Synaptic Gating and ADHD: A Biological Theory
of Comorbidity of ADHD and Anxiety
1School of Psychiatry, University of New South Wales, Prince of Wales Hospital, Randwick, Australia
To derive a biologically based theory of comorbidity in Attention Deficit Hyperactivity Disorder (ADHD). Theoretical concepts and
empirical studies were reviewed to determine whether the behavioral inhibition concept provided an understanding of biological
processes involved in comorbidity in ADHD. Empirical studies of ADHD have shown comorbidity of ADHD and anxiety, while studies of
behavioral inhibition tend to suggest independent disruptive and anxiety traits. This paradox can be resolved by an understanding of the
dynamics of mesolimbic dopamine (DA) systems, where reward and delay of reinforcement are determined by tonic/phasic DA
relationships, resulting in impulsive ‘fearless’ responses when impaired. On the other hand, comorbid anxiety is related to impaired
synaptic processes, which selectively gate fear (or aggressive) responses from the amygdala at the accumbens. Monosynaptic
convergence between prefrontal, hippocampal, and amygdala projection neurons at the accumbens allows the operation of a synaptic
gating mechanism between prefrontal cortex (PFC), hippocampus, and amygdala. Impairment of this mechanism by lowered PFC
inhibition allows greater amygdala input, and anxiety-related processes more impact, over the accumbens. In conclusion, a dual theory
incorporating long-term tonic/phasic mesolimbic DA relationships and secondly impairment of PFC and hippocampal inputs to synaptic
gating of anxiety at the accumbens has implications for comorbidity in ADHD, as well as for possible pharmacological interventions,
utilizing either stimulant or axiolytic interventions. The use of DA partial agonists may also be of interest.
Neuropsychopharmacology (2004) 29, 1589–1596, advance online publication, 28 April 2004; doi:10.1038/sj.npp.1300469
Keywords: ADHD; dopamine; comorbidity; synaptic gating; behavioral inhibition
While there has been considerable interest in comorbidity
in Attention Deficit Hyperactivity Disorder (ADHD), as an
indicator of possible genetic subtypes (Biederman et al,
1992; Hudziac and Todd, 1993; Pliszka, 2000; Thapar et al,
2001), the biological basis of ADHD subtypes and
comorbidity is still poorly understood. During the 1990s,
inhibitory theories of ADHD have been largely dominated
by Barkley’s (1997a) theory of executive function, based on
incapacity to inhibit prepotent responses, stopping ongoing
responses, and inability to delay competing responses.
Barkley (1997b) linked inhibition to four executive neu-
ropsychological functions, which depended on it for
effective execution: nonverbal working memory; internali-
zation of speech (verbal working memory): self-regulation
of affect-motivation-arousal; and reconstitution (behavioral
analysis and synthesis). By linking his theory to neuropsy-
chological measures of executive function, Barkley implied
that inhibition was predominantly a cortical function.
In 1983, at the third annual High Point Hospital on
Attention Deficit Disorder, Herbert Quay (Quay, 1988a,b;
1993; 1997) suggested that Attention Deficit Disorder with
Hyperactivity Disorder (ADDH) might be due to an
underactive behavioral inhibitory system (BIS), as de-
scribed by Gray (1987). Gray described two antagonistic
systems exerting an influence on the possibility of a
behavioral response. The behavioral activation system
(BAS) responds to cues or conditional stimuli for reward
and actively avoids punishment. The BIS inhibits behavior
in response to cues or conditioned stimuli, which produce
fear or anxiety, and the nonoccurrence of an expected
While Quay’s modification of Gray’s theory had implica-
tions for a theory of comorbidity, there remain a number of
clinical features of ADHD either not explained or not
considered by either Barkley’s executive functioning or
Quay’s BIS theories. Neither theory provides an explanation
of the developmental features of ADHD, which often
become apparent around age 3–4 years at a time when
non-ADHD children are gaining more control over their
behavior. The BIS theory postulates a lack of anxiety in
psychopathy, but is unclear whether this also applies to
ADHD. The paradox that children with ADHD often display
Online publication: 26 March 2004 at http://www.acnp.org/citations/
Received 13 January 2004; revised 18 March 2004; accepted 23 March
*Correspondence: F Levy, School of Psychiatry, University of New
South Wales, Prince of Wales Hospital, Randwick NSW 2031,
Australia, Tel: þ61 2 93828213, Fax: þ61 2 93828105,
Neuropsychopharmacology (2004) 29, 1589–1596
& 2004 Nature Publishing GroupAll rights reserved 0893-133X/04 $30.00
fearlessness and impulsivity and yet may also manifest
anxiety (Biederman et al, 1993; Graetz et al, 2001) has not
been explained. The rapid and sometimes dramatic action
of stimulant medications in remedying many of the
symptoms of ADHD has also not been explained, nor have
side effects of high medication doses such as tearfulness or
obsessive rigidity been understood in biological terms.
