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Possible Involvement of a Central Noradrenergic System in Automutilation Induced by Clonidine in Mice*
POSSIBLE
INVOLVEMENT SYSTEM
IN BY
OF
A
CENTRAL
NORADRENERGIC
AUTOMUTILATION CLONIDINE
Abdul RAZZAK**,
Michihiro
IN
INDUCED MICE*
FUJIWARA,
Ryozo
OISHI
and Showa UEKI Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812, Japan Accepted September 27, 1976
Abstract-Automutilation
induced
by a single
large dose
of clonidine
was potentiated
by pretreatment with methamphetamine, caffeine and theophylline, while it was inhibited by acute administration of reserpine, a-methyl-p-tyrosine, phenoxybenzamine, phen tolamine and chlorpromazine. r..-Dopa, 5-hydroxytryptophan and p-chlorophenylala nine had no effect on this abnormal behavior. Biochemical studies on brain monoa mines revealed that noradrenaline was markedly increased and dopamine slightly so, but 5-hydroxytryptamine a central noradrenergic
was never changed by clonidine. These results suggest that system may be involved in automutilation induced by clonidine
in mice.
Clonidine is an antihypertensive agent, acting centrally by inhibition of the sympathetic outflow (1, 2, 3) and it has been suggested that this drug stimulates central noradrenergic receptors (4, 5, 6).
Clonidine easily passes through the blood brain barrier (7, 8).
A
marked sedative effect has been observed in man, and this observation prompted clinical trials with this drug in agitated mental patients (9). In experimental animals, clonidine has been shown to produce a variety of effects such as sedation in dogs and cats, and decrease in locomotor activity in mice at low dosage levels and it also exhibited sympathomimetic signs such as exophthalmos and horripilation (1, 10). Clonidine at large doses, induced aggressive behavior such as biting and attacking and also caused intense tremor in mice (11). Previous investigations by the authors of such aggressive behavior induced by large doses of this drug indicated that the biting behavior was facilitated by the central noradre nergic mechanism (12). Clonidine was also found to induce automutilation in mice housed individually in the absence of objects to bite (13). to examine whether or not the noradrenergic
The present investigation was undertaken
mechanism played a major role in inducing
automutilation as well. MATERIALS AND METHODS Male mice of ddN strain, weighing 18-22 g, were used. Clonidine suspended in a 0.5 * Reprint requests to : Department of Pharmacology, Faculty of Pharmaceutical Sciences,Kyushu University, Fukuoka 812, Japan. ** Permanent address: Department of Pharmacology, College of Veterinary Medicine, University of Baghdad, IRAQ.
carboxymethyl tables.
cellulose (CMC) was injected i.p.
For other drugs, see the figures and
The animal was placed on a smooth surface table and each mouse was individually
covered with a transparent glass beaker of 15 cm in diameter and the occurrence of auto mutilation was observed for a period of 1 hr following clonidine administration.
Ten mice
were used for each experiment. Male mice of ddN strain, weighing 18-22 g, were used for the assay of noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) in the brain. The number of animals used in each experiment are indicated in the table. The mice were decapitated after i.p. administration of either clonidine or CMC.
In each experiment for NA and DA assay,
the brain (except the cerebellum and olfactory bulb) was homogenized in 6 ml of 0.4 N per chloric acid containing 1 °/ EDTA-2Na and 0.1 °; sodium metabisulfite. was centrifuged at 17,000, g at 5-C for 20 min.
The homogenate
The supernatant fluid was adjusted to
pH 8.3 with sodium hydroxide solution, 0.1 ml of 2M Tris buffer solution (pH 8.3) was added after which the preparation was transferred to a 10 ml glass-stoppered tube containing 100 mg activated Al2O3. The tube was shaken for 5 min and the precipitated A1.,03 was washed four times with redistilled water.
The catecholamines were then eluted by vigorous
shaking of A1203 with 1 ml of 0.1 N HCl for 10 min.
The supernatant was transferred to
a 10 nil polyethylene centrifuge tube and spun at 12,000 x g at 5'C for 10 min. aliquot of the clear sample was taken for analysis.
