2006). DA-deficient mice
also exhibit conditioned place preference to morphine,
suggesting that DA is not required for making predictions
or associations with cues previously paired with reward
(Hnasko et al. 2005). Conversely, mice with chronically
elevated extracellular levels of DA produced by knock-
down of the DA transporter show no effects in Pavlovi an
and operant learning for reward, even though this manip-
ulation significantly enhances the tendency to work for a
food reward (Cagniard et al. 2006). These studies suggest
that DA per se is not required for associative learning about
reward or the accurate processing of reward itself. Rather,
they are more consistent with the idea that DA is instrumen-
tal in pursuing and focusing the behavior on current goals
and shielding them from distraction (Durstewitz et al. 1999,
2000a; Salamone et al. 2005; Cannon and Palmiter 2003;
Denenberg et al. 2004; Heusner et al. 2003; Hnasko et al.
2005; Sotak et al. 2005).
It should be noted that DA-deficient mice or DA
transporter knockdown mice may express compensatory
Psychopharmacology (2007) 191:609625 617
Page 9
mechanisms to counteract potential effects on associative
learning, which could make it difficult to reconcile these
data with earlier studies that showed a role of DA in
associative learning related to reward. Yet, there are
additional issues related to the physiological properties of
the mesocorticolimbic DA system that place constraints
on what the syst em is capable of in terms of modulating
precise associations. If DA signals are to ena ble correct
predictive links between a CS and the US, then they
must be tightly associated with the occurrence of the
stimuli, so that stimuli that follow the US in time get not
mislabeled as predictors. Similarly, the synaptic changes
supposed to encode the predictive link need to be
specific for this CSUS combination and should not
represent an indiscernible temporal integral across many
different subsequent US with differing reward values,
magnitudes, and likelihoods.
Again, the firing properties of DA neurons seem to fit
the prediction error scheme perfectly, yet temporally con-
strained messages are not effectively transmitted by DA.
DA release is often slow and prolonged, and DA effects on
target neurons in PFC usually develop over a protracted
timecourse, lasting for tens of minutes. Simply put, the
postsynaptic effects of DA in PFC neurons lack temporal
precision in their onset and in their offset. Microdialysis
studies show that behaviorally relevant events, whether
they be appetitive or aversive, increase PFC DA levels
slowly and for prolonged periods (Phillips et al. 2004;
Feenstra and Botterblom 1996; Di Chiara et al. 1999).
Similarly, the presentation of a CS associated with cocaine
elevates levels of DA in the striatum for 5 s as assessed
using fast -scan cyclic voltammetry (Phillips et al. 2003). In
the PFC, we observed that the response to a similar brief
4 s release of DA exerts extremely protracted postsynaptic
effects. Stimulation of the VTA at 20 Hz/2 s evoked a 4s
rise in DA in PFC measured using fast-scan cyclic
voltammetry, but this phasic rise in DA produced a change
in the evoked excitability of PFC neurons that developed
over a 10-to 15-min period and often lasted over an hour in
vivo (Lavin et al. 2005). In the same cells, spontaneous
firing was decreased for many minutes, similar to what has
been reported using extracellular single unit recordings
(Au-Young et al. 1999). This phenomenon of slowly de-
veloping and protracted effects is mimicked by application
of DA or its selective receptor agonists in vitro on a variety
of ionic currents in PFC neurons and in a variety of pre-
parations (Yang 2000; Umemiya and Raymond 1997;
Cameron and Williams 1993; Huang and Kandel 1995;
Gribkoff and Ashe 1984; Se amans et al. 2001a,b;
Trantham-Davidson et al. 2004; Seamans and Yang 2004;
Gorelova et al. 2002 ; Gorelova and Yang 2000; Chen and
Yang 2002; Urban et al. 2002 ; Gonzalez-Burgos et al. 2005;
Henze et al. 2000; Kroener et al. 2006; Gorelova et al.
2002; Gulledge and Jaffe 2001; Wang and ODonnell 2001
Fitch et al. 2006; Matsuda et al. 2006; Yang and Chen
2005; Young and Yang 2005; Yang and Seamans 1996;
Floresco et al. 2001a,b; Cheer et al. 2005). Although the
mechanisms that underlie this slow modulati on are not
entirely clear and it remains possible that eventually a fast
acting DA effect will be discovered, given the current state
of knowledge, the sluggish and protracted effects of DA
appear to represent the predominate mode of action of DA
on target neurons in the PFC.
