from milliseconds to minutes may be of particular rele-
vance to cognition as measures of temporal precision
in humans have been found to correlate well with mea-
sures of general intelligence and working memory
(Troche & Rammsayer, 2009). Furthermore, timing defi-
cits are apparent in disorders such as schizophrenia, au-
tism, and attention-deficit hyperactivity disorder (Meck,
2005), suggesting that timing may serve as an endophe-
notypic measure of psychiatric disease.
A large body of research has now demonstrated that
time perception in both animals and humans can be dis-
rupted by the administration of pharmacological agents
Double Dissociation of Dopamine Genes and
Timing in Humans
Martin Wiener, Falk W. Lohoff, and H. Branch Coslett
■A number of lines of evidence implicate dopamine in timing
[Rammsayer, T. H. Neuropharmacological approaches to human
timing. In S. Grondin (Ed.), Psychology of time (pp. 295–320).
Bingley, UK: Emerald, 2008; Meck, W. H. Neuropharmacology
of timing and time perception. Brain Research, Cognitive Brain
Research, 3, 227–242, 1996]. Two human genetic polymorphisms
are known to modulate dopaminergic activity. DRD2/ANKK1-
Taq1a is a D2receptor polymorphism associated with decreased
F., Farde, L., Nakashima, Y., Propping, P., et al. Polymorphisms in
the dopamine D2receptor gene and their relationships to striatal
dopamine receptor density of healthy volunteers. Molecular
Psychiatry, 4, 290–296, 1999]; COMT Val158Met is a functional
polymorphism associated with increased activity of the COMT
enzyme such that catabolism of synaptic dopamine is greater in
S., McInerney-Leo, A., Nussbaum, R., et al. Midbrain dopamine
and prefrontal function in humans: Interaction and modulation
by COMT genotype. Nature Neuroscience, 8, 594–596, 2005].
To investigate the role of dopamine in timing, we genotyped
65 individuals for DRD2/ANKK1-Taq1a, COMT Val158Met, and a
third polymorphism, BDNF Val66Met, a functional polymorphism
affecting the expression of brain-derived neurotrophic factor
B. S., Bertolino, A., et al. The BDNF val66met polymorphism
affects activity-dependent secretion ofBDNF andhumanmemory
and hippocampal function. Cell, 112, 257–269, 2003]. Subjects
were tested on a temporal discrimination task with sub- and
supra-second intervals (500- and 2000-msec standards) as well
as a spontaneous motor tempo task. We found a double disso-
ciation for temporal discrimination: the DRD2/ANKK1-Taq1a
polymorphism (A1+ allele) was associated with significantly
greater variability for the 500-msec duration only, whereas the
COMT Val158Met polymorphism (Val/Val homozygotes) was
associated with significantly greater variability for the 2000-msec
duration only. No differences were detected for the BDNF
Vall66Met variant. Additionally, the DRD2/ANKK1-Taq1a poly-
morphism was associated with a significantly slower preferred
motor tempo. These data provide a potential biological basis for
the distinctions between sub- and supra-second timing and sug-
gest that BG are integral for the former whereas pFC isimplicated
in the latter.■
Although the ability to precisely mark the passage of time
is crucial for perception and action, surprisingly little is
known about the neurobiology of temporal processing.
Additionally, processes underlying the perception of time
affecting the dopamine system (Rammsayer, 2008; Meck,
1996), suggesting that this neurotransmitter system, which
may underlie such crucial functions as working memory
(Cools, 2008) learning (Klein et al., 2007) and reward value
(Pierce & Kumaresan, 2006), is important for the per-
ception of time. In an attempt to distinguish the roles of
different dopamine receptor subtypes in interval timing,
Meck (1986) administered a number of different neuro-
leptic drugs, including chlorpromazine, haloperidol, pimo-
zide, promazine, and spiroperidol to animals performing
an interval timing task. Drawing on evidence ofthe binding
affinities to dopamine, norepinephrine, and serotonin
receptors for each drug, Meck demonstrated that the abil-
ity of a drug to induce a 15–20% shift in the psychophysical
function significantly correlated only with the binding affin-
ity for dopamine receptor D2.
Rammsayer and colleagues have conducted a number of
experiments over the past two decades investigating the
effects of dopamine antagonists on interval timing in hu-
mans. Rammsayer (1989a) first demonstrated that admin-
istration of 3 mg of the D2receptor antagonist haloperidol
University of Pennsylvania
© Massachusetts Institute of TechnologyJournal of Cognitive Neuroscience X:Y, pp. 1–11
attentional set-shifting and error prediction (Dreher &
Grafman, 2002; Middleton & Strick, 2000). The mesolim-
bic and mesocortical pathways both project from the ven-
tral tegmental area, with mesolimbic neurons targeting
the nucleus accumbens of the ventral striatum, and meso-
cortical neurons primarily targeting pFC. The mesolimbic
pathway is thought to underlie motivation and reward
(Pierce & Kumaresan, 2006), whereas the mesocortical
pathway underlies working memory (Cools, 2008; Aalto,
Bruck, Laine, Nagren, & Rinne, 2005; Kimberg, DʼEsposito,
& Farah, 1997).