Seeman and Madras (1999) have reviewed mechanisms of
action of antihyperactivity medications (methylphenidate
(MPH) and dexamphetamine). They proposed that clini-
cally relevant doses of stimulants might increase extra-
cellular background levels of dopamine (DA) above that of
action potential-dependent release of DA. As tonic DA is
considered to mitigate the amplitude of phasic, action
potential-dependent DA release, this results in relatively
reduced amplitude of impulse-associated DA, less activation
of postsynaptic DA receptors, and thus less psychomotor
Finally, comorbidity and/or subtypes have not been
addressed by either theory.
The concept of inhibition has been widely applied, but
remains somewhat mysterious and ubiquitous. While
Barkley (1997a) applied the concept to executive functions,
Gray (1987) applied the concept of inhibition to the BIS
system (based on septo-hippocampal impairment), consid-
ered to be central in the control of anxiety. Quay (1997)
suggested that the inability of children with ADHD to
inhibit behavior in response to cues signalling fear was a
core deficit. Oosterlaan (2001) suggested that an overactive
BIS was the underlying substrate for temperamental
inhibition and might predispose a child to the development
of anxiety disorders. Thus, the BIS theory postulates
opposing states for anxiety and ADHD (Oosterlaan and
Sergeant, 1996). Barkley’s concept of inhibition in ADHD is
predominantly a cortical theory, the BIS theory of ADHD is
postulated to be due to under-functioning of the septo-
hippocampal system, while LeDoux (2002) places greater
emphasis on the amygdala. LeDoux has described the
behavioral inhibition system as a network that ‘detects and
responds to aversive stimuli, those that produce pain,
punishment, failure, or loss of reward, or that elicit novelty
and uncertainty,’ resulting in inhibition of ongoing
behavior with increased arousal and vigilance. LeDoux
suggests that fear (reaction to a present stimulus) and
anxiety (concern about what might happen) can be
separated into amygdala-based and hippocampal/prefrontal
networks, but differs from Gray in attributing a greater role
to the amygdala than hippocampus in threat processing.
