- Email: [email protected]
Automutilation induced by clonidine in mice
European Journal of Pharmacology, 30 (1975) 356--359 © North-Holland Publishing Company
Short c o m m u n i c a t i o n A U T O M U T I L A T I O N I N D U C E D BY C L O N I D I N E IN MICE Abdul RAZZAK, Michihiro FUJIWARA and Showa UEKI Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
Received 18 November 1974, accepted 16 December 1974
A. RAZZAK, M. FUJIWARA and S. UEKI, Automutilation induced by clonidine in mice, European J. Pharmacol. 30 (1975) 356--359. Clonidine ( 2-( 2,6-dichlorophenylamino)-2-imidazoline hyd~ochloride, Stl 55, Catapres), after administration of a single large dose, was found to induce automutilation in mice housed individually in the absence of objects to bite. This abnormal behavior was not significantly altered with chronic administration of the drug, and showed no sex difference. The mechanism underlying this automutilation seems to be different from that of the aggressive behavior induced by the same drug in mice caged in groups. Clonidine
Automutilation
Abnormal behavior
1. Introduction Clonidine (2-(2,6-dichlorophenylamino)2-imidazoline h y d r o c h l o r i d e , St155, Catapres) is a n e w t y p e o f a n t i h y p e r t e n s i v e drug acting centrally b y inhibition o f the s y m p a t h e t i c o u t f l o w ( K o b i n g e r and Walland, 1967; S c h m i t t et al., 1967; Nayler et al., 1969). In e x p e r i m e n t a l animals, the drug has been s h o w n t o p r o d u c e a variety o f effects, such as m a r k e d sedation in dogs and cats, at a very low dosage level, decrease in l o c o m o t o r activit y in mice and also to p r o d u c e s y m p a t h o m i metic signs like e x o p h t h a l m o s and horripilation ( H o e f k e and Kobinger, 1966). Clonidine at larger doses, h o w e v e r , was f o u n d to induce aggressive behavior such as biting and attacking as well as intense t r e m o r in mice (Morpurgo, 1968). Previous investigation b y the a u t h o r s o f such a b n o r m a l b e h a v i o r i n d u c e d b y large doses o f this drug indicated t h a t the biting b e h a v i o r was facilitated b y the adrenergic m e c h a n i s m and inhibited b y the cholinergic
mechanism, while the t r e m o r was facilitated b y b o t h t h e adrenergic and cholinergic mechanism. However, n e i t h e r the biting n o r the t r e m o r are related t o the serotonergic mechanism (Ueki et al., 1973). During the course o f these investigations, t h e a u t h o r s incidentally f o u n d t h a t clonidine i n d u c e d a u t o m u t i l a t i o n in mice after single a d m i n i s t r a t i o n o f a large dose. The present e x p e r i m e n t s deal with this finding. 2. Materials and methods d d N strain mice o f b o t h sexes, weighing 1 8 - - 2 2 g, were used in the e x p e r i m e n t s . Clonidine was suspended in a 0.5% c a r b o x y m e t h y l cellulose (CMC) solution, and injected i.p. The animals were placed on a s m o o t h surface table and each m o u s e was c o v e r e d with a t r a n s p a r e n t glass b e a k e r o f 15 cm in d i a m e t e r for behavioral observation. In s o m e experiments, mice were observed in a wire mesh cage. All the e x p e r i m e n t s were p e r f o r m e d at r o o m t e m p e r a t u r e o f 22 + 1 ° C.
