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Amphetamine analogues and brain amines
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Transcript of Amphetamine analogues and brain amines
Lfie Sciences Vol, il, Part I, pp, 83-98, 1972.
Pergamon PressPrinted in Great Britain
er~Te~xs ~eLOwas e~m ssuzx er~a~s
Diana Morgen, Sonja Lofstrandh, and Brmino Costa
Laboratory of Precliaical Pharmscology, èiational Institute of ëental Sealth,
Saint Sliaabeths Sospital, Washington, D.C . 20032
(Received 15 September 1971 ; in ünal form 17 December 1971)
summers
the interactions of various amphetamine analogueswith brain monoamine systems have been investigated includingthe affect of theca conpainds on norepinephrine (NS) sadeerotonin (5-~) concentrationr in various brain arase,brais tryptophan concentrations, èIB and 5-BT uptake systaneand monoamine oridase (!WO) activity in these areas .
The rasulta indicate that the ring-substituted p-chloro or m-trifluoromethyl-compounds, e.g., p-chloro-asiphatami~ and norfeafluramine, merkadly reduce brain 5-~ .concentrations, possibly because of an is vivo inhibitionof tryptophan hydrozylasa .
Various amphetamine analogues have been shown to reduce neuronal contest
of certain monoamines . Amphetamine lowers only brain norepinephrine (äE)
concentrations, whereas its p-halogenated enaloguss lower only braia
serotonin (5-HT) concentrations . Further imreetigation has bean made into
the action of amphetamine analogues on amine concentrations, uptake and
metabolise is specific areas of rat braia and the possible mechanisms
involved are discussed .
thods
ësla Sprague-Dswlsy rate (180-200 g) received appropriate i.p . doses of
the various drugs studied and ware guillotined at suitable times (e .g . 4 hr)
after injection .
The brain was removed and dissected into parts
(telancephalon, braiastam, hypothalasus) accordiag to the method of
1layarson (1) . These parts ware than stored at -15~C until assays of 5-flT
1~ sad tryptophan were done by a:iating methods
(2, 3) .
The
84
Release o~ Monoamines bY Amphetamines
Vol. 11, No. 2
significance of any differences in amine concentrations between treated and
control aaimsls vas assessed using the Student's t test .
The in vitro accumulation of radiwctive NE (10-7M) and 5-Sf (10-6M) vas
studied in slices of brain areas according to the method of Hendley and
Sgydsr (4) and the influence of 10-5M concentrations of various drugs vas
investigated . MAO inhibition by the drugs vas assessed using either 2 mM
tyraaine (5) or 1 .2 mM 5-HT (6) as substrate .
Tryptophan hydrorylase
activity vas estimated by the method of Lovenberg, Jequiar, and Sjoerdsms (7) .
The compounds studied were d,-l-and dl-methamphetamine HC1 (Abbott
Labs .), mephentermine sulphate (Warner Lambert Research Institute, N. J .),
d-or 1-p-chloroamphatamiae hydrogen tartrate (L~vens Remiske Fabrik,
Ribenhavn), dl-p-chloromethamphetamine HC1 (Smith Rune and French
Laboratories, Pa .) chlorphentermine HCL (Warner Lambert Research Institute)
dhfaafluranine HC1 and dl-norfenfluramine (Robins Lab ., Richmond, Va .) dl
8~ 41407 (1-methory-l-(3-trifluromnthylphenyl)-2-propylamiae HC1 (Smith,
Kline and French Labs . Pa .) .
L-7-3H-norapiaephrine (3 Ci/mmole) and 5-hydrorytryptaminn 3-C14-
creatiaina sulfate (50 mCi/mmole) were obtained from Amarsham/Seeds and
L-3-14C-tryptophan (25 mCi/mmole) and 14C-tyramine (2.8 mGi/mmole) from
New England Nuclear Corporation.
Results
(aZ Bffact of Various amphetamine Analogues on Brain Amino Concentrations
d- sad 1- Methamphetamine (55 ~amol/kg) did not aignificaatly alter 5-HT
concentrations of various brain erase after 4 hours (Figure la) .
NE
lwals in the telencaphalon were, however, 35x lover than controls after
treatment with the d-isomer (Figure lb) .
