Neurochemical Mechanisms in Disease P20 pptx

Monoamine Transporter Pathologies 175
site just above the extracellular gate (Singh et al., 2007; Zhou et al., 2007). This
structure may reveal a similar binding site for the mammalian monoamine trans-
porters, although some have questioned if the TCA binding site of LeuT
Aa
is likely
to be reflective of such a site in the monoamine transporters (Henry et al., 2007;
Rudnick,2007).
1.5 Vesicular Monoamine Transporters
Although plasma membrane monoamine transporters are responsible for the reup-
take of neurotransmitters from the synapse, vesicular monoamine transporters
(VMAT) sequester monoamines into synaptic vesicles in preparation for fusion
with the plasma membrane and release into the synapse (Schuldiner et al., 1995).
Vesicular uptake is coupled to a proton gradient across the vesicle membrane
rather than the sodium gradient used with the plasma membrane transporters
(Schuldiner et al., 1995). These vesicular transporters are not neurotransmitter-
specific; rather, they transport the monoamines nonselectively (Johnson, Jr., 1988;
Henry et al., 1998).
VMAT is predicted to have similar membrane topology to the plasma mem-
brane monoamine transporters, although they do not share homologous sequences
(Erickson et al., 1992). Hydrophobicity studies predict 12 TMHs with amino and
carboxy termini located in the cytoplasm (Erickson et al., 1992). The large extra-
cellular loop between TMHs III and IV of the plasma membrane transporters is
located between TMH I and II in VMAT (Erickson et al., 1992). VMAT1 is located
in the neuroendocrine cells of the adrenal medulla and intestinal tract, whereas
VMAT2 is found in monoaminergic neurons of the central nervous system (Erickson
et al., 1996).
Because VMAT regulates the level of cytosolic monoamines, researchers have
examined a role for VMAT in disease states. Although no direct pathological links to
aberrant VMAT function have been described, altered dopamine regulation can lead
to drug addiction, Parkinson’s disease, and schizophrenia (Mazei-Robison et al.,

2008). Psychostimulants have been demonstrated to affect dopaminergic signaling
by altering DAT and VMAT function (Fleckenstein et al., 2009). Such alterations
can be neurotoxic and may provide a role f or the monoamine transporters in
Parkinson’s disease (Fleckenstein et al., 2009).
2 Regulation of Plasma Membrane Monoamine Transporters
Plasma membrane monoamine transporters serve an important regulatory role in
maintaining appropriate levels of monoamines in the synapse (Torres et al., 2003a).
Aberrant regulation of transporter expression and function has been implicated in
several disease states (Howell and Kimmel, 2008). The monoamine transporters
are regulated by interaction with a number of substrates and antagonists with vary-
ing affinities for the transporters at the plasma membrane (Sulzer et al., 1995;
Gutman and Owens, 2006; Fleckenstein et al., 2007). In addition to transporting
176 N.R. Sealover and E.L. Barker
their respective neurotransmitters, the monoamine transporters can lose substrate
selectivity under certain conditions. DAT and NET can each transport dopamine
and norepinephrine (Giros et al., 1994), and SERT displays an increased preference
for dopamine at elevated temperatures (Saldana and Barker, 2004). Amphetamines
such as methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA,
“ecstasy”) are also substrates of the monoamine transporters, as are some neurotox-
ins such as 1-methyl-4-phenylpyridinium (MPP
+
) (Torres et al., 2003a). In addition,
the monoamine transporters are influenced by several classes of antagonists,
including cocaine and antidepressants (Torres et al., 2003a).
Monoamine transporter regulation can occur by altering transporter surface
expression. Monoamine transporters contain sites for potential phosphorylation in
the cytoplasmic loops and the carboxy terminal region (Jayanthi and Ramamoorthy,
2005). Samuvel and colleagues demonstrated that p38 mitogen-activated protein
kinase (MAPK) regulates SERT by inhibiting cell surface expression (Samuvel
et al., 2005). Treatment of cells and synaptosomes with the PKC activator, phor-

