Pharmacology Btochemtstry& Behavtor, Vol 4, pp. 703--707. Copyright © 1976 by ANKHO International Inc. All rights of reproduction in any form reserved Printed m the U S.A.
Modulation of Cycloheximide-Resistant Memory by Sympathomimetic Agents MARIE E GIBBS 1
Department o f Psychology, LaTrobe University, Bundoora Victoria 3083, Australia ( R e c e i v e d 15 J u n e 1975)
GIBBS, M. 15:. Modulatton of cyclohe~tmide-resistant memory by sympathomunettc agents PHARMAC. BIOCHEM. BEHAV. 4(6) 703-707, 1976 - Amphetamine overcomes the amnesia caused by cyclohexlmlde (CXM) provided Jt ,s administered closely following the learning trial In day-old chickens with one trial passwe avmdance learning, there is a short-term, labile memory existing tbr 90 mm following training under the influence of CXM. Amphetamine has been shown to keep the memory at precisely the level exhibited by the labile, cyclohexmllde-reslstant memory trace at the time of reject,on Noreplnephrme, methoxamlne (an ~ adrenerglc snmulant) and ~soprenahne (a t3 adrenerglc stimulant) each mimic the amphetamine effect m CXM-pretreated chickens. That the action of amphetamine could be due to its release of norepmephrme is supported by the finding that It could be blocked by both ~ adrenergm (plperoxane) and/3 adrenerglc antagomsts (propranolol). it has been suggested that this labile memory trace depends on the functioning of a sodmm pump Norepmephrme may be modulating memory format,on by an action on the sodmm pump since m prehmmary biochemical assays norepmephrme stnnulated the sodmm pump (Na÷]K+ ATPase) actw,ty m chicken forebram total homogenate. Norepmephrme Labile protein-independent memory a and/3 adrenerglc receptor blockers
a and ~3adrenerg~c stunulants
IN d a y old c h i c k e n s m e m o r y for passwe a v o i d a n c e t r a i n i n g has b e e n s h o w n to be a t w o stage process [ 9 , 2 1 ] . T h e first is a s h o r t - t e r m , l a b d e phase w h i c h declines to amnesxc levels of r e t e n t i o n m 90 m m . T h e s e c o n d process is a l o n g - t e r m m e m o r y storage w h i c h d e p e n d s o n the n o r m a l s h o r t - t e r m labde phase a n d p r o t e i n synthesxs for its f o r m a h o n , In a p r e c e d i n g p a p e r [2] ~t has b e e n s h o w n t h a t a m p h e t a m i n e c o u n t e r a c t s t h e a m n e s i c effect o f CXM p r o v i d e d it is a d m i n i s t e r e d b e f o r e t h e labile, p r o t e i n i n d e p e n d e n t m e m o r y has d e c h n e d . U n d e r s u c h c o n d i t i o n s r e t e n t i o n has b e e n f o u n d to be d i r e c t l y related to t h e level of labtle m e m o r y at t h e time of a m p h e t a m i n e a d m i n i s t r a t i o n (Fig. 4). T h e r e f o r e , w h e n r e t e n t i o n is h~gh s h o r t l y after learning, t h e a d m i n i s t r a t i o n o f a m p h e t a m i n e at this time results in a very stmilar r e t e n t i o n 3 hr later b u t w h e n the r e t e n t i o n has fallen to a low level because of the presence of CXM a m p h e t a m i n e ~s u n a b l e to ~mprove the r e t e n t i o n at 3 hr. T h e c e n t r a l n e r v o u s p r o p e r t i e s o f a m p h e t a m i n e have b e e n h n k e d to its a c t i o n o n ' s e v e r a l p u t a t i v e n e u r o t r a n s m i t t e r systems. T h e m o s t p r o m i n e n t a c t i o n appears to be t h e release o f n o r e p i n e p h r i n e a n d a n u m b e r o f a c t i o n s have b e e n d e m o n s t r a t e d , all o f w h i c h w o u l d be e x p e c t e d to increase the c o n c e n t r a t i o n of n o r e p l n e p h r l n e at s y n a p s e s m the c e n t r a l n e r v o u s system. It releases n o r e p m e p h r i n e [23] and mh~b~ts m o n o a m m e oxldase activity [ 4 ] . A m p h e t a m i n e also causes t h e release o f d o p a m m e and i n h i b i t s ~ts r e u p t a k e [ 1 9 ] . L o c o m o t o r h y p e r a c t w i t y and aggressive
Sodmm pump