A. R a z z a k et al., Clondine-induced automutilation
3. Results 3.1. Observation on a smooth surface table
Both 10 male and 10 female mice were given clonidine at a dose of 50 mg/kg i.p., and were placed on a smooth surface table and each mouse was covered separately with a glass beaker. 15 min after drug administration, 40% of both male and female mice showed self-mutilation, and this behavior continued for more than 1 hr. The mice bit and cut off their own digits of the forelimbs with occasional vocalization (fig. 1). They sometimes bit even the hindlegs, leaving bleeding wounds. This behavior was invariably accompanied by sympathomimetic signs such as exophthalmos, piloerection and tremor. The remaining mice (60%) showed the same sympathomimetic signs and tremor without exhibiting automutilation. Clonidine, at doses of 5 to 30 mg/kg i.p.,
357
induced hyperactivity, exophthalmos, piloerection and tremor, without inducing automutilation. When the drug was administered at a dose of 70 mg/kg i.p.,' the mice showed only intense tremor and no locomotion and 20% of the mice exhibited automutilation occasionally accompanied by clonic convulsion, while the remaining 80% developed clonic convulsion without showing automutilation, and 2 mice died 2 hr later. When given at a dose of 100 mg/kg i.p., all the mice developed clonic convulsion followed by death. 3.2. Effects o f experimental conditions on clonidine-induced automutilation
10 mice were used for each experiment. After clonidine was administered at a dose of 50 mg/kg i.p., the mice were placed on a smooth surface and covered individually with a glass beaker and a food pellet or a rod was given. In such an experimental condition, on-
Fig. 1. The forelimb of a mouse, which showed automutilation after administration of clonidine 50 mg/kg i.p., is s h o w n on the right. The first, second and third fingers were cut off. The intact forelimb of a normal m o u s e is s h o w n on the left side of the photograph.
358
A. Razzak et al., Clondine-induced automutilation
ly 20% of the mice showed automutilation, and the remaining mice (80%) bit a food pellet or rod presented without exhibiting automutflation. In all mice, however, exophthalmos, pfloerection and tremor were invariably observed. When the mice were caged separately in wire mesh cages (20 X 15 X 15 cm) and treated with clonidine 50 mg/kg i.p., the mice bit the wire net of the cage without exhibiting automutilation. Next, the effect of isolation housing on the occurrence of automutilation in mice was examined. Groups of 10 mice each were subjected to isolated housing for a period of either I week (short term isolation) or 4 weeks (long term isolation) in wire mesh cages (12 X 14 X 16 cm) with food and water given ad libitum. After isolation housing, the mice of each group were given clonidine 50 mg/kg i.p., and placed on a smooth surface and covered separately with a glass beaker for behavioral observation. The occurrence of automutilation was 40% in both groups. After 10 mice, housed in groups, were subjected to food deprivation for 24 hr, clonidine 50 mg/kg i.p. was given, the mice placed on a smooth surface and covered separately with a glass beaker, then automutilation appeared in 40% of the mice. It is therefore concluded that neither isolation nor starvation affect the occurrence of clonidine-induced automutilation.
3.3. Effect of chronic treatment with clonidine Daily administration of clonidine 50 mg/kg i.p. was repeated for 10 days in 10 mice, housed in groups and given food and water ad libitum. For daily observation after the drug was given each mouse was put on a smooth surface and covered with a glass beaker. The incidence of automutilation was 40% on the 1st day, but was 50% on the 3rd day, thereafter it remained unchanged until the end of the experiment.
4. Discussion When mice were housed in a wire net cage together with other mice, clonidine at doses of 10 to 50 mg/kg i.p. caused characteristic aggressive behavior such as biting, attacking and fighting; i.e. the mice bit metal wire net of the cage or a rod presented and vigorously attacked and bit any body parts of their cagemates, causing bleeding wounds on the tail (Morpurgo, 1968). It was found, however, in the present experiment, that clonidine induced such a curious behavior as automutilation in mice placed individually on a smooth surface and covered by a glass beaker, and this behavior was elicited by clonidine only at doses larger than 50 mg/kg i.p. No such an abnormal behavior induced by clonidine has been so far reported in the literature. Automutilation never occurred in mice housed with cagemates or housed individually in a wire net cage and was markedly inhibited by the presence of food or of a rod. These results seem to indicate that clonidine induces automutilation only when a mouse is placed alone in the absence of objects to bite. The occurrence of automutilation decreased as the dosage of clonidine was increased to 70 mg/kg i.p. mainly because of the development of clonic convulsions, and all mice died from convulsions at a dose of 100 mg/kg i.p. Neither isolated housing nor starvation facilitated the occurrence of automutilation. The authors cannot at present explain the mechanism of this abnormal behavior; the mechanism however seems different from that of the aggressive behavior induced in grouphoused mice. Further studies are necessary to elucidate the mechanism of this abnormal behavior. Acknowledgement This investigation was s u p p o r t e d in p a r t by a research grant f r o m t h e Ministry of E d u c a t i o n of J a p a n a n d b y a grant f r o m t h e Naito F o u n d a t i o n , to w h o m t h e a u t h o r s are cordially i n d e b t e d . C l o n i d i n e was k i n d l y s u p p l i e d b y C.H. Boehringer Sohn.
