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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2 . N . H . Neff, P . F . Spain, A . Groppetti, C . T . Wang and 8 . Costa,

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8 . A . Pletechnr, G. Hartholini, H. Bruderar, W. P . Burkard and R . F . Gey,

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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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