Éva Bíró 1 , Gábor Tóth 2 , Gyula Telegdy 1
Pearson Professional Ltd 1996
Effect of receptor blockers on brain natriuretic peptide and C-type natriuretic peptide caused anxiolytic state in rats 6 1
Table 1 Effects of different doses of CNP on anxiety state of rats tested in the elevated plus-maze paradigm. Results are presented a s m e a n s ± S E ' P < 0 . 0 5 (ANOVA. Tukey's test)
Groups No. of animals Open/total time
%
Open/total entries
Control (saline) 7 29.53 ± 2.48 48.21 ±5.74
25 ng CNP 7 26.65 ± 2.68 35.48 ±3.86
50 ng CNP 9 38.98 ± 3.90 41.88 ±5.65
100 ng CNP 9 54.51 ±7.46" 46.16 ±4.68
200 ng CNP 9 66.69 ± 3.48" 54.31 ±4.48
400 ng CNP 9 58.3 ± 6.35 54.29 ±5.53
1000 ng CNP 9 31.45 ±3.71 41.81 ±3.5
Table 2 Effects of neurotransmitter blockers on CNP-induced anxiolytic state in rats. Results are presented a s means ± SE" P<0.05 (ANOVA, Tukey's ; test)
G r o u p s No. of a n i m a l s Open/total time
% Open/total entries Haloperidol (10 pg/kg i.p.)
Control (saline) 6 23.20 ±2.89 35.56 ± 3.98
CNP (200 ng i.c.v.) 7 50.14 ±4.13" 56.19 ±6.24
Haloperidol + saline 6 28.3 ±4.13 41.67 ±4.77
Haloperidol + CNP 7 35.64 ±6.45 50.00 ± 5.59
Phenoxybenzamine (2 mg/kg.i.p.)
Control (saline) 6 24.94 ±1.97 47.92 ±4.2
CNP (200 ng i.c.v.) 8 44.85 ±5.97" 41.49 ±3.43
Phenoxybenzamine + saline 7 29.87 ±3.04 55.17 ±6.49
Phenoxybenzamine + CNP 7 49.52 ±3.12 49.52 ± 4.01
Propranolol (10 mg/kg i.p.)
Control (saline) 6 24.81 ±1.78 40.20 ± 4 . 7 5
CNP (200 ng i.c.v.) 8 44.41 ± 3.06" 47.44 ± 3.72»
Propranolol + saline 7 25.44 ±3.99 35.66 ±7.32
Propranolol + CNP 9 25.38 ±1.90 47.59 ± 5.25
Atropine (2 mg/kg i.p.)
Control (saline) 7 22.32 ± 2 . 4 3 41.77 ±4.47
CNP (200 ng i.c.v.) 7 52.72 ± 6.32" 47.72 ± 5.04
Atropine + saline 8 19.5 ±2.73 40.73 ± 5.30
Atropine + CNP 8 52.16 ±2.16" 37.17 ±2.18
Methysergide (5 mg/kg i.p.)
Control (saline) 7 20.92 ±2.14 41.43 ±3.84
CNP (200 ng i.c.v.) 8 50.96 ± 2.73» 43.58 ± 3.81
Methysergide + saline 7 19.03 ±0.78 43.55 ± 4.68
Methysergide + CNP 7 50.75 ±3.38» 48.62 ±4.76
Bicuculline (1 mg/kg i.p.)
Control (saline) 7 20.29 ±3.85 38.5 ±4.58
CNP (200 ng i.c.v.) 8 44.69 ±5.13» 44.11 ± 2.58
Bicuculline + saline 8 22.00 ±3.15 45.89 ± 4.46
Bicuculline + CNP 7 50.35 ±2.16» 43.81 ± 5.22
Naloxone (0.1 mg/kg i.p.)