A. Razzak et al., Clondine-induced automutilation
References Hoefke, W. and W. Kobinger, 1966, Pharmakologische Wirkungen des 2-(2,6-DichlQrophenylamino)2-imidazolin-hydrochlorids, einer neuen antihypertensiven Substanz, Arzneim. Forsch. 16, 1038. Kobinger, W. and A. Walland, 1967, Investigation into the mechanism of the hypotensive effect of 2-(2,6-dichlorophenylamino)-2-imidazoline • HC1, European J. Pharmacol. 2, 155. Morpurgo, C., 1968, Aggressive behavior induced by large doses of 2-( 2,6-Dichlorophenylamino )2-imidazoline hydrochloride (ST155) in mice, European J. Pharmacol. 2, 374.
359
Nayler, W.G., J. Price, J. Stone and T.E. Lowe, 1969, Further observation on the cardiovascular effect of ST155 (catapres), J. Pharmarol. Exptl. Therap. 166, 364. Schmitt, H., H. Schmitt, J.R. Boissier and J.F. Guidicelli, 1967, Centrally mediated decrease in sympathetic tone induced by 2-(2,6-dichlorophenylamino-2-imidazoline hydrochloride, Catapresan, ST155, European J. Pharmacol. 2, 147. Ueki, S., A. Razzak and M. Fujiwara, 1973, Characteristic of abnormal behavior induced by 2-(2,6Dichlorophenylamino )-2-imidazoline hydrochloride (ST155) in mice, Jap. J. Pharmacol. 23, 103 Suppl.
Short c o m m u n i c a t i o n A U T O M U T I L A T I O N I N D U C E D BY C L O N I D I N E IN MICE Abdul RAZZAK, Michihiro FUJIWARA and Showa UEKI Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
Received 18 November 1974, accepted 16 December 1974
A. RAZZAK, M. FUJIWARA and S. UEKI, Automutilation induced by clonidine in mice, European J. Pharmacol. 30 (1975) 356--359. Clonidine ( 2-( 2,6-dichlorophenylamino)-2-imidazoline hyd~ochloride, Stl 55, Catapres), after administration of a single large dose, was found to induce automutilation in mice housed individually in the absence of objects to bite. This abnormal behavior was not significantly altered with chronic administration of the drug, and showed no sex difference. The mechanism underlying this automutilation seems to be different from that of the aggressive behavior induced by the same drug in mice caged in groups. Clonidine
Automutilation
Abnormal behavior
1. Introduction Clonidine (2-(2,6-dichlorophenylamino)2-imidazoline h y d r o c h l o r i d e , St155, Catapres) is a n e w t y p e o f a n t i h y p e r t e n s i v e drug acting centrally b y inhibition o f the s y m p a t h e t i c o u t f l o w ( K o b i n g e r and Walland, 1967; S c h m i t t et al., 1967; Nayler et al., 1969). In e x p e r i m e n t a l animals, the drug has been s h o w n t o p r o d u c e a variety o f effects, such as m a r k e d sedation in dogs and cats, at a very low dosage level, decrease in l o c o m o t o r activit y in mice and also to p r o d u c e s y m p a t h o m i metic signs like e x o p h t h a l m o s and horripilation ( H o e f k e and Kobinger, 1966). Clonidine at larger doses, h o w e v e r , was f o u n d to induce aggressive behavior such as biting and attacking as well as intense t r e m o r in mice (Morpurgo, 1968). Previous investigation b y the a u t h o r s o f such a b n o r m a l b e h a v i o r i n d u c e d b y large doses o f this drug indicated t h a t the biting b e h a v i o r was facilitated b y the adrenergic m e c h a n i s m and inhibited b y the cholinergic
mechanism, while the t r e m o r was facilitated b y b o t h t h e adrenergic and cholinergic mechanism. However, n e i t h e r the biting n o r the t r e m o r are related t o the serotonergic mechanism (Ueki et al., 1973). During the course o f these investigations, t h e a u t h o r s incidentally f o u n d t h a t clonidine i n d u c e d a u t o m u t i l a t i o n in mice after single a d m i n i s t r a t i o n o f a large dose. The present e x p e r i m e n t s deal with this finding. 2. Materials and methods d d N strain mice o f b o t h sexes, weighing 1 8 - - 2 2 g, were used in the e x p e r i m e n t s . Clonidine was suspended in a 0.5% c a r b o x y m e t h y l cellulose (CMC) solution, and injected i.p. The animals were placed on a s m o o t h surface table and each m o u s e was c o v e r e d with a t r a n s p a r e n t glass b e a k e r o f 15 cm in d i a m e t e r for behavioral observation. In s o m e experiments, mice were observed in a wire mesh cage. All the e x p e r i m e n t s were p e r f o r m e d at r o o m t e m p e r a t u r e o f 22 + 1 ° C.