Despite the considerable interest aroused by the work of
both Quay and Barkley, there have remained features of
ADHD, not explained by either theory. Barkley (1997a)
reviewed the evidence supporting a deficiency in behavioral
inhibition in ADHD. This included behavioral observations
of impulsivity, difficulty in conforming to instructions,
difficulty in inhibition of prepotent responses, and poor
According to Barkley (1997a), a new theory of ADHD was
needed because current research was ‘nearly a-theoretical,
at least as regards its basic nature,’ with the exception of the
Quay/Gray model and the work of Sergeant, van der Meere
and colleagues (Sergeant, 1988, 1995; Sergeant and van der
Meere, 1988; van der Meere et al, 1989). Sergeant et al
(1999) argued that a poor inhibitory deficit in ADHD was
insufficiently specific to conclude that the core of ADHD is
an inhibition deficit, because poor inhibitory performance
is not specific to ADHD. They argued that energetic factors
are critical to the performance deficits of ADHD. According
to Barkley (1997a) these researchers successfully employed
information processing theory and its associated energetic
model (arousal, activation and effort) to isolate central
deficits in ADHD, but did not provide a large-scale theory
construction, so as to provide a unifying account of the
various cognitive deficits associated with ADHD. Barkley
also suggested that a deficit in behavioral inhibition in
ADHD should be associated with less affective and
motivation self-control, but concluded that emotional self-
control could also be associated with frustration due to
cognitive deficits such as working memory or comorbid
The present theory adds the concept of impaired tonic/
phasic DA relationships in mesolimbic DA systems giving
rise to impaired reward mechanisms and impulsivity (BAS);
and secondly a deficit in synaptic gating processes in
specific ventral striatal (accumbens) synapses resulting in
comorbid anxiety. These processes may be interrelated by
cortical/subcortical re-entrant circuits as described by
Heimer (2003) below.
Comorbidity and ADHD
Epidemiological studies of ADHD (Graetz et al, 2001) have
reported higher scores on the Anxious/Depressed scale of
the Achenbach Child Behavior Checklist (CBCL), and on all
three Externalizing scales of the CBCL. Some studies suggest
that 50–80% of children with ADHD also meet diagnostic
criteria for other disruptive behavior disorders, namely
Oppositional Defiant Disorder (ODD) (Waldman and
Lilienfeld, 1991) and Conduct Disorder (CD) (Thapar et al,
2001) or for Learning Disorders and Communication
Disorders (Tannock, 1998). Waldman et al (2001) showed
considerable overlap in the genetic and environmental
influences on ADHD, CD, and ODD.
There are also higher rates for internalizing problems
such as anxiety (Goodyear and Hynd, 1992). Pliszka (2000)
reviewed studies, which examined the comorbidity of
ADHD with ODD, CD, and affective, anxiety, and learning
disorders. He reported that anxiety and ADHD appeared to
be inherited independently and that studies examining
stimulant response in children with ADHD/anxiety have
yielded conflicting results.
Pliszka et al (1999) suggested that approximately 25% of
children with ADHD had comorbid anxiety disorders, but
indicated that this figure could be affected by changes in
diagnostic systems and possible symptom overlap.
Pliszka (1992) reported that ADHD subjects with
comorbid anxiety had a significantly poorer response to
stimulant medication than those without anxiety, suggesting
they might represent children who develop secondary
inattentiveness, or perhaps a different type of ADHD. The
effects of MPH on working memory and behavior in
anxious and nonanxious children with ADHD have been
Synaptic gating and ADHD
investigated (Tannock et al, 1995a). They found that MPH
improved working memory in the nonanxious group but
not in the comorbidly anxious group. Thus, while there are
suggestions that comorbid ADHD/anxiety may represent a
distinct subgroup, there are few etiological studies of the
comorbidity of childhood anxiety and ADHD, and fewer
The MTA study of ADHD (1999) was confined to children
with ADHD Combined Type, and showed that in this group,
combined medication treatments offered greater benefits
than community care for oppositional/aggressive behaviors,
internalizing symptoms, peer interactions, and parent–child
relations. The present model suggests a biological basis for
these findings, in terms of affective regulation provided by
more optimal synaptic gating mechanisms resulting from
The stop signal task in which the subject is required to
stop an ongoing behavior in response to a signal has been
shown to be relatively specific to ADHD and to improve
with stimulant treatment (Tannock et al, 1995b). The task is
considered to activate prefrontal cortex (PFC) and basal
ganglia. Impaired prefrontal activation in ADHD has been
reported by Silberstein et al (1998).
