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Behavioral effect of intracerebrally injected carbachol on unrestrained cats
Pharmacology Biochemistry and Behavior, Vol. 2, pp. 141-143. ANKHO International Inc., 1974. Printed in the U.S.A.
BRIEF COMMUNICATION Behavioral Effect of Intracerebrally Injected Carbachol on Unrestrained Cats
cAszc6 DECSI Institute o f Pharmacology, Medical University P~cs, 7643 P~cs, P.O. Box 99, Hungary
(Received 1 O c t o b e r 1973)
DECSI, L. Behavioral effect of intracerebrally injected carbachol on unrestrained cats. PHARMAC. BIOCHEM. BEHAV. 2(1) 141-143, 1974. - The rage reaction which can be evoked by carbachol stimulation of the hypothalamus on freely moving cat is not specific for the hypothalamus by far. It can also be elicited by carbachol stimulation of the septal region, thalamus (intralaminary nuclei), central grey matter, red nucleus, caudate nucleus, mesencephalic reticular formation as well as by injecting the drug into the cerebral ventricle. No rage reaction can be evoked by carbachol stimulation of the globus pallidus, putamen, dorsal hippocampus, ventral hippocampus, anterior, basal, central or lateral amygdaloid nucleus and the cerebral white matter. The significance of these findings is discussed. Carbachol
Rage
Intracerebral microinjection
D I R E C T chemical stimulation o f the h y p o t h a l a m u s with carbachol (carbamylcholine) in freely moving cats has been d e m o n s t r a t e d to evoke a characteristic e m o t i o n a l behavioral reaction [2, 3, 4, 7, 11, 12, 13, 14, 16] showing a c o m p l e x behavioral pattern with definite agressivity in some cases, and with fear-like b e h a v i o r in others. On the basis of the most characteristic and most f r e q u e n t manifestations, and also for the sake of simplicity, we have termed it a rage reaction. (Whether it is real or sham rage lies b e y o n d the scope of the present discussion.) This reaction to i n t r a h y p o t h a l a m i c carbachol has proved quite a consistent finding and can be evoked f r o m several h y p o thalamic sites. There are some scattered data in the literature on a similar reaction pattern s o m e t i m e s observed after injecting c h o l i n o m i m e t i c s in some o t h e r parts o f the brain in the course of e x p e r i m e n t s p e r f o r m e d for some o t h e r purpose [1, 2, 7, 9, 10, 12, 13]. However, we do n o t k n o w o f any systematic investigations which aimed at mapping the subcortical organization of this reaction pattern n o t even in terms of gross a n a t o m i c localization. Since, however, it is rather i m p r o b a b l e that the rage reaction should only involve the h y p o t h a l a m u s , e x p e r i m e n t s were started in this l a b o r a t o r y a few years ago to elucidate what o t h e r subcortical brain structures might participate in the organization of this reaction pattern.
ically implanted cannulae and electrodes. F o r measuring the intensity of the rage reaction we used a m e t h o d developed by us earlier. This is based on the observation that the manifestations of the rage reaction involve not only the general a t t i t u d e of the animal, its gross behavior, l o c o m o t i o n , etc., but is also accompanied by characteristic vocalization. Thus we simply recorded the growling and hissing of the animal on magnetic tape and estimated the intensity of the reaction by adding up the times of vocalization during a certain period (generally 20 min) after the injection of carbachol. The general principles of the m e t h o d used have been described in detail previously [4, 14, 16]. Chemical stimulation was p e r f o r m e d by injecting 5 #1 of b u f f e r e d carbachol solution at pH 7.3, by means of a m i c r o i n j e c t o r in a b o u t 30 sec. More than 200 cats were used and a total of 