A. R a z z a k et al., Clondine-induced automutilation
3. Results 3.1. Observation on a smooth surface table
Both 10 male and 10 female mice were given clonidine at a dose of 50 mg/kg i.p., and were placed on a smooth surface table and each mouse was covered separately with a glass beaker. 15 min after drug administration, 40% of both male and female mice showed self-mutilation, and this behavior continued for more than 1 hr. The mice bit and cut off their own digits of the forelimbs with occasional vocalization (fig. 1). They sometimes bit even the hindlegs, leaving bleeding wounds. This behavior was invariably accompanied by sympathomimetic signs such as exophthalmos, piloerection and tremor. The remaining mice (60%) showed the same sympathomimetic signs and tremor without exhibiting automutilation. Clonidine, at doses of 5 to 30 mg/kg i.p.,
357
induced hyperactivity, exophthalmos, piloerection and tremor, without inducing automutilation. When the drug was administered at a dose of 70 mg/kg i.p.,' the mice showed only intense tremor and no locomotion and 20% of the mice exhibited automutilation occasionally accompanied by clonic convulsion, while the remaining 80% developed clonic convulsion without showing automutilation, and 2 mice died 2 hr later. When given at a dose of 100 mg/kg i.p., all the mice developed clonic convulsion followed by death. 3.2. Effects o f experimental conditions on clonidine-induced automutilation
10 mice were used for each experiment. After clonidine was administered at a dose of 50 mg/kg i.p., the mice were placed on a smooth surface and covered individually with a glass beaker and a food pellet or a rod was given. In such an experimental condition, on-
Fig. 1. The forelimb of a mouse, which showed automutilation after administration of clonidine 50 mg/kg i.p., is s h o w n on the right. The first, second and third fingers were cut off. The intact forelimb of a normal m o u s e is s h o w n on the left side of the photograph.
358
A. Razzak et al., Clondine-induced automutilation
ly 20% of the mice showed automutilation, and the remaining mice (80%) bit a food pellet or rod presented without exhibiting automutflation. In all mice, however, exophthalmos, pfloerection and tremor were invariably observed. When the mice were caged separately in wire mesh cages (20 X 15 X 15 cm) and treated with clonidine 50 mg/kg i.p., the mice bit the wire net of the cage without exhibiting automutilation. Next, the effect of isolation housing on the occurrence of automutilation in mice was examined. Groups of 10 mice each were subjected to isolated housing for a period of either I week (short term isolation) or 4 weeks (long term isolation) in wire mesh cages (12 X 14 X 16 cm) with food and water given ad libitum. After isolation housing, the mice of each group were given clonidine 50 mg/kg i.p., and placed on a smooth surface and covered separately with a glass beaker for behavioral observation. The occurrence of automutilation was 40% in both groups. After 10 mice, housed in groups, were subjected to food deprivation for 24 hr, clonidine 50 mg/kg i.p. was given, the mice placed on a smooth surface and covered separately with a glass beaker, then automutilation appeared in 40% of the mice. It is therefore concluded that neither isolation nor starvation affect the occurrence of clonidine-induced automutilation.