Architecture of Nucleus Accumbens (NAcc)/Ventral
Mogenson et al (1980) described the role of the NAcc in
functioning as an interface between limbic and motor
systems (‘from motivation to action’). Mogenson quoted
Graybiel’s findings that the NAcc is a key structure in
linking motivation and action at the interface of the limbic
system with motor mechanisms, receiving direct connec-
tions from amygdala, hippocampus, and other limbic
forebrain structures, as well as indirect connections via
mesolimbic dopaminergic projections from the ventral
tegmental area. The NAcc has direct motor connections to
the globus pallidus and indirect connections via the
substantia nigra and nigrostriatal dopaminergic system.
Mesolimbic DA projections to the NAcc in rats were also
implicated by abolition of the hyperactivity effect of
systemically administered amphetamine by damage to
ventral tegmental projections to the NAcc by injections of
Accordingto Dreyer (http://www.unifr.ch/biochem/
DREYER/Brain%20Areas/striatAcc.htm), the ventral stria-
tum including the NAcc receives input from cortical areas
other than the motor and sensory areas of the frontal and
parietal lobes. It receives input mainly from areas that do
not project to the dorsal striatum notably the temporal
(including the hippocampal formation), limbic, and orbito-
frontal cortical areas as well as the basolateral amygdala.
The ventral striatum in turn projects to the ventral
pallidum. Information is then relayed via the dorsomedial
and ventral anterior nuclei of the thalamus to the cingulate,
orbitofrontal and PFC and to the ventral tegmental area of
the brainstem. The ventral circuitry parallels the dorsal
circuitry and is considered to be involved with behavioral
phenomena, reward and punishment, and in integrating
cognitive with emotional responses. Thus, the ventral
striatum, including the accumbens is considered critical in
integrating cognitive and emotional responses.
Groenewegen et al (1997) demonstrated by labelling and
tracing experiments in rats, the topography of a number of
circuits involving PFC, ventral striatum, and the medio-
dorsal thalamic nucleus. This arrangement was considered
to be consistent with parallel functionally segregated basal
ganglia-thalamocortical circuits, which pass from distinct
parts of the (pre)frontal cortex via the striatum, pallidum/
substantia nigra, thalamus, and back to premotor/PFC.
Heimer (2003) has described the ventral striatal (includ-
ing accumbens), pallidal system and extended amygdala as
the major components of the ‘new anatomy’ of the basal
forebrain. He describes three re-entrant circuitsFthe
anterior cingulate, the lateral orbito-frontal, and the medial
orbito-frontal, which are closed in that they originate and
terminate in the same area of the frontal lobe, but suggests
that they can also interact. He suggests that the entire
cerebral cortex including the hippocampus and major parts
of the amygdala project to the basal ganglia and are
involved in the regulation of specific emotional functions
and adaptive behaviors ranging from fear-anxiety, and
addictive-reward, and appetitive behavior. The ventral
striatum integrates various cortical and subcortical inputs
to adapt ‘motivational’ behavior in a similar way to that in
which the motor loop through the dorsal parts of the basal
ganglia is important for movement control.
French and Totterdell (2002) used in vivo injection of
biotinylated dextran amine (BOA) in rats to demonstrate
that individual accumbens cells received afferent input from
both the ventral subiculum of the hippocampus and the
PFC. They postulated that the accumbens (a central
component of the ventral striatum) is centrally positioned
to integrate signals arising from limbic and cortical areas,
and thus modulate motor output related to goal-directed
behavior. The investigators believed this monosynaptic
convergence to be the first anatomical support for the
hypothesis that hippocampal input to the accumbens ‘gates’
input from the PFC as postulated by O’Donnell and Grace
(1995) who showed that accumbens neurons manifest
bistable membrane potentials, alternating between a hy-
perpolarized and a relatively depolarized state, which is
more likely to fire action potentials in response to PFC
inputs when depolarized. French and Totterdell (2003)
examined synaptic input to the projection neurons of the
accumbens, the medium-sized density spiny neurons by
labelling with biottinylated dextran amine. They demon-
strated anatomically that monosynaptic convergence be-
tween the ventral subicular region of the hippocampus and
the basolateral region of the amygdala occurred at the level
of proximal as well as distal dendrites. This anatomical
arrangement with the accumbens was similar to that
demonstrated above between PFC and the ventral sub-
iculum and accumbens, providing anatomical support for
the hypothesis that the PFC, hippocampus, and amygdala
are capable of monosynaptic gating at the level of the medial
shell of the accumbens. They postulated that a reciprocal
arrangement allowing an opposing gating action of limbic
input upon another function at accumbens level, might
allow either excitatory or inhibitory postsynaptic responses.