17 various regions studied. The results obtained are summarized in Table 1. RESULTS Table 1 shows that the rage reaction can be evoked n o t only f r o m the h y p o t h a l a m u s but also f r o m the septal region, the non-specific (more exactly, the intralaminary) nuclei of the thalamus, the central grey matter, the red nucleus, the caudate nucleus, the mesencephalic reticular f o r m a t i o n , and also by injecting carbachol directly into the cerebral ventricle. It cannot be evoked by carbachol stimulation of the globus pallidus, p u t a m e n , ventral and dorsal h i p p o c a m p a l formations, anterior, basal, central or
METHOD The e x p e r i m e n t s were p e r f o r m e d on cats with chron141
142
DECSI TABLE 1 POSITIVE AND NEGATIVE RESPONSES TO INTRACEREBRALLY INJECTED CARBACHOL
Regions from which a rage reaction can be elicited by carbachol / 0 . 6 2 - 5 ug /
Regions from which no rage reaction can be elicited by carbachol [ up to 20 #g /
Hypothalamus
Globus pallidus
Septal region
Putamen
Thalamus / intralaminary cell group /
Ventral hippocampal formation
Central grey matter
Dorsal hippocampal formation
Red nucleus
Anterior amygdaloid nucleus
Caudate nucleus
Basal amygdaloid nucleus
Mesencephalic reticular formation
Central amygdaloid nucleus
Cerebral ventricle
Lateral amygdaloid nucleus White matter
lateral cell g r o u p s o f t h e a m y g d a l a , and f r o m t h e w h i t e m a t t e r ( o t h e r regions have n o t y e t b e e n i n v e s t i g a t e d ) . T h u s t h e r e can b e n o d o u b t t h a t several s u b c o r t i c a l areas are i m p l i c a t e d in t h e o r g a n i z a t i o n o f t h e rage react i o n e v o k e d b y c h o l i n e r g i c s t i m u l a t i o n o f t h e brain. These areas m i g h t as well c o n s t i t u t e a f u n c t i o n a l circuit, cholinergic s t i m u l a t i o n of a n y part o f w h i c h results in a rage reaction. T h e r e a c t i o n p a t t e r n s e v o k e d f r o m various areas are n o t e x a c t l y alike. T h e r e is s o m e d i f f e r e n c e in l o c o m o t o r activity (little in the case o f t h e h y p o t h a l a m u s , m u c h in t h a t o f the t h a l a m u s or r e t i c u l a r f o r m a t i o n ) , in t h e a c c o m p a n y i n g a u t o n o m i c signs ( m o s t m a r k e d w i t h h y p o t h a l a m i c s t i m u l a t i o n ) , and also in t h e f r e q u e n c y and i n t e n s i t y of t h e a t t e m p t s to a t t a c k a n y o b j e c t or small a n i m a l p u t b e f o r e the cat. DISCUSSION T h e rage r e a c t i o n is easily a b o l i s h e d b y t o p i c a l pret r e a t m e n t w i t h a few m i c r o g r a m s o f a t r o p i n e . In a d d i t i o n , it can b e a n t a g o n i z e d b y local a p p l i c a t i o n o f a f u n c t i o n a l a n t a g o n i s t ( a d r e n e r g i c s t i m u l a n t ) a n d also f r o m some r e m o t e parts of t h e circuit. F o r i n s t a n c e , t h e rage r e a c t i o n e v o k e d b y c a r b a c h o l s t i m u l a t i o n o f the h y p o t h a l a m u s is abolished by simultaneous beta-adrenergic stimulation of t h e t h a l a m u s , or, t h e rage r e a c t i o n e v o k e d b y c a r b a c h o l s t i m u l a t i o n of the t h a l a m u s is i n h i b i t e d b y s i m u l t a n e o u s b e t a - a d r e n e r g i c s t i m u l a t i o n o f t h e red n u c l e u s [ 5 , 6 ] . T h u s , at first sight it seems t h a t we are faced w i t h a