A small reduction in hypothalamic
NS was also seen . The 1-isomer showed no effect on NE concentrations in
various brain areas .
.
Vol
.
11, No
.
2
Release
ad Monoamines by Amphetamines
86
aKrNE
w~hOAsOms"
u
äe
w~
iaw ~ v
rt
sa
~w
~w
Figure
la
Figure
lb
5-~
(la) and äS(lb) concentrations in various brain areas of rats receiving
~ethamphatamine
(liA), msphantsrmine (!~) and Sam+ 41407 (1-matho~-1-(3-
trifluorosethylphaayl)-2-propylamine
HiCl) intraparitonaally four hours earlier
.
Concentrations
of the amine era displayed as percent of controls, but
significance
of the differences ws calculated from the mean concentration
(nmolas/g)
of 5-BT and ~ in rats receiving saline
.
7~a concantrationa
(snaoles/g)
wras 5-HTs igpothalasus 7
.6
t 0
.4,
brain stem 4
.2
t 0
.3,
talancaphalon
2
.6
t 0
.2 ;
ä8s hypothalasus 11
.2
t 0
.3,
brain stem 4
.3
t 0
.3,
talancaphalon
2
.3
t 0
.08 .
8ach value is the avarsge of at least 4
aatiatstiona .
88
Release ad Monoamines tq Amphetamines
Vol. 11, No. 2
Mephentermine (30 Eamol/kg) a structural analogue of amphetamine with an
additional methyl group on the a-carbon atom affected I~ and 5-HT concentrations
only slightly, causing less than 20S reduction of NE (Figure lb) and 5-HT in
telencephalon and 5-HT is brainstem (Figure La) .
Introduction of a chlorine eubstituent group in the pare position, as in
p-chloroamphetaminn (g, 9) enhances the action of the amphetamine on brain
5-FiT concentrations sad attenuates that on NE Levels .
d- or 1-p-Chloroamphetamine (25 Nmol/kg) slightly reduced NE concentrations
in telencephalon to 80x of control levels (Figure 2b), but 5-HT levels
(Figure 2a) in the same area fell to 35Z (d-isomer) and 20x (1-isomer) of
control levels .
Figure 2a
NE
Figure 2b
.nooe..r.ooiwp0.000C7TR~ MT
5-HT (2a) and NE (2b) concentrations is brain areas after d-p-chloroamphetamine
(d~-p-C1-A), 1-p-chloroamphetamine (1 p-C1-A), dl-p-chloromethamphetamine
(dl-p-C1-MA), and chlorphentermine (CP) as percentage of control values . Ssch
value is the average of at least 4 estimations .
Vol. ll, No. a
Releaee ad Monoamines by Amphetamines
87
Ftisrthermore, the hypothalamic concentrations of 5-BT rare reduced to values
65x (d-isomer) end 60Z (1-isomer) of norvel animale ; eisilar reductions rare
found in brain stem of rate receiving the two isomers . 1t~e molecule rith an
extra N-methyl group, dl-p-Cl-methamphatamine, oleo failed to modify the brain
NS concentrations (Figure 2b) and ras lass effective in diuinishing 5-HT
concentrations than dl-p-cloroaophatamina (Figure 2a) . A 35 Nmol/kg dosa
caused only a 40~ reduction of 5-ST in telancephalon and did not affect
hypothalamic or brain stem levels .
The cX-dimsthylated analogue, chlor-
phaatnrmina (35 Wool/kg), had only a alight effect on NS (Figure 2b) similar
to p~hloroamphetamine,but it reduced 5-HT to 66x of control values in both
telancephaloa and hypothalamus (Figure 2a) . Thus, the presence of tro methyl
groups in the cX-position reduced the effectiveness of the pzhloroaaphetamine
in decreasing brain 5-HT concentrations at 4 hrs .
Another ring substituent in the molecule of asphetamine rhich enhances
interaction rith the central serotonergic system is the -CF3 group (10) .
Fenfluramine, at a dose level of 30 Wool/kg causes a long-lasting depletion
of telancephalon 5-HT; only at a dose of 90 Wool/kg is the depletion of 5-Sf
associated rith a N8 depletion (11) . Furthermore, norfenfluramine, a compound
lmora to be a metabolite of fenfluramine (12, 13, 14),depletes 5-HT in the .
telancephalon for over 48 hours (Figure 3) .