This mechanism was also considered to allow integration
and association of information from both hippocampus
(spatial information) and amygdala (association between
primary reinforcer and conditioned stimuli). French et al
Synaptic gating and ADHD
(2003) examined the synaptic input from the basolateral
amygdala to the spiny pyramidal projection neurons of the
hippocampal subiculum. Electron microscopy demon-
strated anatomically that the basolateral amygdala prefer-
entially innervates spiny subiculum neurons, providing a
possible synaptic mechanism underlying memory enhance-
ment associated with emotions.
Synaptic Gating Theory
Spinelli and Pribram (1966) demonstrated that processes,
which delay recovery from afferent inputs, effectively
discouple or inhibit input systems, while any parameter
that enhances recovery effectively links input systems. Thus
recovery or inhibition of synaptic neurotransmission is
likely to be a central factor in the control of affective states.
Physiologically based models have been amplified by
pharmacological techniques, which allow investigation of
neurotransmitter functions in cortico-limbic systems. Grace
(1995; 2000ab) suggested that when DA is released into the
striatal synaptic cleft in response to action potentials, it is
rapidly removed from the synapse by a highly efficient
reuptake system. On the other hand, tonic DA level is
considered to be mediated by stimulation of presynaptic
heteroreceptors on DA terminals by corticostriatal gluta-
mergic projections. Tonic DA exerts a suppressive influence
on subcortical DA systems and is regulated, in part by
frontal and cortical afferents to the accumbens (Figure 1).
The NAcc receives input from a number of limbic-related
cortical structures, including the PFC, hippocampus, and
amygdala (Grace, 2001). In particular, the hippocampus and
amygdala strongly influence the ability of the PFC to
activate accumbens cell firing. As a result these systems
alternately modulate the flow of information from the PFC
through the NAcc, where it can ultimately influence
thalamocortical function via projections through the ventral
pallidum. According to Grace (2001) the NAcc is the striatal
region in which the limbic system has overlapping inputs.
As described above, accumbens neurons exist in a bistable
state, with their membrane potential alternating between a
hyperpolarized nonfiring state and a depolarized plateau
lasting several hundred milliseconds, during which spike
activity is generated.
Grace (2001) also suggests that the amygdala gates events
based on their affective valence. ‘The amygdala also
influences the accumbens by facilitating prefrontal stimuli
but only within a very narrow single-event related time-
interval.’ Thus, this bistable accumbens state allows the
operation of a synaptic gating mechanism between pre-
frontal and limbic influences on behavior. ‘Studies have
suggested that the subiculum of the hippocampus is
involved in a type of context-dependent gating influence
over the ability of the PFC to control thalamocortical
information processing, enabling the organism to stay on-
task and focused. This mesocortical DA system provides a
potent direct influence overactivity within the PFC. Among
the many functions of the PFC is the generation of a set of
potential responses that the subject can utilize to react to a
stimulus. Thus, while the hippocampus generates long
duration activity in the accumbens neurons, keeping the
subject focussed on the current task, the amygdala provides
a more, brief event-related gating of prefrontal throughput
in the accumbens.’
Goto and O’Donnell (2002) have reported timing-
dependent limbic–motor synaptic integration in the NAcc.
