Med. Pharmacol, exp.

17: 534-542 (1967)

Departamento de Ciencias Fisiológicas Faculdade de Medicina da Santa Casa

Sao Paulo

Effects of Chronic Administration of

f t - (3,4-Dimethoxyphenyl)-Ethylamiiie and

f t - (3,4,5 -Trimethoxyphenyl)-EthyIamine

on the Climbing Rope Performance of Rats 1

By E. A. C a r l in i , M. T e r e s a A. S ilv a , L. C. C e s a r e 2
and R. M. Endo 2

A great amount of interest has been developing recently in comparing the

effects of mescaline (trimethoxyphenylethylamine) and homoveratrylaminc
(dimethoxyphenylethylamine). Mescaline is a well-known hallucinogenic agent
and homoveratrylaminc, according to some authors (Friedhoff and Furiya,
1967; Bourdillon ct al., 1965) but denied by others (Perry et at., 1966), is present
in the urine of schizophrenic patients. Both drugs have structural resemblance
to dopamine, a substance that might have some function as neurotransmitter
in the central nervous system (Van Possum, 1966; Ilcrz and Zieglgangsberger,
1966). An alteration of dopamine concentration and/or activation of its receptors
in certain areas of the central nervous system has been suggested as responsible
for appearances of disturbances, such as compulsive gnawing behavior (Ernst
and Smctik, 1966) and catatonia (Darbeau ct at., 1966 a; Lusvarglii et at., 1967).
Mescaline and homoveratrylamine are also able to provoke electrocncephalo-
graphic arousal in the rabbit (Takeo and Ilimwich, 1957).
These facts led us to undertake the present experiments, in which the effects
of these drugs were studied on the climbing rope performance of rats, a method
that has been employed by several authors to study psychotomimetic drugs
(Freedman ct at., 1958; Mahler and Humoller, 1959; Winter and Flataker, 1956;
Vogel, 1967).

1 Work partially supported by the Fundado de Amparo á Pesquisa do

Estado de Sao Paulo (FAPESP).
2 Bolsistas ‘iniciatao científica’, FAPESP.
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Received: November 28, 1967.

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 Carlini, Silva, Cesare and Endo 535

Methods

The method of Winter and Flataker (1956) was used with minor modifi­
cations. Forty-eight male Wistar rats, weighing about 130 grams at the begin­
ning of the experiment, were trained to climb a vertical rope 160 cm long,
starting from an inferior platform to a superior one, where they were allowed
30 sec food reinforcement. When all animals were able to negociate the rope
in less than 7 sec, they were divided into 5 groups, control, 20, 40 and 80 mg/kg
homoveratrylamine and 40 mg/kg mescaline. Homoveratrylamine, IIC1 (Cal-
biochem) and mescaline sulfate (Sigma Chemical Co.) were used. The amounts
are expressed in terms of the bases. Except for the mescaline group (8 animals),
all others had 10 animals each. The rats received the drugs, at doses stated
above, through inlraperitoneal route; control group received 0.9% NaCl solution.
The animals were fasted 20 to 22 h before each experimental section.
In each experimental section the climbing time was measured, with help
of a stop-watch, just before the injections and then at 20 or 30 min intervals
up to 3 h. If an animal failed to reach the food after 1 min, this was considered
as a failure and the trial was scored as 60 sec. The injections were given daily
but the trials were run either every day or every second or third days. Out of
the total, the mescaline group received 9 injections and were submitted to
6 experimental sections, whereas for homoveratrylamine groups 32 injections
and 16 experimental sections were performed.
After calculating in all trials the average climbing lime for the groups,
the data were plotted in graphs where ordinates represented the climbing time
in seconds (1 sec equal to 0.5 cm) and abscissas the time after injections, in
minutes (1 h equal to 5 cm). The areas in the graphs, circumscribed by the
curves of control and treated groups were measured with the help of a plani-
meter; this allowed us to express in cm2 the climbing performance in each
experimental section. The figure shows in detail the data obtained with 40 mg/kg
mescaline (1st and 6th experimental sections) and 40 mg/kg homoveratryl­
amine (1st and 16th experimental sections).