b e h a v l o u r have b e e n a t t r i b u t e d to this release o f no p h r m e [19] whereas s t e r e o t y p e d b e h a v l o u r ha: a t t r i b u t e d to the release o f d o p a m m e [ 12] Schrc Squares [14] have suggested t h a t a m p h e t a m i n e m a y l effect o n behav~our vm a serotonerg~c ( 5 H T ) mec and it has also b e e n r e p o r t e d t h a t a n h h i s t a m m e s w~i some c e n t r a l n e r v o u s a c t i o n s of d - a m p h e t a m i n e s [12 T h e p r e s e n t s t u d y was to d e t e r m i n e w h e t h e r th( of a m p h e t a m i n e o n m e m o r y could be linked to an p o s t u l a t e d a c t i o n s o n t r a n s m i t t e r release. It b e c a m e t h a t n o r e p m e p h r m e release was p r o b a b l y respons: the effect o f a m p h e t a m i n e o n labile m e m o r y as nore r m e a n d also the a n o r a d r e n e r g l c s t i m u l a n t , m e t h o a n d the ~ n o r a d r e n e r g l c s t i m u l a n t , l s o p r e n a h n e cou r e p r o d u c e the effects of a m p h e t a m i n e T w o n o r a d l receptor antagonists- plperoxane and propranolol e m p l o y e d to d e t e r m i n e ff the a m p h e t a m i n e a c t i o n , to the release o f n o r e p i n e p h r i n e H o w e v e r It was lm to see w h e t h e r the o t h e r p o s t u l a t e d a c t i o n s for a m i n e were involved a n d for t h a t r e a s o n t h e drL p e n d o l was used to b l o c k d o p a m i n e receptors, c y p r dene was used to b l o c k 5 H T r e c e p t o r s and m e p y r a m used to b l o c k h i s t a m i n e r e c e p t o r s . T h e drugs chos~ s t a n d a r d p h a r m a c o l o g i c a l a n t a g o m s t s or agonsats t r a n s m i t t e r s revolved [ 1 ]. C h i c k e n s have a r e d u c e d b l o o d b r i m barrier for t a m m e s d u r i n g the first m o n t h a f t e r h a t c h i n g [18 and behav~oural r e s p o n s e s to s y s t e m i c a l l y admi~
Formerly M. E. Watts. 703
( 704 btogentc amines are similar to those observed after direct apphcatton of amines into the brain of adult birds [16]. This reason made the subcutaneous admmlstration of the drugs possible, this was desirable as the CXM was admm~stered intracranially. METHOD
100.
A
CXMPRETREATMENT
z_ o:~ 80.
Modulation of Cycloheximide-Resistant Memory by Sympathomimetic Agents MARIE E GIBBS 1
Department o f Psychology, LaTrobe University, Bundoora Victoria 3083, Australia ( R e c e i v e d 15 J u n e 1975)
GIBBS, M. 15:. Modulatton of cyclohe~tmide-resistant memory by sympathomunettc agents PHARMAC. BIOCHEM. BEHAV. 4(6) 703-707, 1976 - Amphetamine overcomes the amnesia caused by cyclohexlmlde (CXM) provided Jt ,s administered closely following the learning trial In day-old chickens with one trial passwe avmdance learning, there is a short-term, labile memory existing tbr 90 mm following training under the influence of CXM. Amphetamine has been shown to keep the memory at precisely the level exhibited by the labile, cyclohexmllde-reslstant memory trace at the time of reject,on Noreplnephrme, methoxamlne (an ~ adrenerglc snmulant) and ~soprenahne (a t3 adrenerglc stimulant) each mimic the amphetamine effect m CXM-pretreated chickens. That the action of amphetamine could be due to its release of norepmephrme is supported by the finding that It could be blocked by both ~ adrenergm (plperoxane) and/3 adrenerglc antagomsts (propranolol). it has been suggested that this labile memory trace depends on the functioning of a sodmm pump Norepmephrme may be modulating memory format,on by an action on the sodmm pump since m prehmmary biochemical assays norepmephrme stnnulated the sodmm pump (Na÷]K+ ATPase) actw,ty m chicken forebram total homogenate. Norepmephrme Labile protein-independent memory a and/3 adrenerglc receptor blockers
a and ~3adrenerg~c stunulants
