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 A
central premise in the ³catecholamine hypothesis² of attention-deficit/hyperactivity
disorder (ADHD) is that dopamine (DA) dysfunction leads to clinical symptoms.
The hypothesis arises, in part, from the clinical efficacy of methylphenidate,
as well as evidence from brain imaging studies that suggest reduced activity
in frontal-striatal regions. The theory, however, overlooks the phenotypic
complexity of the disorder and the possible interactions between the dopamine
and serotonin (5-HT) neurotransmitter systems.
ADHD
is a heterogeneous disorder manifesting itself in various behavioral dimensions
including inattention, hyperactivity, and impulsivity often co-occurring
with other child behavioral disorders including comorbid oppositional
defiant disorder and conduct disorder. It is likely that different neurotransmitter
systems and the relative balance between them have varying degrees of
influence over these behavioral dimensions. Variation in genes involved
in these neurotransmitter systems are likely to mediate this delicate
balance and have an effect on the function of these chemicals in the brain.
The purpose of this review is to discuss the neurobiology of ADHD in light
of a serotonin hypothesis. A review of human and animal studies in support
of a role for serotonin in ADHD and related behaviors is presented. A
discussion is included of the interaction between the serotonin and dopamine
neurotransmitter systems in the context of dopamine-mediated behaviors
and possible implications for ADHD.
Although
serotonin has been studied less thoroughly in the neurobiology of ADHD,
its role in the pathophysiology of this disorder has become an area of
intense investigation recently. Considerable evidence suggests a role
for this neurotransmitter in the etiology of behavioral disorders characterized
by disinhibition including alcohol abuse, suicide, bulimia, antisocial
personality disorder, conduct disorder, and aggression. As ADHD is a behavioral
disorder largely characterized by deficits in inhibition and is a well-known
precursor for many adult disorders of impulse control, a role for 5-HT
in ADHD has been hypothesized. Indeed, there is mounting evidence from
both human and animal studies that serotonergic neurotransmission is necessary
for mediating several of the behaviors present in ADHD.
Both
direct and indirect measures of central serotonergic function have been
assessed in children with disruptive behavior disorders. Cerebrospinal
fluid levels of the serotonin metabolite 5-hydroxyindoleacetic acid or
responses in pharmacological challenge tests indicate abnormal serotonergic
function. Results from such studies, however, have been inconsistent.
Some show reduced central 5-HT function, whereas others indicate higher
5-HT function (Kruesi et al., 1990; Pine et al., 1997). Peripheral measures
of blood serotonin have been reported as reduced in children with ADHD
(Spivak et al., 1999). Although psychostimulant medications appear to
be most effective in the treatment of ADHD, there is some evidence that
certain serotonin-enhancing agents including tricyclic antidepressants
and selective serotonin reuptake inhibitors (SSRIs) are also effective
in reducing symptoms in these children. Often these may be used as second-line
agents for patients who do not respond adequately to stimulants.
A
growing number of animal studies suggest the involvement of serotonin
in mediating behaviors such as attention, impulsivity, and hyperactivity.
Rodents that had a greater degree of serotonin utilization in the frontal
cortex performed worse on a task measuring attention and impulsivity (Puumala
and Sirvio, 1998). A recent study of a mouse model of ADHD provided evidence
linking serotonin to the control of hyperactive behavior (Gainetdinov
et al., 1999). In this study, the researchers developed a strain of hyperactive
mice by knocking out the gene responsible for the dopamine transporter
(DAT-KO).
In
the absence of the dopamine transporter, there is an increase in extracellular
levels of dopamine which is thought to lead to the increased locomotion
seen in the knockout mice. Treatment of the mice with psychostimulant
drugs produced a calming effect not seen in wildtype mice. Furthermore,
this reduction in hyperactivity was not associated with changes in extracellular
levels of dopamine in the striatum (Fig.
1, experiment 1). The results suggest that the response to these drugs
is through a mechanism other than blockade of the DAT, as the transporter
is not present in the knockout mice.
The
researchers then treated the same mice with several serotonergic drugs.
These included both SSRIs and serotonin precursors, and both produced
a calming effect in the mice that was independent of any changes in dopamine
levels (Fig. 1, experiment
2). The authors suggest that serotonin neurotransmission plays a role
in mediating the hyperactive behavior in these mice.
Additional
animal studies have suggested that specific serotonin receptors may be
involved in impulsive and hyperactive behaviors. Investigations with knockout
mice that lack the 5-HT1B receptor show increased cocaine acquisition
and alcohol intake, as well as hyperactivity and aggressive behavior (Brunner
et al., 1999). This receptor is expressed in a variety of brain regions
including areas involved in motor control such as the striatum and cerebellum.
In an earlier study, Saudou and colleagues (Saudou et al., 1994) developed
homozygous knockout mice also lacking the 5-HT1B receptor gene
and assessed for various behaviors. When wildtype and knockout mice were
treated with the 5-HT1B agonist RU 24969, stimulation of locomotor
activity was observed in the wildtype mice that was absent in the mutant
mice, suggesting that the hyperlocomotor effect of this agonist was mediated
by 5-HT1B receptors. Rats treated with the same 5-HT1B
agonist in another report showed a dose-dependent increase in locomotor
hyperactivity (Rempel et al., 1993).
There
is a considerable amount of interaction between the dopaminergic and serotonergic
neurotransmitter systems (Kelland and Chiodo, 1996). One hypothesis for
the involvement of 5-HT in the development of ADHD is the regulatory control
of 5-HT over DA neurotransmission. Disruption of the 5-HT system will
disrupt the DA system and affect DA-mediated behaviors.