They used in vivo intracellular recordings to record
excitatory postsynaptic potentials (EPSPs) in the lateral
shell and medial core region of the NAcc, after stimulation
from the ventral subuliculum, prelimbic cortex, posterior
basolateral amygdala, or paraventricular nucleus of the
thalamus. They showed that coincident PFC and limbic
inputs reduce EPSP variability, suggesting that correlated
activity between the PFC and limbic structures results in
stable activity in the accumbens, whereas asynchronous
inputs depend on the order of arrival: limbic inputs enhance
subsequent PFC inputs, and PFC inputs dampen subsequent
limbic-evoked EPSPs, possibly via feed-forward inhibition
by interneurons or axon collaterals of projection neurons.
While the pharmacological mechanism is not well under-
stood, the investigators suggest that accumbens neurons
fluctuate between UP states (membrane potential staying
UP for at least 100ms), which might involve persistent
activation of ionic currents that facilitate both simultaneous
and subsequent PFC inputs, while the DOWN state, a
negative resting potential requires strong barrage of limbic
inputs in order to depolarize accumbens neurons. Corre-
lated limbiccortical activity is important for cognitive
functions, and may be a means of appropriate behavior
selection. In the current context the demonstration of
differing effects of coincident and asynchronous PFC and
limbic activity suggests a possible gating mechanism,
whereby PFC activity can gate limbic input depending on
the state of the neurons and the timing of inputs.
According to Grace (2001) the amygdala is involved in
emotional or affective properties of stimuli, enabling the
subject to respond to events that are emotionally charged,
and therefore of immediate survival value. In pathological
states, the amygdala input may be overdriven to the extent
Figure 1 Tonic/Phasic Model of DA System Function.
Synaptic gating and ADHD
that the maintenance of focus is overly disrupted by minor
events. As described by Arnsten (2000) high levels of DA
and norepinephrine may have additive effects on informa-
tion processing in PFC, reducing signals and increasing
noise. Arnsten points out that although PFC functions are
often essential for successful organization of higher-order
behavior, there may be some conditions, when it may be
adaptive to ‘shut down’ these complex, reflective operations
and to allow more automatic or habitual responses,
dependent on posterior cortical or subcortical structures
to control behavior.
Schultz (2000) and co-workers (Suri and Schultz, 2001;
Mirenowicz and Schultz, 1994) have used single neuron
recording techniques in monkeys to investigate the condi-
tions in which DA neurons respond to rewarding or
potentially rewarding stimuli. They have shown that
dopaminergic neurons in the VTA (A8, A9, A10), which
project to the NAcc and frontal cortex show short phasic
activation after reward presentations, and visual or auditory
stimuli that predict reward. By contrast only a few
dopamine neurons show phasic activations to punishers
(conditioned aversive visual or auditory stimuli).
Monoaminergic disruptions of amygdala, PFC, and
accumbens equilibrium are likely to be involved in a
number of psychopathologies. Sagvolden et al (2004) have
postulated that the behavior and symptoms of ADHD derive
from altered dopaminergic function with a consequent
failure to modulate nondopaminergic
glutamate and GABA) signal transmission. They postulate
that a hypo-functioning mesolimbic dopamine branch
produces altered reinforcement of behavior and deficient
extinction of previously reinforced behavior, giving rise to
delay aversion, impulsivity, and failure to ‘inhibit’ responses
or disinhibition. A hypo-functioning mesocortical branch is
postulated to cause attentional deficits, while a hypo-
functioning nigrostriatal branch gives rise to impaired
Sagvolden et al (2004) have argued that the main
component of altered reinforcement processes in ADHD
children, is a steeper delay-of-reinforcement gradient, or
time interval between response and effective reinforcer,
resulting in less effective reinforcement and also less
effective extinction of previously established, but no longer
reinforced responses. This explains why ADHD childrens’
behavior is temporarily less impulsive in response to potent
and frequent reinforcers. When a delay gradient quickly
drops to zero responses must be very close to a reinforcer to
be captured by it and only a single response will be
captured. The implication of a steep reward gradient in
ADHD implies a reduced capacity for reward (operant
conditioning), hence the indifference to social acceptability
often manifested as oppositional or conduct problems.