bol 12-myristate13-acetate (β-PMA) reduces monoamine transport capacity (V
max
)
without altering substrate affinity (K
m
) (Samuvel et al., 2005). Other agents that
maintain the phosphorylated state of the monoamine transporters such as phos-
phatase inhibitors also reduce V
max
(Vaughan et al., 1997; Ramamoorthy et al.,
1998; Jayanthi et al., 2004; Apparsundaram et al., 1998b, a). The phosphatase
inhibitor, okadaic acid, downregulates DAT, NET, and SERT activity (Ramamoorthy
et al., 1998). These studies suggest that phosphorylation of monoamine t ransporters
impairs plasma membrane expression. SERT and protein phosphatase 2A (PP2A)
form a complex that is regulated by p38 MAPK activation (Zhu et al., 2005). This
complex is inhibited by PP2A inhibitors and PKC activators (Bauman et al., 2000).
This complex is stabilized in the presence of the substrate 5-HT (Bauman et al.,
2000). These studies provide a mechanism for the regulation of transporter function
through the interaction of SERT with PP2A.
Monoamine transporter function is also regulated by glycosylation. The large
extracellular loop between TMH III and TMH IV of the monoamine transporters
contains consensus sites for glycosylation (Melikian et al., 1994, 1996). The glyco-
sylated form of the transporter is the mature form that undergoes insertion into the
plasma membrane (Sitte et al., 2004).
Functional monoamine transporters are predicted to form oligomers (Milner
et al., 1994; Jess et al., 1996; Kilic and Rudnick, 2000). One study reports the exis-
tence of a dimer of dimers (Kilic and Rudnick, 2000). This tetramer is proposed
to be the functional form that exists in the plasma membrane (Kilic and Rudnick,
2000). A leucine heptad repeat in TMH II and a glycophorin-like motif in TMH VI
are thought to play a role in stabilizing the oligomeric form of DAT (Torres et al.,

2003b). The formation of SERT dimers results from a putative interaction involving
TMH XI and TMH XII (Just et al., 2004).
The monoamine transporters are also regulated by a feedback mechanism
that involves monoamine autoreceptors located on the presynaptic cell membrane
(Hjorth et al., 2000; Schmitz et al., 2002; Garcia et al., 2004). These autoreceptors
detect the levels of various monoamines in the synapse and modulate the release of
Monoamine Transporter Pathologies 177
monoamines to keep appropriate levels of neurotransmitter in the synapse (Hjorth
et al., 2000; Schmitz et al., 2002; Garcia et al., 2004). The exact mechanism of this
feedback loop is unknown (Hjorth et al., 2000; Schmitz et al., 2002; Garcia et al.,
2004). The autoreceptors are the D2 short isoform (D2 s), α
2A
, and 5-HT
1B
recep-
tors for dopamine, norepinephrine, and serotonin, respectively (Xie et al., 2008).
The feedback loop may also be controlled by the trace amine-associated receptor
1 (TAAR1). TAAR1 is a G protein-coupled receptor that is activated by the bio-
genic monoamines, trace amines, and psychostimulants (Borowsky et al., 2001).
Xie and colleagues demonstrated the regulation of DAT by TAAR1 and the regula-
tion of TAAR1 signaling by D2 s (Xie and Miller, 2007; Xie et al., 2007). Similar
studies have been conducted with NET and SERT to show the regulation of these
transporters by TAAR1 and monoamine autoreceptors (Xie et al., 2008).
3 Transporter Gene Polymorphisms
Several genetic polymorphisms have been identified for the genes encoding the
monoamine transporters. A brief review of these genetic variations and possible
associations with disease states is presented below and in Table 1. A comprehensive
review by Hahn and Blakely examines the impact of genetic variations of the SLC6
gene family (Hahn and Blakely, 2007).
Table 1 Summary of identified polymorphisms for NET, DAT, and SERT