How could DA provide sufficiently specific information
to the PFC about the predictive link between a CS and a
reward, if its effects are so slow to develop and lingering
and the effects of even a phasic release of DA may last tens
of minutes? A prediction e rror signal must have two
essential properties: (1) It should be retrospective in the
sense that only stimulus associations preceding the to-be-
predicted event in time are influenced by the predi ction
error signal because by definition, only these can be
temporal predictors of the subsequent reward. Hence, this
hypothesis requires that both the onset and the offset of the
prediction error signal are sufficiently fast such that stimuli
occurring later, after the actual rewarding event, are not
mislabeled as potential predictors of the event. (2) There
must be some mechanism that ensures that different
prediction error signals are not integrated over extended
periods of time in such a manner that they, for instance,
simply cancel each other out. For instance, a rewarding plus
a subsequent punishing event may not simply sum up to
make a neutral eventthe animal may still want to seek out
the former while avoiding the latter. Moreover, it may be
important that neutral stimuli following the specific US do
not get mislab eled as to-be-predicted rewards, simply
because the prediction error signal is active for too long.
Hence, for this condition to be fulfilled, once again either
the initial physical carrier of the prediction error signal
(DA) must have a sufficiently quick offset, or the molecular
and phys iological processes initiated by DA must be
terminated or desensitize sufficiently rapid. Thus, this
requirement would imply that the cellular processes that
translate the prediction error signal into synaptic changes
are effectively sensitive only to changes in DA concentra-
tion, no t DA concentration itself.
From the previous discussion, we review a wealth of
evidence suggesting that DA has a very slow decaying time
course, much too slow to provide a sufficiently rapid
termination of the prediction error signal. This necess itates
that the p ostsynaptic cell must somehow be able to
terminate DA effects shortly after the release event occurs.
However, a mechanism that is calibrated to detect only
changes in DA concentration, besides the fact that evidence
for it is currently lacking, will only have a limited
operational range. Hence, the fact that DA itself lingers
618 Psychopharmacology (2007) 191:609625
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around for so long and decays only very slowly especially
in PFC, is certainly not helpful for such a mechanism either,
as it bears the risk that the operational range is quickly
exceeded by piling up reward signals. Furthermore, many if
not all of the DA-induced cellular processes have a very
slow offset time themselves, independent of the presence of
DA. For instance, D1-induced changes in GABA
could persist for tens of minutes after washout of the
agonist (Seamans et al. 2001a,b). Putting this together, it
seems unlikely that the DA-induced cascade has sufficient-
ly rapid offset times or desensitization properties that would
prevent prolonged temporal integration of prediction error
As reviewed here, the buildup of DA in extracellular
space is itself not very rapid. Furthermore, DA exerts all of
its postsynaptic effects through metabotropic, G-protein-
coupled receptors in PFC, with many of the subsequent
molecular processes having time constants in the range of
seconds to minutes (Bhalla and Iyengar 1999; Greengard
2001; Nishi et al. 2002, 2005). In fact, it takes many seconds
to minutes for the expression of DA-induced changes in the
properties of voltage-gated or synaptic channels.
To summarize, both the onset and offset times of the
processes associated with DA relea se seem too slow to
support the signaling properties required for an effective
prediction error signal. Because the onset of the signal is at
least seconds too slow, stimuli subsequent to the to-be-
predicted event could be falsely labeled as predictors, if DA
carries this signaling burden. Moreover, because DA offset
is too slow, prediction error signals could be integrated
across time such that different events with different reward
signs and magnitudes would be confounded, a nd no clear
predictive links could be efficiently formed. Because DA
release is spatially diffuse and receptors are extra synaptic it
furthermore implies that many if not most synapses are
affected by a DA release event. This may pose no problem
for a reinforcement theory as long as DA onset and offset
signals were sufficiently fast. However, because this is not
the case, the anatom y and kinetics of the PFC DA system
probably rule out any potential solution based on tight spatial
As we have argued here and previously, corelease of
glutamate from DA neurons could be one mechanism that
provides an alternative solution to this dilemma (Lavin et
al. 2005; Seamans and Yang 2004). It is tempting to
speculate that glutamate is able to carry the burden of fast
reward processing. This may occur through the conver-
gence of glutamate released by DA and non-DA VTA
neurons with other excitatory inputs in the cortex and basal
ganglia to trigger the formation of specific predictive links
to reward related stimuli. However, DA may help to
maintain the representation of the initial predicting stimulus
(Durstewitz et al. 2000a,b), even in the face of distraction,
such that the associative link across time can be formed. It
follows that mice that are DA deficient are still able to
make reward related associations, but they may not be as
effective at processing reward-related information as their
wild type counterparts.