Control (saline) 6 21.13 ±2.87 40.24 ± 2.82
CNP (200 ng i.c.v.) 8 47.89 ± 2.74» 45.77 ± 2.63'
Naloxone + saline 7 23.67 ±3.16 41.30 ±4.39
Naloxone + CNP 7 45.87 ± 3.81» 43.79 ± 4.56
© Pearson Professional Ltd 1996 Neuropeptides (1996) 30(1), 59-65
6 2 Biro et al
rats. P r e t r e a t m e n t w i t h p h e n o x y b e n z a m i n e , a n a -a d r e n o r e c e p t o r -a n t -a g o n i s t , in -a d o s e of 2 m g / k g i.p., 3 0 m i n b e f o r e B N P a d m i n i s t r a t i o n did not m o d i f y t h e 'anxiolytic-like' activity of BNP. There w a s an increase in t h e p e r c e n t a g e t i m e s p e n t in t h e o p e n arms (ANOVA F3, 3 3 = 4 . 0 5 , P<0.0156, T u k e y ' s test), a n d a marked i n c r e a s e in t h e f r e q u e n c y o f e n t r i e s i n t o t h e o p e n arms (ANOVA F3, 3 3 = 1 . 3 8 , P < 0 . 2 6 6 , T u k e y ' s test) as c o m p a r e d w i t h t h e c o n t r o l rats. F o l l o w i n g pretreatment w i t h t h e p-a d r e n o r e c e p t o r b l o c k e r proprp-anolol 10 m g / k g , i.p. t h e r e w a s n o increase in t h e p e r c e n t a g e t i m e s p e n t in t h e o p e n a r m s (ANOVA F3, 3 7 = 3 . 4 9 , P < 0 . 0 2 6 , Tukey's test) o r in t h e f r e q u e n c y o f e n t r i e s into t h e o p e n a r m s (ANOVA F3, 37=3.97, P < 0 . 0 1 5 , T u k e y ' s test) as c o m p a r e d w i t h c o n t r o l animals, i n d i c a t i n g t h e b l o c k i n g effect of t h e pa d r e n e r g i c s y s t e m . In t h e g r o u p pretrepated with t h e m u s -carinergic a c e t y l c h o l i n e receptor blocker atropine, t h e r e w a s n o t a significant increase in t h e p e r c e n t a g e t i m e s p e n t i n t h e o p e n a r m s (ANOVA F3, 3 2 = 1 2 . 3 3 , P C 0 . 0 0 0 1 , T u k e y ' s test) or i n t h e f r e q u e n c y of entries into t h e o p e n a r m s o f t h e e l e v a t e d p l u s - m a z e paradigm as c o m p a r e d w i t h t h e c o n t r o l rats (ANOVA F3, 32=3.99, P < 0 . 0 1 7 , T u k e y ' s test). P r e t r e a t m e n t with t h e GABA r e c e p t o r b l o c k e r b i c u c u l l i n e (1 m g / k g i.p.) did n o t b l o c k t h e i n c r e a s e in t h e p e r c e n t a g e t i m e spent in t h e o p e n a r m s (ANOVA F3, 3 6 = 5 . 5 1 , P < 0 . 0 0 3 5 , Tukey's test), n o r t h e i n c r e a s e in t h e f r e q u e n c y of entries into t h e o p e n a r m s o f tire m a z e (ANOVA F3, 3 6 = 0 . 8 5 , PC0.47, Tukey's test) as c o m p a r e d w i t h t h e c o n t r o l animals. T h e increase in t h e p e r c e n t a g e t i m e s p e n t in t h e o p e n arms was not a f f e c t e d b y p r e t r e a t m e n t w i t h t h e 5 H T receptor b l o c k e r m e t h y -s e r g i d e (5 m g / k g i.p.) (ANOVA F3, 29=7.36, P < 0 . 0 0 1 , T u k e y ' s test); nor w a s t h e m a r k e d increase in t h e fre-q u e n c y of entries i n t o t h e o p e n arms (ANOVA F3, 2 9 = 0 . 8 5 , P C 0 . 0 4 7 9 , T u k e y ' s test) as c o m p a r e d with t h e c o n t r o l rats. Pretreatment w i t h t h e e n d o g e n o u s opioid s y s t e m b l o c k e r n a l o x o n e (0.1 m g / k g i.p.) pretreatment did n o t b l o c k t h e increase in t h e p e r c e n t a g e t i m e s p e n t i n t h e o p e n a r m s (ANOVA F3, 3 3 = 6 . 5 4 , P < 0 . 0 0 1 6 , T u k e y ' s
test), n o r t h e i n c r e a s e in the frequency of entries i n t o t h e o p e n a r m s of t h e elevated p l u s - m a z e (ANOVA F3, 3 3 = 1 . 8 9 , P < 0 . 1 5 , Tukey's test) as c o m p a r e d w i t h t h e c o n t r o l a n i m a l s .