Polymorphism Effect of Polymorphism Possible Pathological Associations
NET
A457P Impaired transport, decreased cell
surface expression
Orthostatic intolerance, increased
heart rate
F528C Elevated transport, decreased TCA
potency
High blood pressure
–3801 (A/T) Transcription factor-based
repression of NET expression
ADHD
DAT
A559V Increased Na
+
sensitivity,
spontaneous DA efflux
ADHD, bipolar disorder
3

untranslated
VNTR (480 bp)
Unknown ADHD
SERT
I425V Increased transport, increased
V
max
, decreased K
m
OCD, Asperger’s syndrome

5-HTTLPR (s) Reduced gene transcription OCD, ADHD, depression
VNTR Regulates transcription No known links
3.1 NET
A number of nonsynonymous single nucleotide polymorphisms (SNPs) that result in
single amino acid substitutions have been identified for the monoamine transporters.
178 N.R. Sealover and E.L. Barker
The hNET SNP A457P was discovered in a familial form of orthostatic intolerance
(Hahn et al., 2003; Shannon et al., 2000). The A457P allele was found to be associ-
ated with increased heart rate and plasma norepinephrine levels (Hahn et al., 2003).
Molecular studies demonstrate t hat hNET A457P has severely impaired transport
function and decreased cell surface expression, revealing a mechanism for impaired
hNET function and cardiovascular disease (Hahn et al., 2003). Approximately 20
more coding region SNPs have been identified for hNET, primarily associated with
altered psychiatric and cardiovascular phenotypes (Hahn et al., 2005). The precise
functional role of many of these variants remains largely undefined. However, the
hNET variant F528C was discovered in patients with high blood pressure (Hahn
et al., 2005). Hahn and colleagues found the hNET variant to have elevated trans-
port levels, decreased tricyclic antidepressant potency, and an insensitivity to PKC
downregulation by β-PMA (Hahn et al., 2005).
In addition to the potential significance of coding region SNPs, variations in the
hNET promoter region have also been identified (Kim et al., 2006). The substitution
of adenine to thymine at –3081 has been linked to ADHD (Kim et al., 2006). The
thymine substitution establishes a palindromic E2-box motif that binds the neural-
expressed repressors of transcription, Slug and Scratch (Kim et al., 2006). Slug and
Scratch bind the E2-box motif and repress SLC6A2 promoter activity only when the
thymine substitution is present. These data suggest that the –3081(A/T) polymor-
phism, resulting in transcription factor-based repression of SLC6A2, may increase
the risk of ADHD development (Kim et al., 2006).
3.2 DAT
The presence of SNPs is not unique to NET. Studies have revealed variants of

DAT and SERT as well. A rare DAT coding SNP, A559V, has been identified
in two male children diagnosed with ADHD (Mazei-Robison et al., 2008) and a
female with bipolar disorder (Grunhage et al., 2000). Cellular studies have demon-
strated an increased sensitivity to intracellular sodium and increased DA efflux
for hDAT A559V in the absence of efflux-inducing amphetamines (Mazei-Robison
et al., 2008). Homology modeling based on LeuT
Aa
, places A559 at the extracel-
lular end of TMH 12 (Mazei-Robison et al., 2008). Studies have implicated TMHs
11 and 12 as forming the interface for monoamine transporter dimerization (Just
et al., 2004). Dimerization is known to be important for serotonin efflux (Seidel
et al., 2005). The increased dopamine efflux observed for A559V may be due to
impairment of transporter dimerization (Mazei-Robison et al., 2008). Interestingly,
Chen and colleagues demonstrated that mutating S528 to alanine in DAT TMH
11 results in increased dopamine efflux (Chen and Justice, 2000). These find-
ings suggest a mechanism by which altered DA efflux may be linked to disease
states.
The DAT gene is located on chromosome 5 and contains a variable number tan-
dem repeat (VNTR) polymorphism in the 3