A 0.5 nil
NA and DA were determined by the
trihydroxyindole method of Chang (14). In the 5-HT assay, the brain (except the cerebel lum and olfactory bulb) was homogenized in 10 nil of 0.1 N HC1 and 5-HT was determined by the method of Snyder et al. (15). All experiments were performed at a room temperature of 22_1 °C.
The statistical
significance of the results was determined by Student's t-test for biochemical studies and by the Fisher exact probability test for behavior observation. RESULTS Effects of various drugs on automutilation induced by clonidine Pretreatment with either caffeine at doses of 10 and 20 mg/kg or theophylline at 20 mg/kg i.p. increased the incidence of automutilation
induced by clonidine 50 mg/kg i.p., and the
mice which showed this behavior, not only bit and cut off the digits of their own forelimb but also bit the thoracic area leaving a bleeding lesion.
When the dose of caffeine or theo
phylline was increased up to 50 mg/ kg i.p., the incidence of automutilation induced by clonidine 50 mg/kg i.p. was reduced. This seemed to be due to the toxic effect of the combi nation of these drugs at such high doses, because these mice showed no movement in the cage and occasionally exhibited clonic convulsion.
Automutilation
was not induced by
clonidine alone at a dose of 20 nmg'kg i.p., but was induced by the drug at the same dose in the mice pretreated with caffeine and theophylline at doses ranging from 20 to 70 mg/kg i.p. (Figs. 1 and 2). Methamphetamine at doses of 0.5-5 mg,/kg i.p. given before clonidine 50 mg/kg i.p., decreased the incidence of automutilation (Fig. 3).
Such may be due to the toxic effect of
FIG.
I
Effects
of
caffeine
dissolved in saline, *p X0 .05 significant
on was
clonidine-induced given
difference
15 vs.
min
automutilation before
clonidine
in
mice.
Cajffeii;c,
clonidine.
20 mg' kg i.n.
FIG. 2 Effects of theophylline on clonidine-induced automutilation in mice. The ophylline, dissolved in saline, was given 15 min before clonidine. *p,=;0.05 signi ficant difference vs. clonidine 20 mgjkg i.p.
combination
of these two drugs at such high doses.
in the cage, when methamphetamine i.p.
In mice pretreated
by clonidine clonidine
combination induced some
at a dose of 50 mg/kg
of clonidine
automutilation
Reserpine,
clonic
i.p.
with clonidine
I nag/kg i.p., clonic convulsion
Met haniphetamine,
convulsion
followed
5 mg/kg,
by death
20 mg; kg i.p. and methamphetamine
50 mg/kg
was induced
given i.p. before
in most animals.
clonic convulsions
when clonidine
A
at doses of 5-20 mg/kg i.p.,
(Fig. 3), but the toxic effects of these two drugs were observed,
of the mice developed
thamphetamine
0.5 mg/kg i.p. was combined
with methamphetamine
50 mg/ kg, induced
Most of the mice showed no movement
was combined
and
with me
20 mg/kg i.p. a-methyl-p-tyrosine
(a-MT),
phenoxybenzamine,
phentolamine
and chlor
FIG. 3 Effects of methamphetamine on clonidine-induced automutilation in mice. Methamphetamine dissolved in saline, was given 30 min before clonidine. **p<--'0.01 significant difference vs. clonidine 20 mg/kg i.p. TABLEI Effects of various drugs on automutilation 50 mg/kg i.p.
induced by clonidine
Control : clonidine 50 mg/kg i.p. *p-----0.05significant difference vs. clonidine 50 mg/ kg i.p. Reserpine was given 18 hr, a-MT 16 hr, phenoxybenzamine 2 hr, phentolamine and chlorpromazine 30 min before clonidine 50 mg/ kg i.p. Reserpine and a-MT were suspended in CMC to a concentration of 0.5 %, phenoxybenzamine and chlorpromazine were dissolved in saline, while phentolamine was diluted in distilled water.
promazine given i.p., dose-dependently reduced the incidence of automutilation by clonidine 50 mg/kg i.p. (Table 1).
induced
L-Dopa at doses of 50-300 mg/kg i.p. given 18 hr before, 5-hydroxytryptophan (5-HTP) at doses of 50-200 mg/kg i.p. given 1 hr before and p-chlorophenylalanine
(PCPA) at doses
CLONIDINE
AUTOMUTILATION
AND
NORADRENERGIC
SYSTEM
of 50-200
mg/kg
automutilation
i.p. given 24 hr before clonidine,
induced
by clonidine
showed
no effect on the incidence
of
50 mg/kg i.p.