_ 88
Release a~ Monoamines hY Amphetamines
Vol. 11, No. 2 .
401
24 32
TIME IN HOURS
Figura 3
40 48
5-HT concentrations as x o£ control values in hypothalamus
(e----e), brain
sten (~----~), and talencephalon (~ ---- ~ ), after an i .p . dose of 40 Nmo1/kg
norfenfluraaina. Bach point is the average of at least 4 estimations . Control
values (nmolas/g) vnra : hypothalaaaue 9 .3 f 0.44, brain stem 3 .0 t 0 .13,
telencephalon 1 .8 t 0.02. Sigaificancn calculated from comparison of the
mean values .
Only at 7 hrs is there a slight 5-El depletion in brain stem and hypothalamus
and at no time is there an affect on NS . The ß-methosy substituted nor-
fanfluraoina (3~f 41407) (55 Nmol/kg) had no affect on either amine (Figures
la, b) .
Vol. ü, No. 2
Release a~ Monoamines b9 Amphetamines
(b) Trsvtovhan concentrations is brain of rate receiving halogenated
dorivativeW oi amphatapine
Tabla 1 shows tryptophan concentrations in the telencephalon at times at
which 5-ST concentrations are decreased i .e . 4 hr after i .p . dose of 1-p-
chloroamphetaniae (25 Nmol/kg) and dl-norfenfluramine (40 Nmol/kg) and 2 hr
after an i .p . doge of d-mathamphetamine (54Nmo1/kg) . There vas not signifi-
cant change after 1-p-chloroamphetamine ; however, tryptophan concentrations
vara rained 75x after d-nethamphetamina and 43x after dl-norfenfluramine .
TASLE 1
CONCSNTBATIOIi OF TRYPTOPBAN IIi TSLBNCEPHALON OF RATS RECEIVING VARIOUSA~~TAlII~ ANALOGRES
All values ara the average of 4 astiautiona
(c) $ffect of drugs on the accumulation of NE and 5-HT in brain slices
Further studies wre done in an attempt to investigate the mechanisms
by which thane drugs might be interacting with eha amen systems . The effects
of thaw drugs on the accumulation of radioactive NE (10-7I~ and 5-FiT (10-6M)
in 20 oin . by brain slices in vitro were studied . The accumulation of NE vas
inhibited by nathaAphstaoiae, dl-p-chloroamphatamina and chlorphentermina
braiaatem, by mathampheta>tina, chlorphentermina and norfanfluramine in
hypothalania, and markedly by all four drugs (10-5
in the striatum (Table 2) .
in
89
DRITG TREATI~NT Nmol/kgi .p .
HRS AFTERINJECTION
TRYPTOFBAN(nmolee/g) fSB
SIGNIFI-CANCS
Saline - 4 12 .25 t 0.68 -
d-Mathamphetanine 54 2 21 .51 t 0.78 P < 0.001
1-p-chloroasphatamine 25 4 10.34 t 0.58 NS
Df.-mrfenfluramine 40 4 17 .50 t 0 .04 P < 0.005
90
Release od Monoamines try Amphetamines
Vol, il, No. 2
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voi. u, xo. a Release ad Monoamines b9 Amphetamines
91
5-ST accumulation ws reduced in the striatum by methasghetamine and chlor-
phentarsdna and in brainsten by p-chloroamphatamine .
slices of rats receiving fanfluramina or norfenfluramine (90 ~ mol/kg) 4 hre
earlier pare used to study the in vitro accumulation of NB and 5-aT, the
5-ST accumulation was unaffected, vhareas a 36x inhibition of NB uptake in
thn hypothalamus van observed With fanfluramiae and a 50'L reduction with
norfenfluramine (Tabla 3) .
TABLB 3
In addition, vhan brain
ACCUMULATIOM OF äB (LO-7M) Aè1D 5-HT (LO-~ IN BRA~i SLICES OF BATS
*P<0.05** P < 0.02
Accumulation is as~ressed as tiseue:oedium concentration ratio .Tissues ware incubated with radioactive MB (10-7MJ and 5-HT (10-~in thn presence of MAO inhibitor according to the oethod of Handlayand Snydar (4) . Each value is the average of 6 determinations .