-untranslated region. This VNTR is
composed of 40 bp repeats that commonly contain nine or ten copies. Multiple
Monoamine Transporter Pathologies 179
investigations have found a link between ADHD and the 480 bp VNTR (Barr et al.,
2001; Chen et al., 2003; Cook, Jr. et al., 1995; Curran et al., 2001; Daly et al.,
1999; Gill et al., 1997; Waldman et al., 1998). Researchers are unclear if the num-
ber of repeats in the 3

untranslated VNTR directly controls the expression level
of the DAT gene or if the allele containing this VNTR is in linkage disequilib-

rium with functional DNA variants that contribute to the ADHD phenotype (Barr
et al., 2001).
3.3 SERT
SERT gene variants have been implicated in neuropsychiatric disorders. Ozaki and
colleagues identified the presence of an I425V coding region SNP in some individ-
uals affected with obsessive compulsive disorder (OCD) and Asperger’s syndrome
(Ozaki et al., 2003). Studies in cultured cells found the I425V mutation to cause an
increased rate of transporter activity with an increase in V
max
and decrease in K
m
(Kilic et al., 2003). Cell surface expression was unchanged for the mutant. The ele-
vated transport is thought to be caused by altered cGMP-dependent protein kinase
activity (PKG). The I425V mutation results in constitutive activation of SERT sim-
ilarly to the way nitric oxide stimulates wild-type SERT via a PKG-dependent
pathway (Kilic et al., 2003). The stimulation of SERT by cGMP is disrupted in
the I425V mutant, although the exact mechanism by which this occurs remains
unknown. Thr 276 is predicted to be in the second intracellular loop, between TMH
IV and V, and is the site of PKG phosphorylation on SERT (Ramamoorthy et al.,
2007). Ile 425 is predicted to reside in the middle of TMH VIII near putative sub-
strate and inhibitor binding sites. It is unclear if the I425V mutation activates the
transporter in a manner that makes Thr 276 phosphorylation irrelevant, or if this
mutation indirectly increases the level of Thr 276 phosphorylation by interfering
with the activity of a phosphatase (Zhang et al., 2007).
Two common polymorphisms have also been reported in the promoter region
of the SERT gene. The first is the insertion or deletion of a 44 bp sequence that
results in a long (L) or short (S) allele termed the 5-HTTLPR (Lesch et al., 1996).
The S variant displays threefold reduced gene transcription, leading to decreased
transporter expression and 5-HT uptake (Lesch et al., 1996). Patients with major
depression who are homozygous for the long allele (L/L) or heterozygous (L/S)

respond better to treatment with the SSRIs fluvoxamine and paroxetine than those
homozygous for the short allele (S/S) (Lesch et al., 1996; Zanardi et al., 2000).
The S allele has been associated with an increased risk of depression, obsessive-
compulsive disorder, and ADHD (Torres et al., 2003a).
The second type of promoter polymorphism is a VNTR in the second intron
composed of 17-bp repeats (Ogilvie et al., 1996). Ten and twelve sets of repeats
are most common (Lesch et al., 1994). Studies with embryonic stem cells and
transgenic embryos implicate the VNTR as playing a role in the regulation of tran-
scription, although no definitive links are known between this VNTR and disease
states (Torres et al., 2003a).
180 N.R. Sealover and E.L. Barker
4 Addiction
4.1 Psychostimulant Addiction
The rewarding and reinforcing effects of psychostimulants appear to rely primarily
on the dopamine system, although studies have demonstrated the ability of sero-
tonin and norepinephrine systems to produce behavioral and neurochemical effects
in response to psychostimulants (Howell and Kimmel, 2008). DAT and VMAT2
are critical players in the regulation of dopamine levels in the synapse and cytosol,
respectively. The GABAergic system can regulate dopaminergic signaling by con-
trolling the firing rate of dopamine neurons (Churchill et al., 1992; Steffensen et al.,
1998). Psychostimulants exert their effects by increasing levels of extracellular
neurotransmitter. Psychostimulants are classified as uptake inhibitors or releasers.
Cocaine is an example of an uptake inhibitor (Table 2). Cocaine exerts its effects by
binding to DAT, NET, or SERT. This binding prevents the transport of neurotrans-
mitter, resulting in increased synaptic neurotransmitter levels. Amphetamines such
as MDMA are classified as releasers. They are substrates of the monoamine trans-
porters. Releasers reverse the direction of transport from inward to outward, leading
to an increase in the levels of neurotransmitter in the synaptic cleft (Fleckenstein
et al., 2007; Rothman and Baumann, 2003).
Repeated exposure to psychostimulants can modify neurotransmitter systems