Putative roles for the three modes of the mesocortical
dopamine system
If corelease occurs, it would be perfectly suited to transmit
the temporally precise information encoded by bursting
activity of DA neurons. Glutamate release onto pyramidal
neurons and interneuro ns is extremely efficient at activating
or inactivating neurons on precise millisecond timescales.
In contrast, as argued above, DA is not well suited for this
task. Therefore, we argue that the fastest processing time-
scale of the DA system is on the order of milliseconds and
is subserved by release of glutamate (Fig. 1 a). We propose
that glutamat e may carry the temporally precise signal
encoded by DA neuron firing that is critical for a prediction
error signal (Schultz 2002).
Upon activating D1 receptors on fast spiking interneu-
rons, a variety of ionic currents are modulated in a pro-
tracted manner (Gorelova et al. 2002; Seamans and Yang
2004); however, the modulation of currents that produce
membrane depolarizations occur on the order of seconds
(Fig. 1). Gorelova et al. (2002) showed that the DA-
mediated depolarization of fast spiking interneurons oc-
curred through modulation of a leak current, while the
increase in excitability to depolarizing current pulses
occurred via modulation of inwardly rectifying and slowing
inactivating K
currents. Although all three currents are
targeted by DA D1 receptors, it is only this fast depolar-
ization via modulation of a leak current that is capable of
activating fast-spiking interneurons directly because DA
modulation of the other currents only serves to increase the
excitability to subsequent inputs.
Fast-spiking interneurons are capable of precisely
timing the firing of pyramidal neuronsasspikesreliably
occur at the offset of IPSPs (Cobb et al. 1995; Tamas et
al. 20 0 0; Fricker and Miles 2001). Because spike-timing
dependent plasticity strongly relies on precise timing of
action potentials (Bi and Poo 1998), DA-mediated depo-
larization of interneurons may augment this process.
While speculati ve , the phasic activa tio n of interne uro ns
could increase the temporal precision of spiking in
pyramida l neurons and thus ensur e that pre a nd postsyn-
aptic spikes fall in the 10 ms window necessary for
synaptic strengthening or depression (Bi and Poo 1998).
This modu latio n of int er neur ons could facili tate a putative
role for DA in regulating associ ative strength between
synapses as discussed above. Its role would not be to
Psychopharmacology (2007) 191:609625 619
Page 11
strengthen synapses directly or to provide specific
reward-related inform ation. Rather, by briefly activating
fast-spiking interneurons temporal precision in neural
firing of target neurons would be amplified for a brief
interval surr ound ing a pha si c DA relea se eve nt . How-
ever, the reverse is also possible as DA-mediated
activation of f ast spiki ng interne uron s could shut down
activity in PFC briefly and thereby hinder the formation
of synapt ic as so ciat ion s. I nd eed , mo st evidence supports
this latter view because the oft reported brief inhibition
in firing of PFC neurons recorded extracellularly by
VTA stimulation or DA i ontophoresis is blocked by a
GABAergic antagonist (Pirot et al. 1992). Moreover, the
spatial t unin g o f w or ki ng memory fields in behaving
primates is abolished by a GA BAergic a nt agonis t an d
enhanced by low d oses of a D1 recepto r antagonist
presumabl y by removing t he D1-mediated modulation of
interneuron activity (Williams and Goldman-Rakic 1995;
Goldman-Rakic et al. 2000).
This relati vel y fast modulation of FS interneurons,
together with the feedforward inhibition of prefrontal cells
through the EPSPIPSP may serve as a stop signal that
could help to shut off further input to the PFC from other
brain regions in situations where a biologically significant
event just occurred, and the stimuli preceding it have to be
maintained and shielded from distraction to allow for the
predictive links to be formed.
Finally, the slowest and most commonly observed mode
of DA modulation in PFC occurs on the order of minutes to
hours (Fig. 1c). This type of long-lasting modulation has
been observed for a variety of currents via both D1 and D2
receptors (Dong et al. 2004; Gao et al. 2001; Gao and
Goldman-Rakic 2003; Gorelova et al. 2002;Gorelovaand
Yang 2000; Gulledge and Jaffe 2001; Henze et al. 2000;
Seamans and Yang 2004; Seamans et al. 2001a,b; Trantham-
Davidson et al. 2004; Yang and Seamans 1996). Many of
these currents, including NMDA and K
currents, are critical
to associational models of synaptic memory. Although
seemingly diverse, computational models of the D1-mediat-
ed modulations suggest that they converge on a single
function, which is to make networks of PFC neurons more
robust to distraction and noise (Compte et al. 2000;
Durstewitz et al. 2000a,b; Durstewitz and Seamans 2002).