real s u b c o r t i c a l f u n c t i o n a l circuit w h i c h m i g h t c o r r e s p o n d t o the gross a n a t o m i c o r g a n i z a t i o n o f the rage r e a c t i o n p a t t e r n . (Its c h e m i c a l o r g a n i z a t i o n is certainly cholinergic and m o s t p r o b a b l y involves m u s c a r i n i c r e c e p t o r s . ) However, t h e circuit e x p l o r e d b y c h e m i c a l s t i m u l a t i o n is n o t c o m p l e t e l y i d e n t i c a l w i t h t h a t e x p l o r e d b y electrical stimu l a t i o n [ 8 ] . F o r this and for o t h e r reasons also an a l t e r n a t i v e e x p l a n a t i o n is possible f o r t h e b e h a v i o r a l effect o f i n t r a c e r e b r a l l y i n j e c t e d c a r b a c h o l in t h e cat. Also, considering t h e r a t h e r wide-spread regions f r o m w h i c h this r e a c t i o n can b e elicited one m i g h t as well be right in a s s u m i n g the c a r b a c h o l - i n d u c e d rage r e a c t i o n to be a general, n o t really specific r e s p o n s e of the b r a i n to intense cholinergic s t i m u l a t i o n o f the a p p r o p r i a t e s u b c o r t i cal s t r u c t u r e s . T h e s t i m u l a t i o n m a y n o t r e m a i n strictly localized since, for i n s t a n c e , e x c i t a t i o n o f t h e r e t i c u l a r f o r m a t i o n or t h a t o f t h e i n t r a l a m i n a r y t h a l a m i c nuclei will c e r t a i n l y spread over t h e w h o l e b r a i n . A c c o r d i n g l y , this r e a c t i o n p a t t e r n m i g h t also be regarded as t h e b r a i n ' s general, non-specific response, n e a r l y always in t h e same f o r m , t o i n t e n s e i n t r a c e r e b r a l s t i m u l a t i o n (be it c h e m i c a l or electrical) j u s t like, for i n s t a n c e , t h e general s y m p a t h e t ic r e s p o n s e , the a l a r m r e a c t i o n to a n y k i n d o f a p p r o p r i a t e e x t e r n a l stimuli. E x p e r i m e n t s are n o w in progress t o e l u c i d a t e t h e a b o v e - o u t l i n e d f u n c t i o n a l circuit (if t h e r e b e a n y ) m o r e e x a c t l y a n d to find some direct clues as to the m o r e detailed a n a t o m i c o r g a n i z a t i o n of t h e a f f e c t i v e - e m o t i o n a l r e a c t i o n s e v o k e d b y direct c h e m i c a l s t i m u l a t i o n o f various b r a i n areas in t h e w a k i n g cat.
REFERENCES 1. Allikmets, L. H., V. A. Vahing and I. P. Lapin. Dissimilar influences of imipramine, benactizyne and promazine on effects of micro-injections of noradrenaline, acetylcholine and serotonin into the amygdala in the cat. Psychopharmacologia 15: 3 9 2 - 4 0 3 , 1969.
2. Baxter, B. L. Comparison of the behavioral effects of electrical or chemical stimulation applied at the same brain loci. Expl Neurology 19: 4 1 2 - 4 3 2 , 1967.
R A G E BY I N T R A C E R E B R A L
C A R B A C H O L IN C A T S
3. Burov, Y. V. and I. G. Kurochkin. Influence of cholinolithic drugs on threat reactions in cats (in Russian). Zurnal Vys~e] Nervno] De]atelnosti (Moscow) 20: 6 6 8 - 6 7 0 , 1970. 4. Decsi, L., K. M. V~rszegi and J. M6hes. Direct chemical s t i m u lation of various subcortical brain areas in unrestrained cats. In: Recent Developments o f Neurobiology in Hungary, 11, edited by K. Liss~k. Budapest: Publishing House of the Hungarian Academy of Sciences, 1969, pp. 182-211. 5. Decsi, L., K. M. V~rszegi and J. Nagy. 38th Congress of the Hungarian Physiological Society. Budapest. 1972. 6. Decsi, L., K. M. V~rszegi and J. Nagy. Second CzechoslovakHungarian Paramacological Symposium. Prague. 1972. 7. Endrbczi, E., G. Schreiberg and K. Liss~k. The role of central nervous activating and inhibitory structures in the control of pituitary-adrenocortical function. Effects of intracerebral cholinergic and adrenergic stimulation. Acta physiol, hung. 24: 2 1 1 - 2 2 4 , 1964. 8. Fernandez de Molina, A. and R. W. Hunsperger. Organization of the subcortical system governing defence and flight reactions in the cat. J. Physiol. 160: 2 0 0 - 2 1 3 , 1962. 9. George, R., W. L. Haslett and D. J. Jenden. The production of tremor by cholinergic drugs: central sites of action. Int. J. Neuropharmac. 5: 2 7 - 3 4 , 1966.