3.3. Effect of chronic treatment with clonidine Daily administration of clonidine 50 mg/kg i.p. was repeated for 10 days in 10 mice, housed in groups and given food and water ad libitum. For daily observation after the drug was given each mouse was put on a smooth surface and covered with a glass beaker. The incidence of automutilation was 40% on the 1st day, but was 50% on the 3rd day, thereafter it remained unchanged until the end of the experiment.
4. Discussion When mice were housed in a wire net cage together with other mice, clonidine at doses of 10 to 50 mg/kg i.p. caused characteristic aggressive behavior such as biting, attacking and fighting; i.e. the mice bit metal wire net of the cage or a rod presented and vigorously attacked and bit any body parts of their cagemates, causing bleeding wounds on the tail (Morpurgo, 1968). It was found, however, in the present experiment, that clonidine induced such a curious behavior as automutilation in mice placed individually on a smooth surface and covered by a glass beaker, and this behavior was elicited by clonidine only at doses larger than 50 mg/kg i.p. No such an abnormal behavior induced by clonidine has been so far reported in the literature. Automutilation never occurred in mice housed with cagemates or housed individually in a wire net cage and was markedly inhibited by the presence of food or of a rod. These results seem to indicate that clonidine induces automutilation only when a mouse is placed alone in the absence of objects to bite. The occurrence of automutilation decreased as the dosage of clonidine was increased to 70 mg/kg i.p. mainly because of the development of clonic convulsions, and all mice died from convulsions at a dose of 100 mg/kg i.p. Neither isolated housing nor starvation facilitated the occurrence of automutilation. The authors cannot at present explain the mechanism of this abnormal behavior; the mechanism however seems different from that of the aggressive behavior induced in grouphoused mice. Further studies are necessary to elucidate the mechanism of this abnormal behavior. Acknowledgement This investigation was s u p p o r t e d in p a r t by a research grant f r o m t h e Ministry of E d u c a t i o n of J a p a n a n d b y a grant f r o m t h e Naito F o u n d a t i o n , to w h o m t h e a u t h o r s are cordially i n d e b t e d . C l o n i d i n e was k i n d l y s u p p l i e d b y C.H. Boehringer Sohn.
A. Razzak et al., Clondine-induced automutilation
References Hoefke, W. and W. Kobinger, 1966, Pharmakologische Wirkungen des 2-(2,6-DichlQrophenylamino)2-imidazolin-hydrochlorids, einer neuen antihypertensiven Substanz, Arzneim. Forsch. 16, 1038. Kobinger, W. and A. Walland, 1967, Investigation into the mechanism of the hypotensive effect of 2-(2,6-dichlorophenylamino)-2-imidazoline • HC1, European J. Pharmacol. 2, 155. Morpurgo, C., 1968, Aggressive behavior induced by large doses of 2-( 2,6-Dichlorophenylamino )2-imidazoline hydrochloride (ST155) in mice, European J. Pharmacol. 2, 374.
359
Nayler, W.G., J. Price, J. Stone and T.E. Lowe, 1969, Further observation on the cardiovascular effect of ST155 (catapres), J. Pharmarol. Exptl. Therap. 166, 364. Schmitt, H., H. Schmitt, J.R. Boissier and J.F. Guidicelli, 1967, Centrally mediated decrease in sympathetic tone induced by 2-(2,6-dichlorophenylamino-2-imidazoline hydrochloride, Catapresan, ST155, European J. Pharmacol. 2, 147. Ueki, S., A. Razzak and M. Fujiwara, 1973, Characteristic of abnormal behavior induced by 2-(2,6Dichlorophenylamino )-2-imidazoline hydrochloride (ST155) in mice, Jap. J. Pharmacol. 23, 103 Suppl.