(d) Inhibition of MAO by amphet~mina aa.LoBuas
Since MAO inhibition by p-chloroamphstanina (15, 16) can asplain the
reduction of brain SHIAA concantrationa elicited by p-chloroamph~tanine, the
MAO inhibitory potency of the other drugs investigated in this study vas
evaluated. Using tyraoina (2 mM) as a substrata, d-p-chloroa~hetamine vas a
batter inhibitor of MAO than 1-p-chloroamphetsmine, anphetaaina, and
methamphatamine . ünder these conditions, norfenflurasine and fanfluramine
(10-3M) inhibited MAO by 40x; oathasphetamina had vary little effect .
PBBTBBATSD WITH~03 BOBFB~IFLUBAMINS
DBUG TBBATMBNT Nooljkg - - HYPOTBShè1~l18 BBAIN STSli STBIATOM-i~-
äSControl - 5 .0 f 0.6 4.2 t 0 .3 15 .1 ± 2 .9Fanfluramine 90 3 .2 t 0 .4* 4 .8 t 0 .4 14 .7 t 4.7Norf~fluramine 90 2.5 ± 0 .5** 2 .8 t 0 .6 12 .2 t 4 .0
5-HTControl - 4.0 t 0.6 4.4 t 0 .5 9.9 t 1 .4Fanfluramiae 90 3 .5 t 0 .3 3.8 t 0 .6 14 .Ot 2 .0äorfanfluramine 90 6.2 t 0.8 5 .8 t 0 .6 9 .2 t 2 .3
92
Release od Monoamines bY Amphetamines
Using 1 .2 mM 5-HT as substrate d-p-chloroamphetamine was again shown
more potent Me10 inhibitor than norfenfluramine aid
centration of 10-4M d-p-chloroamphétamine produces
whereas fenfluramine ie scarcely active
shows a 34X inhibition .
(e) Inhibition of tryptophan hydroxvlaee by amphetamine analogues
In agreement with previous reports there was no detectable inhibition
is vitro of brain tryptophan hydroxylase by 1-p-chloroamphetamine (17)
(10-3M) or by fenfluramine (18) (LO-3M) . Preliminary reaulta, however, seem
to indicate that at high concentrations (10-3M) norfenfluramine is able to
inhibit tryptophan hydroxylase and its possible significance in the reduction
of 5-HT concentrations by norfenfluramine should be considered .
Discussion
The mechanism of the reduction of 5-HT concentrations produced by
various amphetamine analogues 1n certain areas of rat brain remains uncertain
(9, 15, 19) . The analogues which produce more significant effects on brain
5-HT, however, e .g ., p-chloroavphetamine, norfenfluramine, and fenfluramine,
do have certain properties in common . p-chloroamphetamine is more lipid
soluble than amphetamine (20) and in rata it accum~~latea to a greater extent
(21) and persists for a longer time in brain than amphetamine does (8, 22) .
Similarly, fenfluramine and norfenfluramine are very lipid soluble and have
alowly from the body (18) .
Indeed, norfenflur-
rat brain at least 24 hra after
i .p . dose (90 Nmol/kg) of fenfluramine and no evidence has been obtained for
p-hydroxylation of the m-trifluoromethyl substituted ring .
One postulated mechanism is a selective release of 5-HT combined pith
MAO inhibition (15, 16, 23) . p-Chloroamphatamine has been shown to be a good
MAO inhibitor especially when 5-HT is the substrate (16, 24) but direct
evidencn for 5-HT release is lacking . Moreover, our reaulta suggest that
whereas the d-isomer is more active as MAO inhibitor, the contrary applies to
been found to be eliminated
amino has been shown (14) to be present in
Vol . 11, No. 2
to be a
fenfluramine . At a con-
an 86x inhibition of M40
(13~ inhibition) ; norfenfluramine
Vol. 11, No. 2
Release ad Monoamines h9 Amphetamines
9S
the Lowering of brain 5-HT concentrations . Indirect evidence also (19) seems
to argua against a releasing affect of brain 5-~ by p-chloroa~hetauiae.
