Psychopharrnaco|ogy
Psychopharmacology 63, 25 28 (1979)
f ' by Springer-Verlag 1979
Postnatal Orotate Treatmen,: Effects on Learning and Memory in Adult Rats H e i d e - L i n d e R t i t h r i c h , W o l f r a m Wetzel, a n d H a n s j t i r g e n M a t t h i e s Institute of Pharmacology and Toxicology, Medical Academy, 301 Magdeburg, German Democratic Republic
Abstract. D u r i n g the p o s t n a t a l p e r i o d , m a l e W i s t a r rats w e r e t r e a t e d w i t h o r o t a t e , either f r o m the 6th to 15th, 16th to 25th, or 2 6 t h to 35th d a y o f life. L e a r n i n g a n d m e m o r y w e r e tested in a d u l t h o o d ~ R a t s t h a t r e c e i v e d o r o t a t e f r o m the 6th to 15th day s h o w e d a b e t t e r r e t e n t i o n o f a l e a r n e d b r i g h t n e s s d i s c r i m i n a t i o n (Ym a z e ) t h a n c o n t r o l s . A n active a v o i d a n c e (pole j u m p ing) was l e a r n e d m o r e q u i c k l y by the rats o r o t a t e t r e a t e d f r o m the 6th to 15th day t h a n by c o n t r o l s . T h e s p o n t a n e o u s l o c o m o t o r activity o f p r e v i o u s l y o r o t a t e t r e a t e d rats was the s a m e as in c o n t r o l s . B o d y w e i g k t m e a s u r e m e n t s r e v e a l e d n o differences b e t w e e n o r o t a t e rats a n d c o n t r o l rats. T h e results suggest t h a t m e m o r y r e t e n t i o n in a d u l t h o o d can be i m p r o v e d by p o s t n a t a l orotate treatment. Key w o r d s : O r o t i c a c i d - P o s t n a t a l d e v e l o p m e n t Memory retention - Brightness discrimination Active avoidance
In p r e v i o u s i n v e s t i g a t i o n s we h a v e s h o w n t h a t o r o t i c acid i m p r o v e s l o n g - t e r m m e m o r y in a d u l t rats ( M a t thies a n d Lietz, i 9 6 7 ; LSl3ner a n d M a t t h i e s , 197! ; O t t et al., 1972; O t t a n d M a t t h i e s , 1970, 1973; O t t , ]979)_ We found both a delayed extinction of a conditioned a v o i d a n c e ( M a t t h i e s a n d Lietz, 1967) a n d an i m p r o v e d retention of a brightness discrimination (Ott and M a t t h i e s , 1971). O t h e r a u t h o r s d e m o n s t r a t e d t h a t the learning performances of poor learners (Becker-Carus, 1972) a n d o f net~rotoxically i m p a i r e d rats (D6si et a!., !972) c a n be i m p r o v e d by o r o t i c acid. P o s t n a t a l o n t o g e n e s i s is a critical p e r i o d for the i n d i v i d u a l d e v e l o p m e n t o f the C N S o f the rat. T h e processes of development and differentiation depend o n p r o t e i n s f o r m e d in d e p e n d e n c e u p o n the n u c l e i c acids ( S a n d r i t t e r et al., t967). T h u s , the a v a i l a b i l i t y o f
p r e c u r s o r s o f r i b o n u c l e i c a c i d m a y be i m p o r t a n t for the formation and maturation of brain structures during p o s t n a t a I d e v e l o p m e n t . F o l l o w i n g these c o n s i d e r a tions, we i n v e s t i g a t e d the i n f l u e n c e o f o r o t i c a c i d a p p l i c a t i o n o n l e a r n i n g b e h a v i o r o f a d u l t rats d u r i n g their early d e v e l o p m e n t .