and result in tolerance or increased sensitivity. This exposure alters the effects of
Table 2 Structures of psychostimulants and K
i
values in μmol/L for inhibition of [
3
H] 5-HT, [
3
H]
NE, and [
3
H] DA uptake at hSERT, hNET, and hDAT, respectively
Structure Name hSET hNET hDAT
Cocaine
0.03
0.48 ±
0.05
0.23 ±
0.03
MDMA
0.73
1.19 ±
0.13
8.29 ±
1.67
Amphetamine
3.84
0.07 ±
0.01
0.64 ±
0.14

H
N
O
O
Methylphenidate
10.71
0.10 ±
0.01
0.06 ±
0.01
0.74±
132.43 ±
38.46 ±
2.41 ±
Data were obtained in Intestine 407 cells transfected with hSERT, hNET, or hDAT (Han and Gu,
2006).
Monoamine Transporter Pathologies 181
drugs on brain neurochemistry and behavior, ultimately disrupting the neurobio-
logical regulation of functions related to addiction (Howell and Kimmel, 2008).
Interestingly, conflicting studies have reported that cocaine administration in rodents
may result in increased, decreased, or unaltered DAT, D1, and D2 receptor levels
(Pilotte et al., 1994; Wilson et al., 1994; Claye et al., 1995; Boulay et al., 1996; Tella
et al., 1996; Letchworth et al., 1997; Letchworth et al., 1999). Repeated cocaine use
has been shown to increase DAT activity in humans (Mash et al., 2002). The ini-
tial increase in extracellular dopamine after cocaine administration is thought to
result in increased DAT function as a compensatory mechanism. Increased DAT
function in turn leads to reduced levels of extracellular dopamine even in the
absence of cocaine. This cycle of altered synaptic dopamine levels and DAT func-
tion is thought to contribute to the addictive properties of psychostimulants such as
cocaine.

Despite significant public health concerns surrounding psychostimulant abuse,
currently no effective pharmacotherapies exist (Howell and Kimmel, 2008). To
date, treatment for cocaine addiction has been the most widely studied of all psy-
chostimulants. Researchers have examined potential benefits of antidepressants
and dopamine receptor agonists and antagonists for cocaine addiction with lit-
tle success. The TCA desipramine was reported to be an effective treatment in
outpatient clinical trials (Levin and Lehman, 1991). Further clinical trials were
not able to confirm this effectiveness (Arndt et al., 1992; Campbell et al., 1994).
Similarly, treatment with the selective serotonin reuptake inhibitor (SSRI) flu-
oxetine, appeared initially promising (Walsh et al., 1994), but further studies
were unable to demonstrate effectiveness over placebo controls (Batki et al.,
1996; Grabowski et al., 1995). Clinical studies with the D2-like receptor agonist
bromocriptine have yielded inconclusive results (Gorelick, 1992). Studies target-
ing GABAergic transmission have shown recent promise (Sofuoglu and Kosten,
2005). Treatment with baclofen, an antispasticity medication and GABA
B
receptor
agonist, has resulted in increased cocaine abstinence in cocaine-addicted patients
(Shoptaw et al., 2003). Similarly, the GABA transporter inhibitor tiagabine that is
used for treating epilepsy has been shown to reduce cocaine dependence (Gonzalez
et al., 2003). These studies implicate the GABAergic system as a promising tar-
get for the development of useful pharmacotherapies for the treatment of cocaine
addiction.
4.2 Alcoholism
Alcoholism i s characterized by the development of tolerance, craving, and with-
drawal (Heinz et al., 2004). Repeated exposure to alcohol results in neuroadaptive
changes in the central dopaminergic and serotonergic systems (Heinz et al., 2004).
Several studies have directly implicated DAT and SERT in alcoholism. A reduction
in SERT expression was found in a sample of alcoholic patients (Heinz et al., 1998)
and a high frequency of the short 5-HTTLPR was observed in alcoholic patients