143 10. Hull, C. D., N. A. Buchwald, B. Dubrovsky and J. Garcia. Brain temperature and arousal. Expl Neurol. 12: 2 3 8 - 2 4 6 , 1965. 11. Kurochkin, I. G. and Y. V. Burov. The effect of psychotropic substances on the behaviour of cats conditioned by introduction of acetylcholine into the hypothalamus (in Russian). Farmakologi]a i Toxikologi]a (Moscow) 34: 2 1 - 2 5 , 1971. 12. Macphail, E. M. and N. E. Miller. Cholinergic brain stimulation in cats: Failure to obtain sleep. J. comp. physiol. Psychol. 65: 4 9 9 - 5 0 3 , 1968. 13. Myers, R. D. Emotional and autonomic responses following hypothalamic chemical stimulation. Can. Rev. Psychol. 18: 6 - 1 4 , 1964. 14. Nagy, J. and L. Decsi. Location of the site of the tranquillizing action of diazepam by intralimbic application. Neuropharmacology 12: 7 5 7 - 7 6 8 , 1973. 15. Nagy, J. and L. Decsi. Simultaneous chemical stimulation of the hypothalamus and dorsal hippocampus in the waking cat. Pharmac. BiocherrL Behav., in press. 16. V~rszegi, K. M. and L. Decsi. Some characteristics of the rage reaction evoked by chemical stimulation of the hypothalamus. Acta physiol, hung. 32: 6 1 - 6 8 , 1967.
BRIEF COMMUNICATION Behavioral Effect of Intracerebrally Injected Carbachol on Unrestrained Cats
cAszc6 DECSI Institute o f Pharmacology, Medical University P~cs, 7643 P~cs, P.O. Box 99, Hungary
(Received 1 O c t o b e r 1973)
DECSI, L. Behavioral effect of intracerebrally injected carbachol on unrestrained cats. PHARMAC. BIOCHEM. BEHAV. 2(1) 141-143, 1974. - The rage reaction which can be evoked by carbachol stimulation of the hypothalamus on freely moving cat is not specific for the hypothalamus by far. It can also be elicited by carbachol stimulation of the septal region, thalamus (intralaminary nuclei), central grey matter, red nucleus, caudate nucleus, mesencephalic reticular formation as well as by injecting the drug into the cerebral ventricle. No rage reaction can be evoked by carbachol stimulation of the globus pallidus, putamen, dorsal hippocampus, ventral hippocampus, anterior, basal, central or lateral amygdaloid nucleus and the cerebral white matter. The significance of these findings is discussed. Carbachol
Rage
Intracerebral microinjection
D I R E C T chemical stimulation o f the h y p o t h a l a m u s with carbachol (carbamylcholine) in freely moving cats has been d e m o n s t r a t e d to evoke a characteristic e m o t i o n a l behavioral reaction [2, 3, 4, 7, 11, 12, 13, 14, 16] showing a c o m p l e x behavioral pattern with definite agressivity in some cases, and with fear-like b e h a v i o r in others. On the basis of the most characteristic and most f r e q u e n t manifestations, and also for the sake of simplicity, we have termed it a rage reaction. (Whether it is real or sham rage lies b e y o n d the scope of the present discussion.) This reaction to i n t r a h y p o t h a l a m i c carbachol has proved quite a consistent finding and can be evoked f r o m several h y p o thalamic sites. There are some scattered data in the literature on a similar reaction pattern s o m e t i m e s observed after injecting c h o l i n o m i m e t i c s in some o t h e r parts o f the brain in the course of e x p e r i m e n t s p e r f o r m e d for some o t h e r purpose [1, 2, 7, 9, 10, 12, 13]. However, we do n o t k n o w o f any systematic investigations which aimed at mapping the subcortical organization of this reaction pattern n o t even in terms of gross a n a t o m i c localization. Since, however, it is rather i m p r o b a b l e that the rage reaction should only involve the h y p o t h a l a m u s , e x p e r i m e n t s were started in this l a b o r a t o r y a few years ago to elucidate what o t h e r subcortical brain structures might participate in the organization of this reaction pattern.