Simulated D1-mediated modulation leads to a deepening and
widening of the basins of attraction of working memory
states of the network, while simultaneously decreasing
background activity. This phenomenon has been described
as an increase in signal to noise or an increase in cortical
efficiency (Winterer and Weinberger 2004). It is advanta-
geous when a single goal state must be maintained in the
face of distractors.
In contrast, D2 receptor activation often has opposing
effects on ionic currents to D1 receptor activation (Seamans
et al. 20 01b; Trantham-Davidson et al. 2004; Zheng et al.
1999) and as a result has an opposing effect on PFC
networks, making them less robust to distraction and noise.
The upside of this type of modulation is that the networks
are much more flexible in incorporating new inputs and in
dealing with more items nearly simultaneously (Durstewitz
et al. 2000a,b). As a result, D2 receptor activation may
provide a resetting mechanism allowing working memory
buffers to incorporate new information. Moreover, D2-
mediated effects on a given postsynaptic current tend to be
somewhat briefer than D1-mediated effects (Seamans et al.
It must be emphasized, that although these effects last
minutes to hours (Fig. 1c) this is only true when the
system is left unperturbed, as is the case in both the acute
brain slice preparation and the in vivo anesthetized
preparation. It is possible that no single effect is so
protracted in an intact awake brain. Preferential D1 vs D2
modulation in PFC occurs at different DA concentrations
(Trantham-Davidson et al. 2004) and as a result they may
have truncating influences on each other when activated
by natural variations i n DA levels. Even the peak D1
mediated effect can be reversed by application of a D2
agonist and vice versa (Seamans et al. 2001b). This
indicates that DA mediated e ffects need not be locked in
for minutes to hours, but can be r eversed under the
appropriate conditions, although even these reversing
effects take seconds to minutes to set in and are too slow
to address the issues raised above. Thus, in vivo, as the
animal i s exploring i ts environment, VTA cell activi ty may
exhibit stimulus-dependent variations that result in varia-
tions in PFC DA levels. Al th ough the variation s ma y n ot
be highly temporally precise o r spatially localized due to
the properties of the PFC DA system, the variations may
continually cross the threshold for preferential D1 vs D2
receptor activation. As a result, PFC networks will
dynamically switch between the two theorized states,
constantly incorporating new information (D2) and then
locking it i n robustly (D1). Likew ise, other neuromodula-
tory syst ems could a lso potentiall y reverse the effects of
DA on a given curr ent. Hence, most of the DA modulation
of PFC ne uron s may in fact only be lo ng-l astin g if nothing
happens to reverse or counteract their effects. Potentially,
in different situations, each current could be in a different
state of modulation depending on the relative D1 vs D2
receptor activation. In this way, the state of the PFC may
be in flux at any given moment. In the context of Fig. 1c,
if any combination of red and green arrows could be
present at any given time, the staggering richness and
complexity of DA signaling b ecomes apparent. T his
richness of neuromodulation may be a key component
that unde rli es complex c ogni tive processes mediated b y
the PFC.
620 Psychopharmacology (2007) 191:609625
Page 12
Acknowledgement This work was supported by the National
Institutes of Health (C06 RR015455), from the Extramural Research
Facilities Program of the National Center for Research Resources, and
NIDA 14698 (AL).
