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Elsevier
245
EJP 147SC
Short communication
M. Stone,
Michel Johnson,
Glen R. Hanson
and James
W. Gibb *
Departmentof Biochemwal
Pharmacology
and Toxicology.Universi(v
of Utah,Salt LakeCi(v,UT84112,U.S.A.
Received 2 October 1986. accepted 16 December 1986
Three psychoactive amphetamine congeners were evaluated for their ability to cause long-term changes in several
neurochemical parameters indicative of central serotonergic function. Two weeks after multiple doses (10 mg/kg) of
3,4-methylenedioxyamphetamine
(MDA) or its N-methylated derivative, 3,4-methylenedioxymethamphetamine
(MDMA), selective and dramatic decreases were observed in regional brain tryptophan hydroxylase (TPH) activities,
and in corresponding concentrations of 5-hydroxytryptamine (5-HT) and its primary metabolite, 5-hydroxyindoleacetic acid (5-HIAA). However, the N-ethylated derivative of MDA, N-ethyl-3,4-methylenedioxyamphetamine
(MDE), was much less potent in its ability to lower brain hydroxyindoles, and in most regions exarmned did not
significantly affect TPH activity. The neurotoxic implications of these results are discussed.
Methylenedioxyamphetamine;
Neurotoxicity;
Amphetamines:
1. Introduction
Recent reports
have implicated
two illicit
amphetamine analogs, 3,4-methylenedioxyamphetamine (MDA)
and 3,4-methylenedioxymethamphetamine (MDMA), as potential serotonergic
neurotoxins (Ricaurte et al.. 1985; Schn'Udt et al..
1986: Stone et at., 1986). These findings are of
particular interest and concern in view of the
widespread recreational use of these and other
closely related compounds (Taylor et al., 1986).
MDA has been described
as a hallucinogenic
amphetamine;
its N-methylated
analog, MDMA
('ecstasy'), elicits qualitatively different effects, reportedly enhancing insight and awareness without
causing perceptual distortion or disturbance of
normal thought processes (Shulgin, 1978).
* To whom all correspondenceshould be addressed: Department of Biochemical Pharmacology and Toxicology, 113
SkaggsHall, University of Utah. Salt Lake City, UT 84112,
u.S.A,
Serotonin
0014-2999/87/$03.50 1987ElsevierSciencePublishersB.V.(BiomedicalDivision)
246
roacetic acid, 2.0 mM EDTA, 0.1 mM 1-octanesulfonic acid, and 12.5% methanol, pH 2.9), the
supernatant
fraction filtered through a 0.2 /tm
microfilter
system (Bioanalytical
Systems Inc.,
West Lafayette, IN), and 50 btl aliquots injected
onto a 10 cm Microsorb reverse-phase column,
The eluent was monitored with an amperometric
electrochemical
detector (model LC-4B; Bioanalyrical Systems, Inc,, West Lafayette, IN), with the
potential set at +0.73 V. Tissue levels were
quantitated
by comparison with stafidards of
known concentration.
TABLE1
Effecton neostr
6 h intervals)a
indicated in pa
ap <0.05, bp.
chomovanillica
Treatment
Saline
MDE
MDA
MDMA
3. Results
2.Materials
andmethods
Two weeks
Male Sprague-Dawley
rats (200-250 g) were
housed five per cage in a temperature controlled
after
MDMA,
TPH
_,00FCONTROL
activity
IxP. ^T,V,TY{
_eo
mo
8o
60
4o
total of fivedoses.Treatmentgroupswereinjected
with 10 mg/kg (expressed as the free base) of
either dI-MDA, dI-MDMA, or dl-MDE, or with
vehicle alone. Rats were killed two weeks after the
initiation of treatment; brain regions were tmmediately dissected free (on ice), and stored at
-80C
until assayed.
20
0,.,Ti
_20
80
60
40
20
0 _-,.AAI
treatment
was
with MDA or
dramatically
*
*
00[__
.L
,
].
t20
100
4-
40
20
0
.,
NEOSTRIATUM
-{-
. .
*
HIPPOCAMPUS
de-
pletion
of5-t'
r_
'
(_
*
_
_i_
F. CORTEX
chemical
5-hydroxyindoleacetic
acid (5-HIAA)concentration
two weeks
after drug treatment.Valuesare the means S.E.M.,expressed
is percent of control. Control values (in/xg/g
tissue) for 5-HT
MO)
was utilized
as
The contralateral
brain
to
response
exception; ofin
fected,yet 5-'
trol, respectix
The effect
markers
ofd_
FigurelB
regional 5-H
spectively, t_
of fig, lA, B
areas and wi,
. ..
Co,
neostriatum (
however,
M[
enzyme activi
(_
eof actor,
pressed,to
neostriatum,
gions of the:
ment with Ix
/X', TREATMENt:
LQ) [] SAUN_
mmuo[
. I53
[] ur^
MOMA
LLL
*
"
'_
treatment,
the three
ar,
dru
dopamine co_
cant reducti
dopamine
(DOPAC)
mt
an,
34.7+1.7:
hippocampus,
48.8+3.0;
frontal cortex, 56.6_+3.7.
(B) Effect on regional serotonin (5-HT) concentration
and (C)
measure concentrations
of monoamines and their
respective metabolites by high-performance liquid
chromatography.