Materials and Methods The experiments were performed on ! 36 male Wistar rats. Because of the poor solubility of orotic acid and due to our desire to use a watersoluble substance for injection, we used either rnethylglucamine orotate (MGO) (Wirtschaftspatent: Patentsc_hrift 116 036) or a new orotic acid derivative, 2-amino-2-(hydroxymethyl)-propan-l,3 diol orotate (STO). The postnatal treatment was performed in four groups of animals : Animals of group I received i.p. 50 mg/kg MGO - 23.5 mg orotic acid/kg daily from the 6th to the 15th day of life; group II received 501ng/kg MGO daily from the 16th to 25th day; group III received 50 mg/kg MGO daily from the 26th to 35th day. Methylglucamine hydrochloride (MGCI) was given to each control group in an equimolar dose at the same times. Animals of group IV received an equimolar dose of STO, related to the amount of orotic acid, daily from the 6th to the 15th day of life. Related controls were injected with either the component 2-amino-2-(hydroxymethyl)propan-l,3-diol hydrochloride (STCI) or NaCt. A scheme of the different treatments is shown in Pig. t. In all groups, an equal number of rats of the same litter were treated with orotate or control solution, respectively. From the birth up to the end of the experiments, ten rats were always kept in one cage. The rats were weaned on the 28th day of life. The rats were weighed every 5 days up to the 35th day, and once a week thereafter, until the 9th week. Behavioral experiments were started at the age of 8 weeks. At first, the rats had to learn a foot-shock-motivated brightness discrimination in a semiautomatic Y-maze (On and Matthies, 1971). The training consisted of 31 consecutive runs (group I, II, III), or 25 runs (group IV), respectively. Runs into the dark alley of the Y-maze were punished by ! mA foot shocks. 24 h later, retention was tested in a relearning session. At the age of 9 weeks~ the rats had to learn an active avoidance in a pole-jumping box. A sound was the conditioned stimulus. Four seconds later, the unconditioned stimulus was applied by current impulses of I mA. The conditioned reaction was elaborated in daily sessions of ten trials per day for 3 days. The intertrial intervals varied between 30 and 90 s. Some rats, showing less than two unconditioned reactions on the 1st day of training, were not used for evaluation.
0033-3158/79/0063/0025/$01.00
26
Psychopharmacology 63 (1979)
[ ] rtS~
tO, 8, 6, 4, 2.
10. 8. 6.
't behavioral tests for all groups
i p~
100.
g•rop 0,01
P
Psychopharmacology 63, 25 28 (1979)
f ' by Springer-Verlag 1979
Postnatal Orotate Treatmen,: Effects on Learning and Memory in Adult Rats H e i d e - L i n d e R t i t h r i c h , W o l f r a m Wetzel, a n d H a n s j t i r g e n M a t t h i e s Institute of Pharmacology and Toxicology, Medical Academy, 301 Magdeburg, German Democratic Republic
Abstract. D u r i n g the p o s t n a t a l p e r i o d , m a l e W i s t a r rats w e r e t r e a t e d w i t h o r o t a t e , either f r o m the 6th to 15th, 16th to 25th, or 2 6 t h to 35th d a y o f life. L e a r n i n g a n d m e m o r y w e r e tested in a d u l t h o o d ~ R a t s t h a t r e c e i v e d o r o t a t e f r o m the 6th to 15th day s h o w e d a b e t t e r r e t e n t i o n o f a l e a r n e d b r i g h t n e s s d i s c r i m i n a t i o n (Ym a z e ) t h a n c o n t r o l s . A n active a v o i d a n c e (pole j u m p ing) was l e a r n e d m o r e q u i c k l y by the rats o r o t a t e t r e a t e d f r o m the 6th to 15th day t h a n by c o n t r o l s . T h e s p o n t a n e o u s l o c o m o t o r activity o f p r e v i o u s l y o r o t a t e t r e a t e d rats was the s a m e as in c o n t r o l s . B o d y w e i g k t m e a s u r e m e n t s r e v e a l e d n o differences b e t w e e n o r o t a t e rats a n d c o n t r o l rats. T h e results suggest t h a t m e m o r y r e t e n t i o n in a d u l t h o o d can be i m p r o v e d by p o s t n a t a l orotate treatment. Key w o r d s : O r o t i c a c i d - P o s t n a t a l d e v e l o p m e n t Memory retention - Brightness discrimination Active avoidance