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  • Source
    • "The GABAergic neurons of the tVTA/RMTg provide a major inhibitory control to VTA DAergic neurons (Kaufling et al., 2010;Matsui and Williams, 2011). In addition to VTA DAergic and GABAergic neurons, early electrophysiological studies of the midbrain suggested the possibility of glutamatergic signaling by some VTA neurons (Wilson et al., 1982;Mercuri et al., 1985;Sulzer et al., 1998;Joyce and Rapport, 2000;Chuhma et al., 2004;Ungless et al., 2004;Lavin et al., 2005;Chuhma et al., 2009). Anatomical identification of glutamatergic neurons has recently become possible due to the cloning of three distinct vesicular glutamate transporters (VGluT1, VGluT2, and VGluT3;Bellocchio et al., 1998;Bai et al., 2001;Fremeau et al., 2001Fremeau et al., , 2002Fujiyama et al., 2001;Hayashi et al., 2001;Herzog et al., 2001;Takamori et al., 2000;Varoqui et al., 2002;Gras et al., 2002). "
    [Show abstract] [Hide abstract] ABSTRACT: The ventral tegmental area (VTA) is an evolutionarily conserved structure that has roles in reward-seeking, safety-seeking, learning, motivation, and neuropsychiatric disorders such as addiction and depression. The involvement of the VTA in these various behaviors and disorders is paralleled by its diverse signaling mechanisms. Here we review recent advances in our understanding of neuronal diversity in the VTA with a focus on cell phenotypes that participate in 'multiplexed' neurotransmission involving distinct signaling mechanisms. First, we describe the cellular diversity within the VTA, including neurons capable of transmitting dopamine, glutamate or GABA as well as neurons capable of multiplexing combinations of these neurotransmitters. Next, we describe the complex synaptic architecture used by VTA neurons in order to accommodate the transmission of multiple transmitters. We specifically cover recent findings showing that VTA multiplexed neurotransmission may be mediated by either the segregation of dopamine and glutamate into distinct microdomains within a single axon or by the integration of glutamate and GABA into a single axon terminal. In addition, we discuss our current understanding of the functional role that these multiplexed signaling pathways have in the lateral habenula and the nucleus accumbens. Finally, we consider the putative roles of VTA multiplexed neurotransmission in synaptic plasticity and discuss how changes in VTA multiplexed neurons may relate to various psychopathologies including drug addiction and depression.
    Full-text · Article · Jan 2016 · Journal of chemical neuroanatomy
  • Source
    • "Finally, it should also be underscored that, despite current and accumulating evidence suggesting a role of dopamine in affecting feedback-related ERPs, it is conceivable that the observed links (in the current and other studies) between dopamine genotype effect and ERP components of reinforcement learning are less direct than often assumed and may be mediated by interactions between transmitter systems. For instance, it has been suggested that a corelease of glutamate from midbrain dopaminergic neurons might underlie midbrain-prefrontal interactions in the sub-second range as the effects of dopamine release in the PFC unfold too slowly (in the time range of seconds to minutes) to provide an effective updating of prediction errors (see Lapish et al., 2007 for a review, Lavin et al., 2005). Also, other than the frontal-striatal pathways, the striatum also projects to the nucleus basalis in the forebrain, which projects via cholinergic fibers to the cortex and might hence provide another route from the ventral striatum to the PFC (for a review, see Haber and Knutson, 2010). "
    Full-text · Dataset · May 2015
  • Source
    • "First, we utilized a single-pulse stimulus, instead of the traditionally used train stimulation, to stimulate the VTA in efforts to examine the timing-dependent effects of dopamine efflux (and not necessarily phasic dopamine release) on mPFC–NAc transmission. Several lines of evidence indicate that a single-pulse electrical stimulation can activate dopamine neuronal firing or evoke dopamine release [30,38] . Furthermore , the 100 ms pairing interval between the mPFC and VTA stimulations was selected on the basis of a previous study, in which a 200 ms interval was used but with train stimulation of the VTA [5], together with the known extracellular half-life of electrically-evoked dopamine release (less than 50–60 ms) [13]. "
    [Show abstract] [Hide abstract] ABSTRACT: In the nucleus accumbens (NAc), dopamine transmission modulates glutamatergic input from the prefrontal cortex (PFC). This neuromodulatory action of dopamine can be disrupted by repeated exposure to psychostimulants such as cocaine. However, it is unclear whether this modulation depends on the precise timing of transmission at the same medium spiny neurons (MSNs) and if so, then whether this timing related modulation is also influenced by cocaine experience. Here, combining cocaine self-administration and in vivo extracellular recordings in anesthetized rats, we show that dopamine efflux in the NAc evoked by electrically stimulating the ventral tegmental area (VTA) exerted timing-dependent regulation of the excitatory accumbens' response to stimulation of the medial prefrontal cortex (mPFC), and that this modulation was also blunted following prolonged abstinence from cocaine self-administration. These data indicate that dopaminergic timing-dependent dysregulation of mPFC-NAc glutamatergic transmission is implicated in cocaine addiction and might contribute to vulnerability to drug relapse after prolonged abstinence. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Mar 2015 · Physiology & Behavior
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