Regulation of the dopamine transporter - Addiction Research ...

DAT Regulation Schmitt & Reith
obviously contribute to the formation of the
5-(NAC)-thioether metabolites. 137 Pretreatment
with the antioxidant compound acetyl-L-carnitine
was also shown to prevent oxidative damage to
neuronal mitochondria in vivo after high-dose
MDMA administration in rats. 140 These data
strongly indicate that the toxicity of MDMA and its
analogues is due chiefly to oxidative stress induced
by the potent and selective serotonergic neurotoxins
formed during metabolism of the parent
compound. Moreover, these findings suggest that
avoidance of repeated dosing and concomitant use
of central nervous system–penetrating antioxidant
compounds are prudent harm reduction strategies
for preventing or limiting the damage inherent to
recreational MDMA use.
If the neurotoxic effects of the MDA-type ring
substituted amphetamines is due primarily to the
formation of prooxidant quinone metabolites, what
can be said of amphetamine derivatives that are
unlikely to form such unstable metabolites, such
as d-methamphetamine? Despite being similar to
amphetamine itself in structure, pharmacokinetics,
and metabolic fate, methamphetamine exhibits increased
toxicity and significantly greater abuse potential
than the parent compound. 20,141 Toxic insult
to both serotonergic and dopaminergic neuronal
systems after high doses of d-methamphetamine has
been routinely demonstrated in experimental animals
(see Cadet et al. 142 for a review). In humans,
chronic high-dose methamphetamine addicts show
moderate deficits in cognitive function, and in vivo
neuroimaging techniques reveal decreased surface
DAT concentration 143 and increased microglial activation
compared with control subjects. 144 Eventual
recovery from these effects appears possible,
but normalization of dopaminergic function is an
extremely slow process, taking months to years. 145
Similarly to neurotoxicity associated with MDA-like
substituted amphetamines, the toxic response to
methamphetamine—particularly in dopaminergic
neurons—also involves oxidative stress by quinonemediated
formation of ROS and subsequent activation
of proapoptotic signaling cascades. 142
Findings that antioxidant compounds can reduce
neurotoxic insult by methamphetamine support of
this theory: for example, high doses of the aforementioned
antioxidant NAC ameliorate the longterm
loss of striatal DAT in moneys after repeated
injections of methamphetamine. 146 However, un-
like with MDA/MDMA, here the likely culprit is
not a metabolic product of the parent stimulant but
rather dopamine itself.
Free-floating dopamine (that is, existing outside
synaptic vesicles) can be spontaneously oxidized
to dopaminoquinone and successively converted to
5-cysteinyl-catechol thioethers in a manner identical
to the reaction of the MDA metabolite 3,4dihydroxyamphetamine
shown in Figure 2. 147 If sufficiently
large concentrations of soluble dopamine
are present, mechanisms to rapidly clear or safely
inactivate dopamine—namely, the DAT and the
catabolic enzyme COMT—will presumably be
saturated. Excess dopamine will thus be nonspecifically
oxidized, resulting in dose-dependent formation
of dopaminoquinone. How might this oxidative
mechanism explain the increased toxicity of
methamphetamine compared with amphetamine
itself? A series of experiments by Goodwin et al.
systematically highlighted, for the first time, some
vital differences between the two compounds in
their respective effects on the DAT and dopaminergic
function. 20 Notably, the authors demonstrated
that d-methamphetamine is fivefold more effective
at stimulating the DAT to release dopamine in
hDAT-expressing HEK cells than d-amphetamine at
identical concentrations. Also, in vivo chronoamperometry
in the rat nucleus accumbens after
administration of an equivalent dose of either
methamphetamine or amphetamine (5 mg/kg) revealed
that methamphetamine significantly prolonged
dopamine clearance time compared with
amphetamine, resulting in greater sustained external
dopamine levels. However, no differences between
the two were detected at a 1-mg/kg dose (Ref.
20, Fig. 5).
Thesedatasuggestthatathigh(yetequivalent)
doses, methamphetamine has a far greater propensity
than amphetamine to produce accumulation
of excess external dopamine. The higher resultant
concentrations of external dopamine conceivably
contribute to the greater addictive potential
of methamphetamine than with amphetamine and
may also render methamphetamine more likely to
cause oxidative neurodegeneration. Although the
specific DAT-mediated pharmacology of methamphetamine
contributes to its particularly high toxicity
and abuse potential, another basic contributing
factor is the dose and administration pattern typical
of human methamphetamine addicts. Recreational
332 Ann. N.Y. Acad. Sci. 1187 (2010) 316–340 c○ 2010 New York Academy of Sciences.