Changes in brain amine levels Clonidine
was given to mice at a dose of 50 mg/ kg i.p. in all experiments
of NA, DA and 5-I-IT. of 0.1 ml/100 g i.p.
In the control group,
after drug administration
increased
at various
periods
at 0.5, 1, and 2 hr after administration
The DA level was slightly increased
showed no change
was given in a volume
were determined
as shown in Table 2.
The brain NA level significantly clonidine.
a 0.5 % CMC solution
The brain levels of each amine
for the assay
throughout
2 hr after clonidine,
the entire course of the experiment
of
but the 5-HT level
(Table 2).
DISCLSS!_ON It has been found that large doses of clonidine and attacking report
vvhen the treated
mice are housed
on such type of aggressive
behavior,
on a smooth
surface table in the absence
In the present
experiment,
induced
were theophylline,
phenoxybenzamine,
automutilation
were studied.
phentolamine that repeated
in rats (16).
the occurrence
of automutilation
with clonidine.
Caffeine
It has been suggested
inhibition
theophylline
increased
was decreased
activate
of central
at such high doses. induced
when combined Depletion
stimulates
with clonidine
of the noradrenergic
was decreased.
agents do penetrate blocking
the central
by clonidine. noradrenergic
(18).
HoxA'ever,
Such may be due to the
Methamphetamine by clonidine
at doses of
50 mg/ kg i.p.
at such high doses.
system (19), induced
of reserpine
Phenoxybenzamine
and blocking
This Me
automutilation
of NA synthesis by
system and the occurrence
Phenoxybenzamine
the blood brain barrier
action.
induced
20 nmg%kgi.p.
of NA by acute administration
a-MT resulted in inhibition with clonidine
the noradrenergic
at high doses, but
50 mg/kg i.p. was combined
or theophylline.
the automutilation
induced
did not induce auto
NA receptors
when clonidine
may be due to toxic effects of these drugs combined which
it were reserpine,
when this agent was combined
automutilation
that both caffeine and theophylline
i.p., inhibited
thamphetamine,
receptor
system on this system
of high doses of theophylline
to increase
with a dose of 50 mg,/kg i.p. of either caffeine
0.5-5 mg/kg
the noradrenergic
The drugs used to stimulate
experiments,
was markedly
toxic effect of these drugs combined
We have also found
in mice placed individually
alone either acutely or chronically
was also found
of automutilation
mecha
and chlorpromazine.
system (17), and that caffeine causes a sensitization the incidence
(12).
and those for blocking
administration
In the present
in mice when administered
In our previous
of objects to bite (13).
caffeine and methamphetamine,
It has been reported
mutilation
such biting behavior
the effects of drugs affecting
by clonidine
such as biting
that the central adrenergic
at doses over 50 mg/kg i.p. Induces automutilation
automutilation
a-MT,
in pairs or in groups (1 1).
we indicated
nism might play a major role in inducing that clonidine
induce aggressive behavior
and phentolamine,
(20, 21, 22).
of automutilation
a-receptor
Chlorpromazine
and chlorpromazine
inhibited
blocking
also has an a automutilation
induced
by clonidine,
treatment
but phentolamine
with L-Dopa,
did not significantly
suppress
this behavior.
5-HTP and PCPA showed no effects on automutilation
Pre
induced
by
clonidine. The biochemical doses of clonidine
studies indicated
that NA was mainly affected by clonidine;
no change
in 5-HT of the brain
agreement
with the findings of Laverty and Taylor (23) in rats.
level appeared
throughout
at 2 hr after clonidine
the experiments.
administration
were sedated and did not exhibit automutilation inhibits monoamine also reported
rat brain. clonidine From that
oxidase as the content
that clonidine
dosage (4, 24).
Braestrup
It is therefore
increased
plausible
these results
behavior.
the NA content
are in good
The slight increase in DA this period almost all mice
It is hardly likely that clonidine
of 5-HT was not changed
by clonidine.