Results

General Effects
Mescaline and homoveratrylamine, at doses of 40 and 80 mg/
kg, produced in the animals, some 15-30 sec after the injections,
the appearance of a marked reddish color in the ears and anterior
paws, which is suggestive of a vasodilatation; also, some sort of
abdominal discomfort which could he inferred from the strong
abdominal contractions was observed in the rats, both effects dis­
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appeared at the end of 30 to 60 min. However, the rats did not

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536 Carlini, Silva, Cesare and Endo, Effects of Chronic

TABLE I
Effects of liomooeratrylamine and mescaline on climbing rope performance
of rats

Mescaline H om ovcratrylam inc

E x p e ri­ Climbing-
m ental In jectio n
tim e *
In jectio n 20 m g/kg C lim bing-tim e * 80 m g/kg
No. No. 40 m g/kg
Section 40 m g/kg

i i 89.6 i ( - ) 2.0 35.0 193.0

2 2 44.0 3 2.5 50.8 179.4
3 3 50.0 6 2.0 57.0 206.5
4 6 25.0 8 8.5 23.0 143.5
5 8 19.5 10 (—) 3.0 31.0 216.5
0 9 2.7 13 1.5 64.0 283.0
7 - - 15 7.0 49.0 276.5
8 - - 18 (-) i o 74.0 308.4
9 - - 23 ( - ) 180 53.2 342.0
10 - - 24 1—) 10 5 32.5 342.0
11 - - 25 0.0 68.0 355.5
12 - - 27 3.1 98.0 333.2
13 - - 28 6.3 127.4 328.0
14 - - 30 4.6 171.4 346.0
15 - - 31 M Ml 153.7 354.5
16 - - 32 (—) 98 161.1 348.6

* Expressed in cm2; see methods for details.

( - ) Negative figure, means that treated animals had better performances
than controls; the area obtained is then expressed in (•—) cm*.

develop tolerance to them; at the end of 32 injections of homo-

veratrylamine and 9 of mescaline, vasodilatation and abdominal
discomfort were observed just as after the first injections.

Effects on Climbing Performance

Both drugs provoke measurable effects, being approximately
equiactive, at a dose level of 40 mg/kg, in delaying the climbing
time of the rats. During the first (50 min after injections, time
when the drug effects on climbing performance were at a maxi­
mum, the animals showed some peculiarities in behavior. Thus,
with 40 mg of mescaline and 80 mg/kg homoveratrydamine the
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rats remained quiet in their cages, as if they were somewhat de-

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 Administration of /?-(3,4-Dimethoxyphenyl)-ethylamine .. . 537

Time after injection (min)

Fig. 1. Climbing rope performance of control ( • ----• ) and treated rats (O— O)-
A and li refer to the effect of 40 mg/kg of mescaline, after the 1st (A) and
the Olh (B) injections; C and D, effect of 40 mg/kg of homoveratrylamine after
the 1st (C) and 32nd (D) injection. Note tolerance only to mescaline.

pressed. Furthermore, most of the animals behaved as they did in

the first days of training, remaining in the inferior platform
sniffing around for several seconds, instead of instantly jumping
to the rope, as they used to do before injections. Also, quite often
the rats remained for a certain time in complete immobility with
the lorepaws on the rope and the hindlegs on the inferior plat­
form, and then suddenly started to climb with a performance
comparable to that of the controls. On occasions the animals, after
starting the climbing, slopped montionless as ‘frozen’ for several
seconds, and then started again upwards in a speed comparable to
that of the controls, or backwards returning to the starting point.
At the superior platform, their behavior was also different from
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that of the pre-drug trials; the rats quite often did not eat the food,
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538 Carlini, Silva, Cesare and Endo, Effects of Chronic

preferring instead to sniff the corners of the platform or to descend

the rope.
Although all the effects mentioned above were common to both
drugs, a major difference was disclosed with the continuance of
the injections. Thus, as seen in the table, rats of mescaline group
became rapidly tolerant to this drug, in such a way that by the
9th injection (6th training section) they behaved on the rope
exactly as the controls. On the other hand, 40 and 80 mg/kg liomo-
veratrylamine rats did not show any sign of tolerance; actually
they became more and more sensitive up to the 32th injection
(16th training section). Twenty mg/kg of homoveratrylamine, on
the other hand, was without effect throughout the experiment.
After the 16th training section, the rats injected with 40 and
80 mg/kg of homoveratrylamine were allowed a 3-day period of
rest and then the eventual influence of D,L-Dopa on the effects of
80 mg/kg of homoveratrylamine was studied. These animals were
randomly divided into 2 equal groups and were then injected with
the methoxyamine at the dose stated; 30 min later both groups
received 20 and 100 mg/kg of u,L-I)opa respectively. No influence
of the amino acid on the effect of homoveratrylamine was ob­
served. Two days later, the same experiment was repeated, but
now, D,L-Dopa was injected 30 min before homoveratrylamine;
again, the amino acid did not show any action.