ically implanted cannulae and electrodes. F o r measuring the intensity of the rage reaction we used a m e t h o d developed by us earlier. This is based on the observation that the manifestations of the rage reaction involve not only the general a t t i t u d e of the animal, its gross behavior, l o c o m o t i o n , etc., but is also accompanied by characteristic vocalization. Thus we simply recorded the growling and hissing of the animal on magnetic tape and estimated the intensity of the reaction by adding up the times of vocalization during a certain period (generally 20 min) after the injection of carbachol. The general principles of the m e t h o d used have been described in detail previously [4, 14, 16]. Chemical stimulation was p e r f o r m e d by injecting 5 #1 of b u f f e r e d carbachol solution at pH 7.3, by means of a m i c r o i n j e c t o r in a b o u t 30 sec. More than 200 cats were used and a total of 17 various regions studied. The results obtained are summarized in Table 1. RESULTS Table 1 shows that the rage reaction can be evoked n o t only f r o m the h y p o t h a l a m u s but also f r o m the septal region, the non-specific (more exactly, the intralaminary) nuclei of the thalamus, the central grey matter, the red nucleus, the caudate nucleus, the mesencephalic reticular f o r m a t i o n , and also by injecting carbachol directly into the cerebral ventricle. It cannot be evoked by carbachol stimulation of the globus pallidus, p u t a m e n , ventral and dorsal h i p p o c a m p a l formations, anterior, basal, central or
METHOD The e x p e r i m e n t s were p e r f o r m e d on cats with chron141
142
DECSI TABLE 1 POSITIVE AND NEGATIVE RESPONSES TO INTRACEREBRALLY INJECTED CARBACHOL
Regions from which a rage reaction can be elicited by carbachol / 0 . 6 2 - 5 ug /
Regions from which no rage reaction can be elicited by carbachol [ up to 20 #g /
Hypothalamus
Globus pallidus
Septal region
Putamen
Thalamus / intralaminary cell group /
Ventral hippocampal formation
Central grey matter
Dorsal hippocampal formation
Red nucleus
Anterior amygdaloid nucleus
Caudate nucleus
Basal amygdaloid nucleus
Mesencephalic reticular formation
Central amygdaloid nucleus
Cerebral ventricle
Lateral amygdaloid nucleus White matter
lateral cell g r o u p s o f t h e a m y g d a l a , and f r o m t h e w h i t e m a t t e r ( o t h e r regions have n o t y e t b e e n i n v e s t i g a t e d ) . T h u s t h e r e can b e n o d o u b t t h a t several s u b c o r t i c a l areas are i m p l i c a t e d in t h e o r g a n i z a t i o n o f t h e rage react i o n e v o k e d b y c h o l i n e r g i c s t i m u l a t i o n o f t h e brain. These areas m i g h t as well c o n s t i t u t e a f u n c t i o n a l circuit, cholinergic s t i m u l a t i o n of a n y part o f w h i c h results in a rage reaction. T h e r e a c t i o n p a t t e r n s e v o k e d f r o m various areas are n o t e x a c t l y alike. T h e r e is s o m e d i f f e r e n c e in l o c o m o t o r activity (little in the case o f t h e h y p o t h a l a m u s , m u c h in t h a t o f the t h a l a m u s or r e t i c u l a r f o r m a t i o n ) , in t h e a c c o m p a n y i n g a u t o n o m i c signs ( m o s t m a r k e d w i t h h y p o t h a l a m i c s t i m u l a t i o n ) , and also in t h e f r e q u e n c y and i n t e n s i t y of t h e a t t e m p t s to a t t a c k a n y o b j e c t or small a n i m a l p u t b e f o r e the cat. DISCUSSION T h e rage r e a c t i o n is easily a b o l i s h e d b y t o p i c a l pret r e a t m e n t w i t h a few m i c r o g r a m s o f a t r o p i n e . In a d d i t i o n , it can b e a n t a g o n i z e