5-HT
neurons send projections to DA cell bodies located in the midbrain regions
including the substantia nigra and ventral tegmental area. In addition,
they project to DA terminals present in the striatum, nucleus accumbens,
and prefrontal cortex. The 5-HT innervation of dopaminergic cell bodies
and terminals allows for the functional regulation by 5-HT of both DA
neuronal firing and DA release. Results from electrophysiological and
neurochemical studies on rodents have generally shown that 5-HT exerts
an inhibitory influence on midbrain dopamine cell bodies. 5-HT influence
over DA release in terminal regions, however, is less clear as both inhibitory
and excitatory effects have been observed (Kelland and Chiodo, 1996).
Different
5-HT receptor subtypes mediate the regulation of 5-HT over DA neurotransmission
and include the 5-HT1A, 5-HT1B, and 5-HT2A
receptors. Certain 5-HT1B and 5-HT1A agonists have
been shown to increase striatal DA release whereas the 5-HT1B
antagonist, GR 127935, inhibits 5-HT-induced dopamine release. These results
provide some evidence for a facilitatory role for 5-HT over DA in the
striatum. Alternatively, the 5-HT2A receptors that are located
on DA neurons inhibit DA firing while antagonism of 5-HT2A
releases DA from this inhibition (Kapur and Remington, 1996).
As
a consequence of the complex interaction between these two neurotransmitter
systems, 5-HT is likely to influence DA-mediated behaviors. The experiments
on DAT-KO mice suggest that the calming effects observed after psychostimulant
and SSRI treatments occur by increasing 5-HT levels. These higher levels
of serotonin then balance the high DA levels that result from the absence
of DAT.
Although
the 5-HT system is likely to be involved in motor activity, it remains
unclear which specific 5-HT receptors are involved in motor control. Evidence
from pharmacological studies has suggested that striatal 5-HT2A
receptors regulate stimulant-induced dopamine release and hyperactivity
(O¹Neill et al., 1999). Treatment of rodents with selective 5-HT2A
antagonists attenuates the locomotor stimulating effects of amphetamine
and cocaine by preventing the increase in dopamine release that causes
hyperactivity (O¹Neill et al., 1999). The 5-HT2A receptor,
therefore, must be activated in order to mediate the effects of dopaminergic
agents. Similarly, several studies have demonstrated the hyperlocomotor
effects of 5-HT1A/1B agonists (Kelland and Chiodo, 1996), which
are most likely mediated via 5-HT1B receptors. Results such
as these provide evidence for a facilitatory role for 5-HT in DA function
and DA-mediated behaviors. This appears to be inconsistent with the hypothesis
that 5-HT is inhibitory to DA function and DA-induced behavior.
The
ability of 5-HT to exert both facilitatory and inhibitory influences over
DA neurotransmission, thus varying the degree of influence over DA-mediated
behaviors, is a complex issue and may be a function of both the brain
region studied, the drugs used, and the 5-HT receptor subtypes involved.
Needless to say, there is an abundance of evidence demonstrating that
dopaminergic neurotransmission is functionally regulated by serotonin,
which has important implications for 5-HT in controlling the behavior
commonly exhibited in ADHD.
To
date, there have been no molecular genetic studies demonstrating specific
serotonin genes as risk factors for ADHD, yet future research in this
area is warranted. Although the mode of inheritance of ADHD is unknown,
it is likely to be polygenic based on its modest relative risks and high
population prevalence. The individual risk contribution per gene, therefore,
may be quite small. This has been one of the greatest challenges in ADHD
genetics research. Furthermore, identifying a gene as a risk factor for
ADHD does not help clarify the aspect of the disorder to which that gene
contributes. Do defects in dopamine genes contribute to the inattention
component of ADHD while serotonin genes determine the impulsive component?
Are dopamine and serotonin both contributing factors in the hyperactivity
displayed by children with ADHD? What genes in these systems account for
the high proportion of children who exhibit comorbid disruptive behaviors
disorders and aggression? There are no definitive answers to these complicated
questions, but it is probable that a delicate balance exists between these
two neurotransmitter systems and that this balance is necessary to maintain
normal behavior in childhood.
The
future of dissecting the genetics of ADHD lies in a shift from searching
for risk-enhancing genes for ADHD as a disorder per se toward searching
for genes contributing to the symptoms of the disorder in a quantitative
approach. A notion such as this would lead to the hypothesis that a higher
genetic load would lead to greater symptom severity. This approach could
help identify which genes contribute to particular symptoms of ADHD. For
example, examination of a group of children with high levels of impulsive
symptoms might identify a serotonin gene as a risk factor, whereas that
gene may not be detected if inattention was measured. Waldman and colleagues
(1998) adopted this kind of approach, showing that the hyperactive-impulsive
symptoms rather than the inattention symptoms of ADHD were associated
with a greater loading of the DAT1 high-risk allele and that this association
increased with symptom severity.
In
conclusion, there is accumulating neurobiological evidence pointing toward
a role for the serotonin system in ADHD. The strongest support from existing
data suggests that serotonin is responsible, at least in part, for mediating
the hyperactive and impulsive components of ADHD behavior. Genes involved
in serotonin receptor function, metabolism/biosynthesis, and reuptake
are good candidates for future molecular genetic studies of ADHD. Thus
the existing view of ADHD as a ³dopaminergic disorder² will broaden toward
the inclusion of serotonin as a contributing factor in its etiology.
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