To dissociate between the dopamine pathways in hu-
mans, Rammsayer (1993, 1997a) tested for differential ef-
fects between the D2antagonists haloperidol (3 mg) and
remoxipride (150 mg) in humans. Remoxipride blocks D2
receptors in the mesolimbic and mesocortical pathways
to humans increased variability on an auditory temporal
discrimination task, in which subjects were required to
val timing in humans has been replicated across numerous
experiments at different interval ranges (Rammsayer,
1989b, 1993, 1997a, 1997b, 1999). However, the effects of
other dopaminergic drugs on humans have not elicited
similar effects. Rammsayer (1989a) found no effect of the
indirect dopamine agonist L-Dopa on interval timing;
furthermore, Rammsayer and Vogel (1992) demonstrated
that alpha-methyl-p-tyrosine, an indirect dopamine antago-
nist, did not alter interval timing. Rammsayer concluded
that dopaminergic modulation of time perception de-
pended on selective effects on dopamine receptors rather
than dopamine synthesis. However, Rammsayer (1997a)
also found no effect of the atypical neuroleptic sulpiride,
a D2/D3receptor antagonist, on time perception abilities.
Additional work on the role of dopamine in time per-
ception has come from studies involving patients with
Parkinsonʼs disease (PD). Several experiments revealed
that patients with PD exhibit deficits on temporal repro-
ductiontasks;notably, the administrationof L-Dopaattenu-
ated these deficits (Malapani & Rakitin, 2003; Malapani,
Deweer, & Gibbon, 2002; Malapani et al., 1998). A further
study demonstrated that administration of a higher dosage
of L-Dopa than that used by Rammsayer (1989a) to older
and younger adults induced a subjective lengthening of
duration on a reproduction task (Rakitin, Scarmeas, Li,
Malapani, & Stern, 2006). These findings culminated in a
quantitative model of timing, suggesting that dopamine
levels could alter the firing rate of neurons acting as a
temporal accumulator (Shea-Brown, Rinzel, Rakitin, &
A consideration of the role that dopamine plays in inter-
val timing is further complicated by the existence of three
different dopamine pathways in the brain, the nigrostria-
tal, mesocortical, and mesolimbic pathways. The nig-
rostriatal pathway projects from the substantia nigra
pars compacta to the dorsal striatum and is thought to
underlie motor programming and responses as well as
(Gerlach & Casey, 1990), whereas haloperidol blocks D2
receptors in all dopamine pathways (Lidow & Goldman-
Rakic, 1994). Haloperidol disrupted performance stimuli
that were greater and less than 500 msec, but remoxipride
disrupted performance exclusively for the longer dura-
tions. Rammsayer concluded that different neural circuits
are recruited for the processing of short- and long-duration
Although these studies argue for the role of dopamine
in temporal processing, several confounds diminish their
conclusiveness. First, medications such as haloperidol re-
duce alertness and arousal. Second, methamphetamine
of interval timing—tend to alter temperature (Sandoval,
Hanson, & Fleckenstein, 2000; Lin, Wang, Wang, & Chern,
1979), a parameter that is known to influence timing
has also been shown to antagonize serotonergic and stim-
ulate α1-adrenergic receptors (Schotte, Janssen, Megens,
& Leysen, 1993; Pazo, De Stein, Tumilasci, Medina, &
De Robertis, 1985), limiting the specificity of behavioral
results to alterations of the dopamine system. Finally, al-
though a substantial number of studies demonstrate def-
icits in performance associated with methamphetamine
administration in animals (Meck, 1996), a growing num-
ber of studies report a failure to replicate this effect (for
a review, see Balci et al., 2008).
The case for a distinction between mesocortical and nig-
rostriatal dopamine pathways may not be as robust as pre-
viously claimed. The conclusion of Rammsayerʼs (1993,
1997a) earlier work was based on pharmacological evi-
dence for differential effects of haloperidol and remoxi-
pride, with remoxipride primarily acting on D2receptors
in the mesolimbic and mesocortical pathways. However,
the evidence that remoxiprideacts exclusivelyonmesolim-
bic and mesocortical pathways is currently inconclusive, as
numerous studies using autoradiographic techniques have
demonstrated alterations at striatal binding sites following
remoxipride administration (Nadal, 2001; Eaton, Tian,
Lookingland, & Moore, 1992). Thus, the differential effects
of haloperidol and remoxipride at different interval ranges
may not be sufficiently explained by preferred action on
the nigrostriatal system.
In light ofthe uncertainties involved in pharmacological
studies, we sought to assess the role of dopamine for
short and long interval timing with behavioral genetic
paradigms. To elucidate the effects of dopamine on time
perception in humans, we investigated two well-known
single-nucleotide polymorphisms known to modulate hu-
man dopamine function. The first, DRD2/ANKK1-Taq1a, is
a C/T substitution located in the ANKK1 gene that is in
linkage disequilibrium with the dopamine D2receptor
gene (Hirvonen et al., 2009; Duan et al., 2003). The pres-
ence of a single allele of the Taq1a polymorphism (A1+)
has been demonstrated to reduce the density of D2recep-
tors in the striatum by 30–40% (Jönsson et al., 1999). The
Taq1a polymorphism has been behaviorally associated
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