It was
in rat brain even at a much lower caused a decrease
that increase in the NA level induced
in MOPEG
in the
by large doses of
in the release of NA.
of drug interaction
noradrenergic
These results
and during
(25) showed that clonidine
may be due to a decrease
a central
i.e. large
caused an increase in NA content with slight increase in DA but there was
and biochemical
system is mainly
involved
studies,
in automutilation
it can be concluded induced
by large
doses of clonidine. Acknowledgements:
This investigation
68429 from the Ministry of Education, Drug Research
Association.
was kindly provided
was supported
Japan,
The assistance
by C.H. Boehringer
in part by research
and by a grant from the Fujisawa
of Miss M. Shirai is also appreciated.
grant No. Neurotropic Clonidine
Sohn.
REFERENCES 1) HOEEKE,W. AND KOBINGLR,W.: Arzncim.-Forsch. 16,1038 (1966) 2) SATTLER,R.W. AND VANZWIETE,P.A.: Europ. J. Pharmacol. 2, 9 (1967) 3) SCHMITT,H., SCHMITT,MME H., BoisslER, J.R. AND GUIDECELLI,J.F.: Europ. J. Pharmacol. 2, 147 (1967) 4) ANDEN,N.-E., CORRODI,H., FUXE, K., HOKEELT,B., HOKEELT,T., RYDIN,C. ANDSVENsso,T.: Life Sci. 9, 513 (1970) 5) CORRODI,H., FUXE, K., LJUNGDAHL,A. ANDOGREN, S.O.: Brain Res. 24,451 (1970) 6) PERSON,T. AND WALDECK,B.: Europ. J. Pharmacol. 11, 315 (1970) 7) BROEKKAMP, C. AND VANRossUM, J.M.: Psychopharmacologia, Berl. 25, 162 (1972) 8) HOLMAN,R.B., SHILLITO,E.E. AND VOGT,M.: Brit. J. Pharinacol. 43, 685 (1971) 9) SIMPSON,G.M., KUNZ-BARTHOLINI,E. ANDWATTS, T.P.S.: J. clin. Pharmacol. 7, 221 (1967) 10) MAJ, J., SOWINSKA,H., BARAN,L. AND KAPTURKIEWICZ, Z.: Life Sci. 11, 483 (1972) 11) MORPURGO,C.: Europ. J. Pharmacol. 3, 374 (1968) 12) RAZZAK,A., FUJIWARA,M., OGAWA,N. AND UFKI, S.: Japan . J. Pharmacol. Suppl. 23, 103 (1973) 13) RAZZAK, A., FUJI-VARA,M. AND UEKI, S.: Europ. J. Pharmacol. 30, 356 (1975) 14) CHANG, C.C.: Int. J. Neuropharmacol. 3, 643 (1964) 15) SYNDER,S.H., AXELROD,J. AND AWEIG, M.: Biochem. Pharmacol. 14, 831 (1965) 16) SAKATA,T., FUCHIMOTO,H.: Japan. J. Pharmacol. 23, 781 (1973) 17) BERKOwITZ,A.B., TARRER,J.H. AND SPECTOR,S.: Europ. J. Pharmacol. 10, 64 (1970) 18) WALDECK,B.: J. Neural Transmission 34, 61 (1973) 19) ANDEN,N.-E.: Amphetamine and Related Compounds, Edited by COSTA,E. AND GARATTINI, S., p. 447, Raven Press, New York (1970) 20) BOISSIER,J.R., SIMON,P. ANDGUIDICELLI,J.F.: Archs int. Pharmacodyn. Ther. 169, 312 (1967)
21) 22) 23) 24) 25)
ANDEN, N.-E. AND STROMBOM,U.: Psychopharmacologia, Berl. 38, 91 (1974) BERGMANN,F., CATANE,R. AND KORCZYN, A.D.: Archs int. Pharmacodyn. Ther. 168, 278 (1967) LAVERTY,R. ANDTAYLOR,K.M.: Brit. J. Pharmacol. 35, 253 (1969) FARNEBO,L.-O. ANDHAMBERGER, B.: Acta physiol. scand. Suppl. 371, 35 (1971) BRAESTRUP,C.: J. Pharm. Pharmacol. 26, 141 (1974)
INVOLVEMENT SYSTEM
IN BY
OF
A
CENTRAL
NORADRENERGIC
AUTOMUTILATION CLONIDINE
Abdul RAZZAK**,
Michihiro
IN
INDUCED MICE*
FUJIWARA,
Ryozo
OISHI
and Showa UEKI Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812, Japan Accepted September 27, 1976
Abstract-Automutilation
induced
by a single
large dose
of clonidine
was potentiated
by pretreatment with methamphetamine, caffeine and theophylline, while it was inhibited by acute administration of reserpine, a-methyl-p-tyrosine, phenoxybenzamine, phen tolamine and chlorpromazine. r..-Dopa, 5-hydroxytryptophan and p-chlorophenylala nine had no effect on this abnormal behavior. Biochemical studies on brain monoa mines revealed that noradrenaline was markedly increased and dopamine slightly so, but 5-hydroxytryptamine a central noradrenergic
was never changed by clonidine. These results suggest that system may be involved in automutilation induced by clonidine
in mice.