In p r e v i o u s i n v e s t i g a t i o n s we h a v e s h o w n t h a t o r o t i c acid i m p r o v e s l o n g - t e r m m e m o r y in a d u l t rats ( M a t thies a n d Lietz, i 9 6 7 ; LSl3ner a n d M a t t h i e s , 197! ; O t t et al., 1972; O t t a n d M a t t h i e s , 1970, 1973; O t t , ]979)_ We found both a delayed extinction of a conditioned a v o i d a n c e ( M a t t h i e s a n d Lietz, 1967) a n d an i m p r o v e d retention of a brightness discrimination (Ott and M a t t h i e s , 1971). O t h e r a u t h o r s d e m o n s t r a t e d t h a t the learning performances of poor learners (Becker-Carus, 1972) a n d o f net~rotoxically i m p a i r e d rats (D6si et a!., !972) c a n be i m p r o v e d by o r o t i c acid. P o s t n a t a l o n t o g e n e s i s is a critical p e r i o d for the i n d i v i d u a l d e v e l o p m e n t o f the C N S o f the rat. T h e processes of development and differentiation depend o n p r o t e i n s f o r m e d in d e p e n d e n c e u p o n the n u c l e i c acids ( S a n d r i t t e r et al., t967). T h u s , the a v a i l a b i l i t y o f
p r e c u r s o r s o f r i b o n u c l e i c a c i d m a y be i m p o r t a n t for the formation and maturation of brain structures during p o s t n a t a I d e v e l o p m e n t . F o l l o w i n g these c o n s i d e r a tions, we i n v e s t i g a t e d the i n f l u e n c e o f o r o t i c a c i d a p p l i c a t i o n o n l e a r n i n g b e h a v i o r o f a d u l t rats d u r i n g their early d e v e l o p m e n t .
Materials and Methods The experiments were performed on ! 36 male Wistar rats. Because of the poor solubility of orotic acid and due to our desire to use a watersoluble substance for injection, we used either rnethylglucamine orotate (MGO) (Wirtschaftspatent: Patentsc_hrift 116 036) or a new orotic acid derivative, 2-amino-2-(hydroxymethyl)-propan-l,3 diol orotate (STO). The postnatal treatment was performed in four groups of animals : Animals of group I received i.p. 50 mg/kg MGO - 23.5 mg orotic acid/kg daily from the 6th to the 15th day of life; group II received 501ng/kg MGO daily from the 16th to 25th day; group III received 50 mg/kg MGO daily from the 26th to 35th day. Methylglucamine hydrochloride (MGCI) was given to each control group in an equimolar dose at the same times. Animals of group IV received an equimolar dose of STO, related to the amount of orotic acid, daily from the 6th to the 15th day of life. Related controls were injected with either the component 2-amino-2-(hydroxymethyl)propan-l,3-diol hydrochloride (STCI) or NaCt. A scheme of the different treatments is shown in Pig. t. In all groups, an equal number of rats of the same litter were treated with orotate or control solution, respectively. From the birth up to the end of the experiments, ten rats were always kept in one cage. The rats were weaned on the 28th day of life. The rats were weighed every 5 days up to the 35th day, and once a week thereafter, until the 9th week. Behavioral experiments were started at the age of 8 weeks. At first, the rats had to learn a foot-shock-motivated brightness discrimination in a semiautomatic Y-maze (On and Matthies, 1971). The training consisted of 31 consecutive runs (group I, II, III), or 25 runs (group IV), respectively. Runs into the dark alley of the Y-maze were punished by ! mA foot shocks. 24 h later, retention was tested in a relearning session. At the age of 9 weeks~ the rats had to learn an active avoidance in a pole-jumping box. A sound was the conditioned stimulus. Four seconds later, the unconditioned stimulus was applied by current impulses of I mA. The conditioned reaction was elaborated in daily sessions of ten trials per day for 3 days. The intertrial intervals varied between 30 and 90 s. Some rats, showing less than two unconditioned reactions on the 1st day of training, were not used for evaluation.
0033-3158/79/0063/0025/$01.00
26
Psychopharmacology 63 (1979)
[ ] rtS~
tO, 8, 6, 4, 2.
10. 8. 6.
't behavioral tests for all groups
i p~
100.
g•rop 0,01
P