(Hammoumi et al., 1999). Studies in rodents demonstrated an ethanol-induced
182 N.R. Sealover and E.L. Barker
release of dopamine that reinforced the mesolimbic reward system (Mereu et al.,
1984; Di Chiara and Imperato, 1988). A recent study by Hillemacher and colleagues
found significant hypermethylation of the DAT promoter in alcohol-dependent
patients compared to healthy control subjects (Hillemacher et al., 2009). They pro-
posed that ethanol consumption in alcoholics may lead to reduced craving due to
hypermethylation-induced downregulation of genes including DAT (Hillemacher
et al., 2009). Hypermethylation of the DAT promoter is thought to inhibit gene
transcription, leading to reduced DAT expression and increased levels of synaptic
dopamine. The mechanism for DAT promoter methylation in response to ethanol
consumption is unknown, although the long-term regulation of gene expression by
epigenetic mechanisms such as DNA methylation has been suggested as playing
a role in the pathophysiology of several psychiatric disorders (Hillemacher et al.,
2009).
5 Anxiety and Depression
Alterations in the serotonergic and noradrenergic systems are well established in the
pathophysiology of mood disorders, including anxiety and depression. Studies have
demonstrated a linkage between the short 5-HTTLPR and psychiatric conditions
(Olivier et al., 2008). Anxiety disorders include panic, phobias, obsessive compul-
sive disorder, and generalized anxiety disorder (GAD) (Keller et al., 2006). These
disorders are often treated by blocking NET with compounds such as reboxetine
or atomoxetine (Morilak and Frazer, 2004). Chronic treatment with reboxetine or
desipramine in rats has been shown to decrease NET binding sites (Gould et al.,
2003; Frazer and Benmansour, 2002). Anxiety disorders carry periods of high emo-
tional distress accompanied by physiological hyperarousal (Keller et al., 2006).
Keller and colleagues demonstrated that NET-deficient mice respond to stress-
inducing environments with heightened autonomic cardiovascular response (Keller
et al., 2006). This cardiovascular response is consistent with a NET deficiency
linked to increased blood pressure and heart rate due to anxiety and fear-inducing

stimuli (Keller et al., 2006).
Several theories have attempted to explain the pathology of depression. One
of these theories is the monoamine theory of depression (Heninger et al., 1996).
This theory proposes that impaired monoaminergic function is the central basis
behind depression. Serotonin and norepinephrine are the two monoamines that have
been primarily implicated in the disease. Pharmacological treatment of depres-
sion has focused on increasing synaptic levels of these two neurotransmitters
(Table 3).
The first class of antidepressants was developed in the early 1950s with the dis-
covery of an antitubercular drug iproniazid that possesses mood-elevating properties
(Nutt, 2002). Iproniazid is a monoamine oxidase inhibitor (MAOI). Monoamine oxi-
dase is the enzyme that breaks down serotonin, dopamine, and norepinephrine. The
inhibition of monoamine oxidase increases levels of monoamines in the synapse.
Monoamine Transporter Pathologies 183
Table 3 Structures of antidepressants and K
i
values in nmol/L for [
3
H] 5-HT or [
3
H] NE inhibition
at hSERT and hNET, respectively
Structure Name hSERT hNET
Desipramine 163 ± 5 3.5 ± 0.6
N
(CH
2
)
3
N(CH