Clonidine is an antihypertensive agent, acting centrally by inhibition of the sympathetic outflow (1, 2, 3) and it has been suggested that this drug stimulates central noradrenergic receptors (4, 5, 6).
Clonidine easily passes through the blood brain barrier (7, 8).
A
marked sedative effect has been observed in man, and this observation prompted clinical trials with this drug in agitated mental patients (9). In experimental animals, clonidine has been shown to produce a variety of effects such as sedation in dogs and cats, and decrease in locomotor activity in mice at low dosage levels and it also exhibited sympathomimetic signs such as exophthalmos and horripilation (1, 10). Clonidine at large doses, induced aggressive behavior such as biting and attacking and also caused intense tremor in mice (11). Previous investigations by the authors of such aggressive behavior induced by large doses of this drug indicated that the biting behavior was facilitated by the central noradre nergic mechanism (12). Clonidine was also found to induce automutilation in mice housed individually in the absence of objects to bite (13). to examine whether or not the noradrenergic
The present investigation was undertaken
mechanism played a major role in inducing
automutilation as well. MATERIALS AND METHODS Male mice of ddN strain, weighing 18-22 g, were used. Clonidine suspended in a 0.5 * Reprint requests to : Department of Pharmacology, Faculty of Pharmaceutical Sciences,Kyushu University, Fukuoka 812, Japan. ** Permanent address: Department of Pharmacology, College of Veterinary Medicine, University of Baghdad, IRAQ.
carboxymethyl tables.
cellulose (CMC) was injected i.p.
For other drugs, see the figures and
The animal was placed on a smooth surface table and each mouse was individually
covered with a transparent glass beaker of 15 cm in diameter and the occurrence of auto mutilation was observed for a period of 1 hr following clonidine administration.
Ten mice
were used for each experiment. Male mice of ddN strain, weighing 18-22 g, were used for the assay of noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) in the brain. The number of animals used in each experiment are indicated in the table. The mice were decapitated after i.p. administration of either clonidine or CMC.
In each experiment for NA and DA assay,
the brain (except the cerebellum and olfactory bulb) was homogenized in 6 ml of 0.4 N per chloric acid containing 1 °/ EDTA-2Na and 0.1 °; sodium metabisulfite. was centrifuged at 17,000, g at 5-C for 20 min.
The homogenate
The supernatant fluid was adjusted to
pH 8.3 with sodium hydroxide solution, 0.1 ml of 2M Tris buffer solution (pH 8.3) was added after which the preparation was transferred to a 10 ml glass-stoppered tube containing 100 mg activated Al2O3. The tube was shaken for 5 min and the precipitated A1.,03 was washed four times with redistilled water.
The catecholamines were then eluted by vigorous
shaking of A1203 with 1 ml of 0.1 N HCl for 10 min.
The supernatant was transferred to
a 10 nil polyethylene centrifuge tube and spun at 12,000 x g at 5'C for 10 min. aliquot of the clear sample was taken for analysis.