Our in vitro studies of thn effect of various amphetamine analogues on the
accumulation of 5-HT in brain tissue slices did not provide clear indication
that these amphetamine analogues reduce 5-HT concentrations in vivo because
they interfere with 5-H1' uptake/release system .
5-HT accunuletioa was reduced
in the brain stem but not in the telsncephalon by p-chloroamphetamiae .
Neither fenfluramine nor norfenflursmine which reduced 5-HT concentrations
predooinantly in telancephalon had any effect oa 5-HT sccumalation, whereas
they both reduced 5-ST concentratiow is vivo is the telencephalon for over
48 hours .
Another possible mechanism is that of interfering with the rate-Hosting
step in brass 5-HT synthesis, i.a . the hydrozylation of tryptophan (25, 26,
27) .
Since brain tryptophan hydrozylasa is not normally saturated with
tryptophaa (28) reduced brain tryptophan concentrations may conceivably
result is decreased 5-HT synthesis. üe, therefore, investigated the possi-
bility that tryptophan concentrations night bs low is brain areas in which
5-HT concentrations era reduced by p-chloroanphetamine and norfenfluramiae,
but found that this is sot so . Concentrations of tryptophan in telen-
caphalon were unchanged after p-chloroamphatamiae and increased after
norfeaflursnine . Other workers reported similar findings in whole brain after
p-chloroasphatamine (19) and as increase in brain tryptophsn concentrations
after fenfluramine (29) .
Inpairmsnt of 5-HT synthesis could nest obviously be effected by
inhibition of tryptophan hydro>91ass itself as appears to be the case with
p-chlorophe~lalanine (30, 31) . ühereas no in vitro inhibition of brain
tryptophan hydrozylass can be da~onstratad by up to 10-3lî of p-chloro-
as~hetanins, an in vivo tryptophan hydrorylsse inhibition of 40-5OX in rat
brain step 2 hr and 16 hr after an i .p . injection of 10 AB/kg p-chloro-
aagrhetasias has recently bean reported (17) .
Zhis finding would suggest that
94
Release a~ Monoamines bY Amphetamines
Vol. i l, No. 2
a metabolite of p-chloroamphetamine is~the in vivo inhibitor but such a
metabolite has yet to ba identified .
Indeed, the metabolism of p-chloro-
amphetamine itself has yet to be studied in detail . Perhaps such studies may
clarify our results on the different intensity of the depletion of brain 5-HT
elicited by the isomers of p-chloroamphetamine .
One ca~ot exclude the possibility that fenfluramine acts through its
conversion to norfenfluramine . It has been found in this study and previously
reported (18) that fenfluramine does not inhibit brain tryptophan hydroxylase
in vitro; however, it appears possible from our preliminary results that
norfenfluramine, at least in high concentrations, can do so . Conversion of
fenfluramine in vivo followed by its possible concentration in nerve endings
(a point which could bt investigated by subcellular fractionation studies)
could thus result is an in vivo tryptophan hydroaylase inhibition and hence
reduce 5-HT concentrations .
Such an in vivo tryptophan hydroxylase inhibition
thus requires further study .
Maickel and his . colleaguea (32) have also reported different effects of
amphetamine analogues in various brain areas, but the significance of these
differences is unezplained . There are, of course, differences in concentration
and turnover of 5-HT (e .g . 25) in various brain areas, but even so it is
difficult to sae why the depletion of telencephalic 5-IiT elicited by a single
dose of norfeafluramiae lasts longer than 48 hra whereas that of hypothalamic
5-~ sot onlq ie less pronounced, but is also shortlaeting .
Recently,
Bjorklund sad his colleagueB (33, 34) detected microapectrofluorimetrically
is brain a fluorophore similar, but not identical, to that produced under
similar conditions from 5-RT . Theq speculated that this could result
from N-methyl-5-hydroxytryptamine or 6-hydrozytryptamine, which also form
fluorophores with spectral characterietica similar to that formed from 5-HT
when they react with ninhydrin . Our reaulta may thus reflect the presence
in specific brain areas of an as yet unidentified indole .
Vol . ü, No. 2
Release ad Monoamines by Amphetamines
95
xsFSR~css
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98
Release ad Monoamines by Amphetamines
Vol. 11, No. 2
18 . J. C . Le Douarec and C . Neveu, Amphetamines and Related Compounds ;
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