Andrew Thompkins

Dr. Welhausen
ENGL 418-010
10/17/2015
Introduction
Amphetamine drugs like Adderall, increase the availability of dopamine inside the human brain
which over time can cause addiction, addiction to amphetamines such as Adderall is a
continuous issue in the youth and in adults who have been prescribed along with the youth and
adults that have not been prescribed. Misuse of these types of drugs can be potentially
dangerous and addicting, studies on different ways to lessen the addictive effects of these types
of drugs are still being conducted today such as Trace Amine-Associated Receptor 1 (TAAR1)
which has been researched as a dopamine modulator [4]. Research has shown that TAAR1
may be another substance that can lessen the addicting effects of amphetamine drugs; however
the precise mechanisms underlying the action of these medications are not completely
understood [3]. In this review article I will explore the effects TAAR1 and the possible
advantages of using it to lessen the additive effects of amphetamines.
Trace Amine-Associated Receptor 1
In 2001, identification of TAAR1 provided evidence for a direct biological effect of trace amines
(TAs) which is a subgroup of biogenic amines previously denoted as false neurotransmitters [5].
TAAR1 is a member of the TAAR family which is a G protein-coupled receptor (GPCR) that
signals through Gs to elevate intracellular cAMP levels in response to TAs [5].TAs have been
implicated in a wide range of neuropathological disorders, which include attention deficit
hyperactivity disorder [5]. Studies have shown a reciprocal regulation between TAAR1 and
monoaminergic transporters, particularly the dopamine transporter (DAT) [5], which suggests
that TAAR1 can modulate dopamine released in the brain. If this is correct, TAAR1 can be a
significant aid to addiction to amphetamines.
Research on the Effects TAAR1
TAAR1 was identified in 2001, and at that point research on its effectiveness was minimal.
TAAR1 is expressed and widely distributed in brain monoaminergic systems and co-localized
with the dopamine transporter in a subset of dopaminergic neurons [8]. To decipher the brain
functions of TAAR1, a selective TAAR1 agonist, RO5166017, was engineered. RO5166017
showed high affinity and potent functional activity at mouse, rat, cynomolgus monkey, and
human TAAR1 stably expressed in Human Embryonic Kidney 293 cells as well as high
selectivity vs. other targets [5]. The TAAR1 from non-human species displays different degrees
of divergence in the amino acid sequence relative to human TAAR1. In particular, the rhesus
monkey TAAR1 shares a high structural similarity to human TAAR1 throughout each domain [8]
which means that for humans, TAAR1 has a high possibility of taking effect in the human brain.
In the brain, the mRNA for TAAR1 is distributed throughout the limbic system and in regions
containing catecholaminergic cell bodies and their projections [2].
In the mouse brain, Taar1 is expressed throughout the limbic and monoaminergic
systems, including the ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) [8]. Taar1
mice are hypersensitive to the effects of amphetamine, with enhanced locomotor activity and

increased striatal release of dopamine [7]. Mice lacking Taar1 have no overt phenotype and
appear similar to wild-type littermates in most neurological and behavioral tests. The absence of
TAAR1 in these mice would consequently result in a D2 disinhibition, which in turn would be
reflected in the observed super sensitivity to psychostimulants such as amphetamine [5].
However, Taar1 mice are hypersensitive to the locomotor-stimulating effect of d-amphetamine
and show elevated striatal release of dopamine after a d-amphetamine challenge [5]. The first
selective TAAR1 antagonist, N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide
revealed that TAAR1 can reduce the basal firing activity of dopamine [5], thus the presence of
activated TAAR1 results in a dopamine modulation in the brain as well as modulating
noradrenaline and serotonin. The research behind TAAR1 proves that it affects the dopamine
sensors in the brain, which is why it could potentially be used to modulate dopamine.
Research on TAAR1 Lessen Addictive Effects of Amphetamines
Studies on the modulation efficiency of TAAR1 have been conducted to see effective TAAR1
should be used as a dopamine modulator. Amphetamines affect D2 dopamine autoreceptors
which cause a release in dopamine, this dopamine release is what can catalyze addition to the
amphetamine. A recent study on TAAR1-overexpressing, drug-naive transgenic mice are
behaviorally less sensitive to amphetamines while a TAAR1 agonist decreases the firing rate of
ventral tegmental area dopamine neurons in WT mice. Consistent with these findings are the
results from another study showing drug-naive TAAR1 KO mice are more sensitive to the
locomotor stimulatory effects of amphetamines. These results suggest that TAAR1-mediated
signaling in dopamine neurons of the ventral tegmental area may reduce cell firing. Alternatively,
TAAR1-mediated signaling might indirectly modulate dopamine neuron activity and the
neurotransmitter by reducing excitatory input, increasing inhibitory input to dopamine neurons or
both [5], [6] and thereby control the firing rate and the resting membrane potential of
dopaminergic neurons. These studies on mice concluded that TAAR1 does indeed lessen the
firing rate of dopamine neurons as well as inhibit them, which results in a lessened addictive
effect from the amphetamine. Therefore, TAAR1 could potentially modulate the firing rate of
dopamine as well as lessen the addictive effects and make the rehabilitation process quicker
and more effective.
Conclusion
The Previous research studies outlined in this paper on mouse, rat, cynomolgus monkey, and
human TAAR1, it is evident that TAAR1 suggest that TAAR1 can be a useful modulator for
dopamine in the human brain. TAAR1 in mice showed a decrease in the firing of dopamine
neurons. Alongside that, the mice showed less of an interest in amphetamines unlike the mice
that were not given TAAR1. Thus this dopamine modulation can potentially significantly lessen
the addition to amphetamine drugs. Based on the previous success in the research on TAAR1,
human trials should be conducted in the foreseeable future.

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