A 0.5 nil
NA and DA were determined by the
trihydroxyindole method of Chang (14). In the 5-HT assay, the brain (except the cerebel lum and olfactory bulb) was homogenized in 10 nil of 0.1 N HC1 and 5-HT was determined by the method of Snyder et al. (15). All experiments were performed at a room temperature of 22_1 °C.
The statistical
significance of the results was determined by Student's t-test for biochemical studies and by the Fisher exact probability test for behavior observation. RESULTS Effects of various drugs on automutilation induced by clonidine Pretreatment with either caffeine at doses of 10 and 20 mg/kg or theophylline at 20 mg/kg i.p. increased the incidence of automutilation
induced by clonidine 50 mg/kg i.p., and the
mice which showed this behavior, not only bit and cut off the digits of their own forelimb but also bit the thoracic area leaving a bleeding lesion.
When the dose of caffeine or theo
phylline was increased up to 50 mg/ kg i.p., the incidence of automutilation induced by clonidine 50 mg/kg i.p. was reduced. This seemed to be due to the toxic effect of the combi nation of these drugs at such high doses, because these mice showed no movement in the cage and occasionally exhibited clonic convulsion.
Automutilation
was not induced by
clonidine alone at a dose of 20 nmg'kg i.p., but was induced by the drug at the same dose in the mice pretreated with caffeine and theophylline at doses ranging from 20 to 70 mg/kg i.p. (Figs. 1 and 2). Methamphetamine at doses of 0.5-5 mg,/kg i.p. given before clonidine 50 mg/kg i.p., decreased the incidence of automutilation (Fig. 3).
Such may be due to the toxic effect of
FIG.
I
Effects
of
caffeine
dissolved in saline, *p X0 .05 significant
on was
clonidine-induced given
difference
15 vs.
min
automutilation before
clonidine
in
mice.
Cajffeii;c,
clonidine.
20 mg' kg i.n.
FIG. 2 Effects of theophylline on clonidine-induced automutilation in mice. The ophylline, dissolved in saline, was given 15 min before clonidine. *p,=;0.05 signi ficant difference vs. clonidine 20 mgjkg i.p.
combination
of these two drugs at such high doses.
in the cage, when methamphetamine i.p.
In mice pretreated
by clonidine clonidine
combination induced some
at a dose of 50 mg/kg
of clonidine
automutilation
Reserpine,
clonic
i.p.
with clonidine
I nag/kg i.p., clonic convulsion
Met haniphetamine,
convulsion
followed
5 mg/kg,
by death
20 mg; kg i.p. and methamphetamine
50 mg/kg
was induced
given i.p. before
in most animals.
clonic convulsions
when clonidine
A
at doses of 5-20 mg/kg i.p.,
(Fig. 3), but the toxic effects of these two drugs were observed,
of the mice developed
thamphetamine
0.5 mg/kg i.p. was combined
with methamphetamine
50 mg/ kg, induced
Most of the mice showed no movement
was combined
and
with me
20 mg/kg i.p. a-methyl-p-tyrosine
(a-MT),
phenoxybenzamine,
phentolamine
and chlor
FIG. 3 Effects of methamphetamine on clonidine-induced automutilation in mice. Methamphetamine dissolved in saline, was given 30 min before clonidine. **p<--'0.01 significant difference vs. clonidine 20 mg/kg i.p. TABLEI Effects of various drugs on automutilation 50 mg/kg i.p.
induced by clonidine
Control : clonidine 50 mg/kg i.p. *p-----0.05significant difference vs. clonidine 50 mg/ kg i.p. Reserpine was given 18 hr, a-MT 16 hr, phenoxybenzamine 2 hr, phentolamine and chlorpromazine 30 min before clonidine 50 mg/ kg i.p. Reserpine and a-MT were suspended in CMC to a concentration of 0.5 %, phenoxybenzamine and chlorpromazine were dissolved in saline, while phentolamine was diluted in distilled water.
promazine given i.p., dose-dependently reduced the incidence of automutilation by clonidine 50 mg/kg i.p. (Table 1).
induced
L-Dopa at doses of 50-300 mg/kg i.p. given 18 hr before, 5-hydroxytryptophan (5-HTP) at doses of 50-200 mg/kg i.p. given 1 hr before and p-chlorophenylalanine
(PCPA) at doses
CLONIDINE
AUTOMUTILATION
AND
NORADRENERGIC
SYSTEM
of 50-200
mg/kg
automutilation
i.p. given 24 hr before clonidine,
induced
by clonidine
showed
no effect on the incidence
of
50 mg/kg i.p.