d b y local a p p l i c a t i o n o f a f u n c t i o n a l a n t a g o n i s t ( a d r e n e r g i c s t i m u l a n t ) a n d also f r o m some r e m o t e parts of t h e circuit. F o r i n s t a n c e , t h e rage r e a c t i o n e v o k e d b y c a r b a c h o l s t i m u l a t i o n o f the h y p o t h a l a m u s is abolished by simultaneous beta-adrenergic stimulation of t h e t h a l a m u s , or, t h e rage r e a c t i o n e v o k e d b y c a r b a c h o l s t i m u l a t i o n of the t h a l a m u s is i n h i b i t e d b y s i m u l t a n e o u s b e t a - a d r e n e r g i c s t i m u l a t i o n o f t h e red n u c l e u s [ 5 , 6 ] . T h u s , at first sight it seems t h a t we are faced w i t h a
real s u b c o r t i c a l f u n c t i o n a l circuit w h i c h m i g h t c o r r e s p o n d t o the gross a n a t o m i c o r g a n i z a t i o n o f the rage r e a c t i o n p a t t e r n . (Its c h e m i c a l o r g a n i z a t i o n is certainly cholinergic and m o s t p r o b a b l y involves m u s c a r i n i c r e c e p t o r s . ) However, t h e circuit e x p l o r e d b y c h e m i c a l s t i m u l a t i o n is n o t c o m p l e t e l y i d e n t i c a l w i t h t h a t e x p l o r e d b y electrical stimu l a t i o n [ 8 ] . F o r this and for o t h e r reasons also an a l t e r n a t i v e e x p l a n a t i o n is possible f o r t h e b e h a v i o r a l effect o f i n t r a c e r e b r a l l y i n j e c t e d c a r b a c h o l in t h e cat. Also, considering t h e r a t h e r wide-spread regions f r o m w h i c h this r e a c t i o n can b e elicited one m i g h t as well be right in a s s u m i n g the c a r b a c h o l - i n d u c e d rage r e a c t i o n to be a general, n o t really specific r e s p o n s e of the b r a i n to intense cholinergic s t i m u l a t i o n o f the a p p r o p r i a t e s u b c o r t i cal s t r u c t u r e s . T h e s t i m u l a t i o n m a y n o t r e m a i n strictly localized since, for i n s t a n c e , e x c i t a t i o n o f t h e r e t i c u l a r f o r m a t i o n or t h a t o f t h e i n t r a l a m i n a r y t h a l a m i c nuclei will c e r t a i n l y spread over t h e w h o l e b r a i n . A c c o r d i n g l y , this r e a c t i o n p a t t e r n m i g h t also be regarded as t h e b r a i n ' s general, non-specific response, n e a r l y always in t h e same f o r m , t o i n t e n s e i n t r a c e r e b r a l s t i m u l a t i o n (be it c h e m i c a l or electrical) j u s t like, for i n s t a n c e , t h e general s y m p a t h e t ic r e s p o n s e , the a l a r m r e a c t i o n to a n y k i n d o f a p p r o p r i a t e e x t e r n a l stimuli. E x p e r i m e n t s are n o w in progress t o e l u c i d a t e t h e a b o v e - o u t l i n e d f u n c t i o n a l circuit (if t h e r e b e a n y ) m o r e e x a c t l y a n d to find some direct clues as to the m o r e detailed a n a t o m i c o r g a n i z a t i o n of t h e a f f e c t i v e - e m o t i o n a l r e a c t i o n s e v o k e d b y direct c h e m i c a l s t i m u l a t i o n o f various b r a i n areas in t h e w a k i n g cat.
REFERENCES 1. Allikmets, L. H., V. A. Vahing and I. P. Lapin. Dissimilar influences of imipramine, benactizyne and promazine on effects of micro-injections of noradrenaline, acetylcholine and serotonin into the amygdala in the cat. Psychopharmacologia 15: 3 9 2 - 4 0 3 , 1969.
2. Baxter, B. L. Comparison of the behavioral effects of electrical or chemical stimulation applied at the same brain loci. Expl Neurology 19: 4 1 2 - 4 3 2 , 1967.
R A G E BY I N T R A C E R E B R A L
C A R B A C H O L IN C A T S
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