3
)
2
Imipramine 20 ± 2 142 ± 8
Amitriptyline 36 ± 1 102 ± 9
Nortriptyline 279 ± 20 21 ± 0.77
Paroxetine 0.83 ± 0.06 328 ± 25
Citalopram 8.9 ± 0.7 30,285 ± 1600
Fluoxetine 20 ± 2 2186 ± 142
Sertraline 3.3 ± 0.4 1716 ± 151
Venlafaxine 102 ± 9 1644 ± 84
Data were obtained in HEK-293 cells transfected with hSERT or hNET (Owens et al., 1997).
184 N.R. Sealover and E.L. Barker
Potentially life-threatening interactions with foods containing tyramine and tryp-
tophan led to the disuse of these drugs and the development of different classes
of antidepressants. Since the discovery of the first MAOI, TCAs, SSRIs, serotonin–
norepinephrine reuptake inhibitors (SNRIs), and some atypical antidepressants such
as buproprion have been used in the treatment of depression. Except for the atypical
antidepressants, the aforementioned classes of antidepressants increase synaptic lev-
els of s erotonin or norepinephrine by inhibiting SERT or NET, r espectively (White
et al., 2005). White and colleagues provide a comprehensive review of the antide-
pressants in each of these classes (White et al., 2005). Despite the development
of new classes of antidepressants, the effectiveness of these therapeutics remains
no better than the MAOIs and patient compliance remains low (Song et al., 1993).
Inhibiting SERT and NET rapidly increases synaptic neurotransmitter levels, but
the maximal clinical effect is not observed until after several weeks of treatment
(Gelenberg and Chesen, 2000). As with chronic administration of NET inhibitors,
long-term exposure to SERT inhibitors results in decreased SERT surface expres-
sion (Benmansour et al., 1999, 2002). These decreased SERT and NET levels may
help to explain the lapse in time from the initial administration of antidepressants to

their maximum clinical efficacy.
6Autism
Autism is a neurodevelopmental disorder that appears in early childhood and results
in severely impaired behavioral functions (Folstein and Rosen-Sheidley, 2001).
Children with autism display poor social interactions, impaired speech develop-
ment, and an interest in repetitive activities (Folstein and Rosen-Sheidley, 2001).
Autism is recognized as a heritable disorder (Macdonald et al., 1989), although
twin-based studies indicate that the disorder is not always inherited (Murphy
et al., 2000). Research indicates that autism is linked to neuronal disorganization
and the disarrangement of neurotransmitter pathways (Pardo and Eberhart, 2007).
The serotonin hypothesis of autism describes the importance of genes that regu-
late the serotonin system. In particular, genes that control serotonin metabolism
and neurotransmission have received much attention (Cook and Leventhal, 1996;
Buitelaar and Willemsen-Swinkels, 2000). The serotonin hypothesis of autism is
supported by an improvement in behavioral functions in autistic patients receiv-
ing treatment with SSRIs (Hollander et al., 2003) or 5-HT2 receptor antagonists
(Pardo and Eberhart, 2007). A recent study by Makkonen and colleagues demon-
strates reduced SERT binding capacity in the medial frontal cortex of children with
autism (Makkonen et al., 2008). This study used single-photon emission computed
tomography (SPECT) to analyze the binding of [
123
I] labeled N-(2-fluoroethyl)-2β-
carbomethoxy-3β-(4-iodophenyl)-nortropane, ([
123
I] nor-β-CIT) to SERT and DAT.
A significant decrease in SERT binding, but not DAT binding was demonstrated.
Whereas a number of factors likely contribute to the pathology of autism, a signif-
icant amount of data indicates a role for the serotonergic system in this complex
disorder.