IN d a y old c h i c k e n s m e m o r y for passwe a v o i d a n c e t r a i n i n g has b e e n s h o w n to be a t w o stage process [ 9 , 2 1 ] . T h e first is a s h o r t - t e r m , l a b d e phase w h i c h declines to amnesxc levels of r e t e n t i o n m 90 m m . T h e s e c o n d process is a l o n g - t e r m m e m o r y storage w h i c h d e p e n d s o n the n o r m a l s h o r t - t e r m labde phase a n d p r o t e i n synthesxs for its f o r m a h o n , In a p r e c e d i n g p a p e r [2] ~t has b e e n s h o w n t h a t a m p h e t a m i n e c o u n t e r a c t s t h e a m n e s i c effect o f CXM p r o v i d e d it is a d m i n i s t e r e d b e f o r e t h e labile, p r o t e i n i n d e p e n d e n t m e m o r y has d e c h n e d . U n d e r s u c h c o n d i t i o n s r e t e n t i o n has b e e n f o u n d to be d i r e c t l y related to t h e level of labtle m e m o r y at t h e time of a m p h e t a m i n e a d m i n i s t r a t i o n (Fig. 4). T h e r e f o r e , w h e n r e t e n t i o n is h~gh s h o r t l y after learning, t h e a d m i n i s t r a t i o n o f a m p h e t a m i n e at this time results in a very stmilar r e t e n t i o n 3 hr later b u t w h e n the r e t e n t i o n has fallen to a low level because of the presence of CXM a m p h e t a m i n e ~s u n a b l e to ~mprove the r e t e n t i o n at 3 hr. T h e c e n t r a l n e r v o u s p r o p e r t i e s o f a m p h e t a m i n e have b e e n h n k e d to its a c t i o n o n ' s e v e r a l p u t a t i v e n e u r o t r a n s m i t t e r systems. T h e m o s t p r o m i n e n t a c t i o n appears to be t h e release o f n o r e p i n e p h r i n e a n d a n u m b e r o f a c t i o n s have b e e n d e m o n s t r a t e d , all o f w h i c h w o u l d be e x p e c t e d to increase the c o n c e n t r a t i o n of n o r e p l n e p h r l n e at s y n a p s e s m the c e n t r a l n e r v o u s system. It releases n o r e p m e p h r i n e [23] and mh~b~ts m o n o a m m e oxldase activity [ 4 ] . A m p h e t a m i n e also causes t h e release o f d o p a m m e and i n h i b i t s ~ts r e u p t a k e [ 1 9 ] . L o c o m o t o r h y p e r a c t w i t y and aggressive
Sodmm pump
b e h a v l o u r have b e e n a t t r i b u t e d to this release o f no p h r m e [19] whereas s t e r e o t y p e d b e h a v l o u r ha: a t t r i b u t e d to the release o f d o p a m m e [ 12] Schrc Squares [14] have suggested t h a t a m p h e t a m i n e m a y l effect o n behav~our vm a serotonerg~c ( 5 H T ) mec and it has also b e e n r e p o r t e d t h a t a n h h i s t a m m e s w~i some c e n t r a l n e r v o u s a c t i o n s of d - a m p h e t a m i n e s [12 T h e p r e s e n t s t u d y was to d e t e r m i n e w h e t h e r th( of a m p h e t a m i n e o n m e m o r y could be linked to an p o s t u l a t e d a c t i o n s o n t r a n s m i t t e r release. It b e c a m e t h a t n o r e p m e p h r m e release was p r o b a b l y respons: the effect o f a m p h e t a m i n e o n labile m e m o r y as nore r m e a n d also the a n o r a d r e n e r g l c s t i m u l a n t , m e t h o a n d the ~ n o r a d r e n e r g l c s t i m u l a n t , l s o p r e n a h n e cou r e p r o d u c e the effects of a m p h e t a m i n e T w o n o r a d l receptor antagonists- plperoxane and propranolol e m p l o y e d to d e t e r m i n e ff the a m p h e t a m i n e a c t i o n , to the release o f n o r e p i n e p h r i n e H o w e v e r It was lm to see w h e t h e r the o t h e r p o s t u l a t e d a c t i o n s for a m i n e were involved a n d for t h a t r e a s o n t h e drL p e n d o l was used to b l o c k d o p a m i n e receptors, c y p r dene was used to b l o c k 5 H T r e c e p t o r s and m e p y r a m used to b l o c k h i s t a m i n e r e c e p t o r s . T h e drugs chos~ s t a n d a r d p h a r m a c o l o g i c a l a n t a g o m s t s or agonsats t r a n s m i t t e r s revolved [ 1 ]. C h i c k e n s have a r e d u c e d b l o o d b r i m barrier for t a m m e s d u r i n g the first m o n t h a f t e r h a t c h i n g [18 and behav~oural r e s p o n s e s to s y s t e m i c a l l y admi~
Formerly M. E. Watts. 703
( 704 btogentc amines are similar to those observed after direct apphcatton of amines into the brain of adult birds [16]. This reason made the subcutaneous admmlstration of the drugs possible, this was desirable as the CXM was admm~stered intracranially. METHOD
100.
A
CXMPRETREATMENT
z_ o:~ 80.