Discussion

We have observed that homoveratrylamine and mescaline pro­

duced several similar effects in rats. No tolerance was developed
to two of those effects: the first, the reddish color in the ears may
be due, at least to homoveratrylamine, to peripheral vasodilatation
because this substance is able to provoke a fall in blood pressure
(Epstein et al., 1932); the second of these effects, the strong ab­
dominal contractions, is common to several other drugs such as
serotonin (Winter and Flataker, 1956), human plasma (Winter
and Flataker, 1958) and d°-tetrahydrocannabinol (Silva and
Carlini).
The climbing time delay described here had been reported
before. Thus, Bergen (1965) observed this effect with 50 mg/kg
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of homoveratrylamine and Freedman et al. (1958), using rats of

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 Administration of y?-(3,4-Dimetlioxyphcnyl)-ethylamine . . . 539

Sherman strain, showed an impairment of climbing performance

with 10 mg/kgof mescaline.
The most interesting fact observed by us, however, was the
lack of tolerance to homoveratrylamine, whereas for mescaline
this was easily obtained. Tolerance to mescaline had been de­
scribed before (Freedman et al., 1958; Smythies et al., 1966), but
our data on homoveratrylamine are in disagreement with those
of Smythies et at. (1966). These authors, using conditioned avoid­
ance shuttle box technique, reported not only tolerance in rats to
mescaline and homoveratrylamine, but also cross-tolerance be­
tween them. This discrepancy deserves further attention.
Smythies et al. (1966) concluded that the inhibition of the con­
ditioned avoidance response by mescaline was of central origin.
We do also believe that this is the origin of the impairment of
climbing performance produced by homoveratrylamine and mes­
caline. This because for many rats the delay in climbing was not
caused by difficulties in the muscular act of climbing, but rather
to time lost in exploratory activity or in immobility at the inferior
platform. Furthermore, Vogel (1967) reported that the changes in
rat performance of climbing the rope appear to correlate directly
with concentration of homoveratrylamine in brain.
It is difficult then to explain the contradiction between our
data and those of Smythies et al. (1966). One possibility is that the
methods employed measured actually different parameters; that it
is possible to provoke tolerance to some effects of mescaline and
homoveratrylamine and not to others, have been demonstrated in
this and other papers (Freedman et al., 1958). The choice of
method may be of importance for behavioral studies with homo­
veratrylamine: for example, Appel and Freedman (1965) found
that 40 mg/kg of the drug was without effect on the bar-pressing
behavior of rats working for food reward.
Also, it is possible that the strain of the rats used by both
groups is involved; it is well known that there are large differences
in response to drugs in animals from different strains (Bovet et al.,
1966: Petrinovich, 1967).
Finally, differences in enzymic mechanisms could explain the
discrepancy. It has been suggested that enzymic factors could be
playing a role in the development of tolerance to drugs active on
the central nervous system (Kato, 1961; Remmer, 1962; Adler,
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1967). On the other hand, striking contrasts have been reported in

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540 Carlini, Silva, Cesare and Endo, Effects of Chronic

the metabolism of homoveralrylamine and mescaline. For ex­

ample, Charalampous and Tansey (1967) observed that humans
excreted 83.1 per cent of homovcratrylamine as dimelhoxyphenyl-
acetic acid, whereas Charalampous et al. (1966) reported that 60
per cent of mescaline administered is excreted unchanged. Fried-
hoff and Hollister (1966) found that 77.1 and 18.1 per cent of the
corresponding acetic acid derivatives are excreted in the urine,
when human patients were given respectively homoveratrylamine
and mescaline. Huszty and Borsy (1966) using rabbit liver tissues
have shown that different enzymes appear to be responsible lor
deamination of both drugs and suggested that this could explain
differences between their pharmacological actions.
Thus, it is also possible that with our rats, tolerance was de­
veloped to one drug but not to the other, because at least 2 enzyme
systems are involved in their degradations, and only one of them
is susceptible to be activated by its own substrate, in the case,
mescaline.
D,L-Dopa, precursor of dopamine, was without effect on climb­
ing performance of homoveratrylamine-trealed rats. It was used
because of the suggestion of Ernst (1965) and Barbeau et al.
(1966 b) that a pharmacological antagonism between homovera­
lrylamine and dopamine might exist in the central nervous system.

Summary
The effects of homoveratrylamine and mescaline in rats were compared
using the climbing rope test. Both drugs impaired the climbing rope performance
at a dose level of 40 mg/kg. After 9 daily injections the rats became tolerant
to mescaline; however, no signs of tolerance were observed with homoveralryl-
amine up to 32 daily injections.
The results are discussed in the light of data obtained by other authors
with the same drugs.

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Authors’ address: M. Teresa A. Silva. Faculdade de Medicina da Santa Casa,

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R. Cesario Mota Jr., 112, Sdo Paulo (Brazil).

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