Changes in brain amine levels Clonidine
was given to mice at a dose of 50 mg/ kg i.p. in all experiments
of NA, DA and 5-I-IT. of 0.1 ml/100 g i.p.
In the control group,
after drug administration
increased
at various
periods
at 0.5, 1, and 2 hr after administration
The DA level was slightly increased
showed no change
was given in a volume
were determined
as shown in Table 2.
The brain NA level significantly clonidine.
a 0.5 % CMC solution
The brain levels of each amine
for the assay
throughout
2 hr after clonidine,
the entire course of the experiment
of
but the 5-HT level
(Table 2).
DISCLSS!_ON It has been found that large doses of clonidine and attacking report
vvhen the treated
mice are housed
on such type of aggressive
behavior,
on a smooth
surface table in the absence
In the present
experiment,
induced
were theophylline,
phenoxybenzamine,
automutilation
were studied.
phentolamine that repeated
in rats (16).
the occurrence
of automutilation
with clonidine.
Caffeine
It has been suggested
inhibition
theophylline
increased
was decreased
activate
of central
at such high doses. induced
when combined Depletion
stimulates
with clonidine
of the noradrenergic
was decreased.
agents do penetrate blocking
the central
by clonidine. noradrenergic
(18).
HoxA'ever,
Such may be due to the
Methamphetamine by clonidine
at doses of
50 mg/ kg i.p.
at such high doses.
system (19), induced
of reserpine
Phenoxybenzamine
and blocking
This Me
automutilation
of NA synthesis by
system and the occurrence
Phenoxybenzamine
the blood brain barrier
action.
induced
20 nmg%kgi.p.
of NA by acute administration
a-MT resulted in inhibition with clonidine
the noradrenergic
at high doses, but
50 mg/kg i.p. was combined
or theophylline.
the automutilation
induced
did not induce auto
NA receptors
when clonidine
may be due to toxic effects of these drugs combined which
it were reserpine,
when this agent was combined
automutilation
that both caffeine and theophylline
i.p., inhibited
thamphetamine,
receptor
system on this system
of high doses of theophylline
to increase
with a dose of 50 mg,/kg i.p. of either caffeine
0.5-5 mg/kg
the noradrenergic
The drugs used to stimulate
experiments,
was markedly
toxic effect of these drugs combined
We have also found
in mice placed individually
alone either acutely or chronically
was also found
of automutilation
mecha
and chlorpromazine.
system (17), and that caffeine causes a sensitization the incidence
(12).
and those for blocking
administration
In the present
in mice when administered
In our previous
of objects to bite (13).
caffeine and methamphetamine,
It has been reported
mutilation
such biting behavior
the effects of drugs affecting
by clonidine
such as biting
that the central adrenergic
at doses over 50 mg/kg i.p. Induces automutilation
automutilation
a-MT,
in pairs or in groups (1 1).
we indicated
nism might play a major role in inducing that clonidine
induce aggressive behavior
and phentolamine,
(20, 21, 22).
of automutilation
a-receptor
Chlorpromazine
and chlorpromazine
inhibited
blocking
also has an a automutilation
induced
by clonidine,
treatment
but phentolamine
with L-Dopa,
did not significantly
suppress
this behavior.
5-HTP and PCPA showed no effects on automutilation
Pre
induced
by
clonidine. The biochemical doses of clonidine
studies indicated
that NA was mainly affected by clonidine;
no change
in 5-HT of the brain
agreement
with the findings of Laverty and Taylor (23) in rats.
level appeared
throughout
at 2 hr after clonidine
the experiments.
administration
were sedated and did not exhibit automutilation inhibits monoamine also reported
rat brain. clonidine From that
oxidase as the content
that clonidine
dosage (4, 24).
Braestrup
It is therefore
increased
plausible
these results
behavior.
the NA content
are in good
The slight increase in DA this period almost all mice
It is hardly likely that clonidine
of 5-HT was not changed
by clonidine.