Tissues were homogenized
in
0.3-0.5 ml mobile phase buffer (0.15 M monochlo-
respectively,were:
4. Discussion
The data
neostriatum,
0.53
-+0.04
and 0.55
-+0.03;
hippocampus,
0.32-+ 0.01
0.37
-+0.02;
frontal
cortex,
0.60-+0,01
and 0.204-0.02.
"P and
< 0.05,
corresponding
control,
by the two-tailed
of
':
the
neurol
analogs, ME
central serot
247
3.1 mM 1-octane-
TABLEI
Effecton neostriataldopaminergicparameters two weeksafter drug treatment.Rats were administeredfivedoses of drug (10 mg/kg;
6 h intervals) and killed two weeks later. Values are the means+S.E.M., expressed as percent of control. Absolute values are
indicated in parentheses, in nmol tyrosine oxidized/g tissue per h (TH activity) or u,g/g tissue (dopamine, DOPAC, HVA).
_P < 0.05, h p < 0.005 versus saline, by the two-tailed Student's t-test. _ Tyrosine hydroxylase, ddihydroxyphenylacetic acid,
_homovanillicacid.
Treatment
(n)
TH_activity
Dopaminc
DOPAC
a
HVA
Saline
6
100.0+ 4.9
100.0--_4.5
100.0-.-3.4
100.0+_3.2
(3121 +_154)
(11.10.5)
(0.87 0.03)
(0.62_+0.02)
MDE
9
98.9+ 3.1
100.54.3
t02.3= 6.9
100.0-+4.8
MDA
6
99.4-+ 3.9
91.29.8
92.0 =10.3
91.9 -+9.7
MDMA
7
110.0+_
6.t
94.7*_4.9
87.4 4.6_
83.93.2b
_,
either MDA or MDMA caused dramatic, longterm decreases in brain TPH activities. At an
earlier time point (18 h after treatment), regional
TPH activity was decreased to < 15% of control
in response to MDA and < 25% of control in
response to MDMA (Stone et al., 1986). In ad-
recovery (fig. lA). At the 18 h time point, MDEtreated rats also exhibited decreased regional TPH
activities ( < 80% of control, unpublished observa-
trol, respectively,
The effects of MDA. MDMA and MDE on
both significantly reduced, to 66 and 73% of conmarkers of dopaminergic function two weeks after
_O-ptophanhydroxylase
doses of MDA,MDMA
ses of drug (10 mg/kg);
s.Valuesare the means
completely recovered in the neostriatum and hippocampus, and significantly recovered in the frontal cortex; concurrently, 5-HT levels had returned
to control values in the neostriatum, while remain-
roi,for n= 5-9animals.
h) were:
ontal
cortex.neostriatum,
56.6 + 3.7.
with MDA or
dramatically
de-
(_)
!
i.,L
.
TREATMENT:
[] SALINE
_
MDA
[] MDMA
[]z]MDE
(_)
,
iii_L
(_
_:_.
_:!L
CORTEX
)concentration
and(C)
oncentration two weeks
.ans+_S.E.M.,expressed
l/_g/g tissue)for 5-HT
ely, were: neostriatum.
us, 0.32+0.01 and 0.37
0.20+_0.02.* P < 0.05,
_trol, by the two-tailed
.)
acid
4. Discussion
248
(continued
methylation
of amphetamine
(to methamphetamine) enhances these characteristic
effects (Biel
and Bopp, 1978).
The lack of a
effect of these
pers, s,en,
uru_s on
central dopamine concentrations
agrees with the
Acknowledgements
Sample
et
al..
1986:
decreased
metabolite
Stone
et
al.,
1986).
the
treat-
ment could be explained by a subsequent campensatory decrease in the release and turnover of
this transmitter,
In summary, the two amphetamine
analogs.
MDA and MDMA, appear to be nearly equipotent
in their ability to cause persistent and dramatic
OlD'ep'e-'ons
of central
sero-onergct 1
neuronal
markers; in contrast, the lack of long-term effects
of multiple doses of MDE
on brain
serotonergic
systems suggests this congener is less apt to cause
irreversible neuronal damage. Although the doses
of MDA and MDMA used in these experiments
were several-fold
higher- than the effective human
dose (1-3 mg/kg; Shulgin, 1978), cumulative cffeets from repeated exposure, different rates or
pathways of metabolism between human and rat.
or
increased
human
itl tv to the d _
sens___vi__
_ru,=
,tndcaurte
,n:
et al., 1985) could present
a serious
toxicological threat to human abusers of these
compounds,
ref ........
perten)tctdx:
This research was supported by USPHS Grants DA 00869
and GM 07579. The authors wish to thank the National
Institute on Drug Abuse for the gifts of dI-MDA hydrochlofide, dI-MDMA by hydrochloride
and dl-MDE hydrochloride.
from pa_
ii
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aher_
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Iai
ordinat,'It th,_
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Graphs.
elcctr{_
of thc
paperforthco,
t[_
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5265.
(MDMA).
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charac
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thepublisher
withIii,
to the publisher b? r_
Vol
1987.
Dr.
131-1
30_0
(l{} {US
$ 1
Thc Dutch
Japan.Australia.Nt-,
guilder
Journal
......
and Thailand
Sub,vt'rlplltm
p,
b_
eat
Airma
order_ c_
100o AE
ofthcyear Suchyah
edioxyamphetamine,
Microgram15, 29.
Amsterdam
within th ......
nths,
tnthcUSA
and('_
Information
(.'enter.:
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/_,
photo('o[;?l.g,
r'_ordlt,
BM Amsterdam,
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