Sagvolden et al (2004) point out that children’s behavior
is gradually brought under discriminative control by the
establishment of verbally governed behavior (responsive to
Schultz et al (1993) studied the responses of dopamine
neurons during the steps of learning a behavioral task. They
showed that in monkeys trained to perform a spatial
delayed response task, via two intermediate tasks, dopamine
neurons showed responses during, but much less, after
learning each task. These responses were most pronounced
in area A10 as compared to areas A8 and A9. Dopamine
neurons also showed phasic responses to instructional and
conditioned incentive stimuli predicting reward, but did not
exhibit activity during the delay between instructions and
triggers. The investigators concluded that while dopamine
neurons respond phasically to alerting stimuli necessary for
task learning, they do not encode representational processes
such as working memory, rather they respond phasically to
basic attentional and motivational stimuli involved in
learning. Goldman-Rakic (1990) has contrasted the type of
behavioral regulation subserved by PFC with stimulus-
response associations. The former ‘delayed response’
abilities depend on the maintenance of representational
memory, while the latter depend on associative condition-
ing to innate prepotent responses, usually at subcortical
level. She describes a functional dissociation between
working and associative memory.
According to Floresco et al (2003), the mesolimbic
dopamine system plays a central role in reward and goal-
directed behavior, and has been implicated in multiple
psychiatric disorders. Understanding the mechanism by
which dopamine participates in these activities requires
comprehension of the dynamics of dopamine release. They
report dissociable regulation of dopamine neuron discharge
by two separate afferent systems in rats; inhibition of
pallidal afferents selectively increases the population
activity of dopamine neurons, whereas activation of
pedunculo-pontine inputs increases burst firing.
According to Floresco et al (2003) synaptic or phasic
levels of dopamine are mediated by bursting events at the
level of the cell body, restricted by high affinity and rapid
uptake systems, and associated with reward-conditioned
prediction. On the other hand, extrasynaptic or tonic
dopamine levels are modulated by presynaptic limbic and
cortical glutamergic inputs. Alterations in tonic levels of
dopamine efflux occur on a much slower time-scale and
allow a wide variety of motor, cognitive, and motivational
functions. The results provide insight into multiple
regulatory systems that modulate dopamine system func-
tion; burst firing inducing massive synaptic dopamine
release, rapidly removed by reuptake before escaping the
synaptic cleft, whereas increased population activity mod-
ulates tonic extrasynaptic dopamine levels that are less
influenced by reuptake, and presumably affect long-term
disposition. In ADHD children, impairment of tonic/phasic
relationships may influence reinforcement gradients de-
scribed by Sagvolden et al (2004), as a result of lowered
availability of tonic DA levels in the mesolimbic and
mesocortical systems, resulting in the stimulus-bound,
impulsive ‘fearless’ behavior of ADHD children. On the
other hand, impaired synaptic gating by PFC at the
accumbens level allows greater access to conditioned
amygdala reactions and the anxiety (or aggression)
described in some ADHD children.
Davis and Whalen (2001) have comprehensively reviewed
animal and human literature concerning the role of the
amygdala in fear conditioning. They found that the
basolateral amygdala is involved in negative and positive
affect, as well as spatial and motor learning. They describe
the ‘extended amygdala’ as target areas that subserve more
specialized functions. These target areas are critical for the
specific symptoms of fear, as well as the experience of fear.
Synaptic gating and ADHD
They believe the complex behavioral pattern seen during a
state of ‘conditioned fear’ has already been hard-wired
during evolution, and that it is only necessary for a stimulus
to activate the amygdala following aversive conditioning.
The paradoxical apparently ‘fearless’ behavior of ADHD
children, yet the presence of anxiety in some ADHD
children may be explained by separate reward and fear
conditioning processes, as postulated by Gray (1975). The
former appears to be related to impaired operant con-
ditioning processes secondary to impairment of mesolimbic
tonic/phasic DA relationships, while fear conditioning is
based on inadequate PFC and hippocampal synaptic gating
of classically conditioned noradrenergic and serotonergic
responses in the amygdala.