It was
in rat brain even at a much lower caused a decrease
that increase in the NA level induced
in MOPEG
in the
by large doses of
in the release of NA.
of drug interaction
noradrenergic
These results
and during
(25) showed that clonidine
may be due to a decrease
a central
i.e. large
caused an increase in NA content with slight increase in DA but there was
and biochemical
system is mainly
involved
studies,
in automutilation
it can be concluded induced
by large
doses of clonidine. Acknowledgements:
This investigation
68429 from the Ministry of Education, Drug Research
Association.
was kindly provided
was supported
Japan,
The assistance
by C.H. Boehringer
in part by research
and by a grant from the Fujisawa
of Miss M. Shirai is also appreciated.
grant No. Neurotropic Clonidine
Sohn.
REFERENCES 1) HOEEKE,W. AND KOBINGLR,W.: Arzncim.-Forsch. 16,1038 (1966) 2) SATTLER,R.W. AND VANZWIETE,P.A.: Europ. J. Pharmacol. 2, 9 (1967) 3) SCHMITT,H., SCHMITT,MME H., BoisslER, J.R. AND GUIDECELLI,J.F.: Europ. J. Pharmacol. 2, 147 (1967) 4) ANDEN,N.-E., CORRODI,H., FUXE, K., HOKEELT,B., HOKEELT,T., RYDIN,C. ANDSVENsso,T.: Life Sci. 9, 513 (1970) 5) CORRODI,H., FUXE, K., LJUNGDAHL,A. ANDOGREN, S.O.: Brain Res. 24,451 (1970) 6) PERSON,T. AND WALDECK,B.: Europ. J. Pharmacol. 11, 315 (1970) 7) BROEKKAMP, C. AND VANRossUM, J.M.: Psychopharmacologia, Berl. 25, 162 (1972) 8) HOLMAN,R.B., SHILLITO,E.E. AND VOGT,M.: Brit. J. Pharinacol. 43, 685 (1971) 9) SIMPSON,G.M., KUNZ-BARTHOLINI,E. ANDWATTS, T.P.S.: J. clin. Pharmacol. 7, 221 (1967) 10) MAJ, J., SOWINSKA,H., BARAN,L. AND KAPTURKIEWICZ, Z.: Life Sci. 11, 483 (1972) 11) MORPURGO,C.: Europ. J. Pharmacol. 3, 374 (1968) 12) RAZZAK,A., FUJIWARA,M., OGAWA,N. AND UFKI, S.: Japan . J. Pharmacol. Suppl. 23, 103 (1973) 13) RAZZAK, A., FUJI-VARA,M. AND UEKI, S.: Europ. J. Pharmacol. 30, 356 (1975) 14) CHANG, C.C.: Int. J. Neuropharmacol. 3, 643 (1964) 15) SYNDER,S.H., AXELROD,J. AND AWEIG, M.: Biochem. Pharmacol. 14, 831 (1965) 16) SAKATA,T., FUCHIMOTO,H.: Japan. J. Pharmacol. 23, 781 (1973) 17) BERKOwITZ,A.B., TARRER,J.H. AND SPECTOR,S.: Europ. J. Pharmacol. 10, 64 (1970) 18) WALDECK,B.: J. Neural Transmission 34, 61 (1973) 19) ANDEN,N.-E.: Amphetamine and Related Compounds, Edited by COSTA,E. AND GARATTINI, S., p. 447, Raven Press, New York (1970) 20) BOISSIER,J.R., SIMON,P. ANDGUIDICELLI,J.F.: Archs int. Pharmacodyn. Ther. 169, 312 (1967)
21) 22) 23) 24) 25)
ANDEN, N.-E. AND STROMBOM,U.: Psychopharmacologia, Berl. 38, 91 (1974) BERGMANN,F., CATANE,R. AND KORCZYN, A.D.: Archs int. Pharmacodyn. Ther. 168, 278 (1967) LAVERTY,R. ANDTAYLOR,K.M.: Brit. J. Pharmacol. 35, 253 (1969) FARNEBO,L.-O. ANDHAMBERGER, B.: Acta physiol. scand. Suppl. 371, 35 (1971) BRAESTRUP,C.: J. Pharm. Pharmacol. 26, 141 (1974)