The demonstration by French and Totterdell (2002, 2003)
of monosynaptic convergence between the ventral subicular
region of the hippocampus, the basolateral region of the
amygdala and PFC on accumbens dendrites provides
anatomical support for the hypothesis that the PFC and
hippocampus are capable of monosynaptic gating of
amygdala input at the level of the medial shell of the
Floresco et al (2001) have shown that the ventral
subiculum is involved in regulating the basal firing
characteristics as well as the overall activity level of VTA
DA neurons in the normal rat. If disrupted early in
development, tonic control of VTA DA neuron activity is
affected, so that phasic activation of DA neuron firing has
an abnormally large impact on impulse dependent DA
release in limbic structures, as postulated by O’Donnell and
Grace (1995), giving rise to heightened limbic DA respon-
sivity. This would be predicted to give rise to an increase in
immediate indiscriminate reward seeking behavior (fear-
lessness) and overactivity, as described by Sagvolden and
On the other hand, the reduction of PFC and hippocam-
pal synaptic DA gating at the accumbens level allows
increased amygdala-based fear or anxiety to be manifest in
some (possibly genetically predisposed) ADHD children.
Thus comorbidity in ADHD children is complex and related
to the tonic/phasic DA relationships in the VTA giving rise
to ‘fearless’ stimulus-bound externalizing behavior as a
result of impaired reinforcement gradients in some ADHD
children, while abnormal PFC and hippocampal gating of
amygdala-based anxiety is observed in other ADHD
children. The present distinctions provide a basis for
possible pharmacological approaches to the treatment of
comorbidity in ADHD. For example, stimulant medications,
which increase tonic dopamine levels are likely to be useful
for impulsivity and fearlessness, whereas axiolytic medica-
tions such as specific serotonin re-uptake inhibitors (SSRIs)
or combined nor-adrenergic/dopaminergic antidepressants
may be useful for comorbid anxiety. The use of dopamine
partial agonists, which are postulated to have differential
effects in mesolimbic and mesocortical pathways, may also
be of interest (Lieberman, 2004).
While the above discussion relates to comorbid fearless-
ness and impulsivity vs anxiety, it does not address the issue
of comorbid aggression. Blair (2001) has described two
forms of aggression, reactive aggression elicited in response
to frustration/threat and goal-directed instrumental aggres-
sion. He suggests that impairment in the capacity to form
associations between emotional unconditioned distress cues
and conditioned stimuli is related to the instrumental
aggression shown by persons with ‘developmental psycho-
pathy.’ Kilcross et al (1997) have described different types
of fear-conditioned behavior mediated by separate nuclei
within amygdala, supporting different forms of fear-related
behavior. They describe limbic cortico-ventral striato-
pallidal circuitry, which provides an interface between the
processing of emotionally salient stimuli and intentional
action, while areas of the orbital PFC that have significant
reciprocal connections with the basolateral amygdala are
implicated in the assignment of affective or ‘somatic’
markers influencing behavior. While these influences are
complex they also appear to be related to dual cortical/
instrumental and amygdala conditioned influences on
aggression, either or both of which could be impaired in a
re-entrant circuit influencing aggression in ADHD children.
The concept of ventral re-entrant circuits elaborated by
Heimer (2003) above allows a useful integration of tonic/
phasic relationships at mesolimbic and mesocortical levels
with gating processes at the amygdala. Impairments of these
circuits may also give rise to a number of other
neuropsychiatric conditions such as schizophrenia or
autism depending on genetic and developmental influences.
I thank Professor Richard Todd, Dr Mina Dulcan, and
Professor Anthony Grace for their helpful comments on the
manuscript, and Dr John Merson and Professor Gordon
Parker for their support of the thesis, which gave rise to the
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