Table 3 s h o w s t h e effects of i.c.v. administration o f C N P (25, 5 0 , 100, 2 0 0 , 4 0 0 or 1000 ng) t o rats t e s t e d in t h e e l e v a t e d p l u s - m a z e paradigm. T h e 100 ng, 2 0 0 n g a n d 4 0 0 n g d o s e s o f C N P significantly increased t h e per-c e n t a g e t i m e s p e n t in t h e o p e n arms as per-c o m p a r e d w i t h t h e c o n t r o l animals. T h e d o s e s of 25, 5 0 a n d 1 0 0 0 n g C N P w e r e i n e f f e c t i v e (ANOVA F6, 58=10.32, P < 0 . 0 0 0 1 , T u k e y ' s test). A statistically significant increase in t h e fre-q u e n c y o f e n t r i e s i n t o t h e o p e n arms of t h e e l e v a t e d p l u s - m a z e t e s t w a s n o t o b s e r v e d at a n y d o s e (ANOVA F6, 5 8 = 1 . 9 6 , P < 0 . 0 8 8 , Tukey's test). The 2 0 0 n g d o s e of C N P w a s s e l e c t e d t o test t h e anxiolytic activity.
T h e e f f e c t s of different neurotransmitter a n t a g o n i s t s relative t o t h e control rats are s h o w n in Table 4.
P r e t r e a t m e n t w i t h t h e dopaminergic receptor b l o c k e r h a l o p e r i d o l (10 p g / k g i.p.) b l o c k e d t h e 'anxiolytic-like' a c t i v i t y o f C N P : t h e r e w a s n o statistically significant dif-f e r e n c e i n t h e p e r c e n t a g e time spent in t h e o p e n a r m s (ANOVA F3, 2 5 = 6 . 1 6 , P C 0 . 0 0 3 3 , Tukey's test); it p r e v e n t e d t h e i n c r e a s e i n t h e f r e q u e n c y of entries into t h e o p e n a r m s o f t h e e l e v a t e d p l u s - m a z e test (ANOVA F3, 2 5 = 2 . 8 6 , P < 0 . 0 6 , T u k e y ' s test) as compared with the control rats.
P r e t r e a t m e n t w i t h t h e a-adrenoreceptor a n t a g o n i s t p h e n o x y b e n z a m i n e (2 m g / k g i.p.) blocked t h e 'anxi-olytic-like' activity o f CNP. There was n o increase in t h e p e r c e n t a g e t i m e s p e n t in t h e o p e n arms (ANOVA F3, 2 7 = 5 . 9 2 , P < 0 . 0 0 3 6 , T u k e y ' s test), nor in t h e f r e q u e n c y o f e n t r i e s i n t o t h e o p e n arms (ANOVA F3, 27=1.57, P < 0 . 2 2 , T u k e y ' s test) as c o m p a r e d with t h e control rats.
P r e t r e a t m e n t w i t h t h e p-adrenoreceptor blocker propra-n o l o l ( 1 0 m g / k g i.p.) a l s o prevepropra-nted apropra-n ipropra-ncrease ipropra-n t h e p e r c e n t a g e t i m e s p e n t in the o p e n arms (ANOVA F3, 3 0 = 1 3 . 2 , P < 0 . 0 0 0 1 , Tukey's test) a n d t h e increase in t h e f r e q u e n c y o f entries into t h e o p e n arms (ANOVA F3, 3 0 = 1 . 3 6 , P<0.27, Tukey's test) as compared w i t h t h e c o n
-Table 3 Effects of different doses of CNP on anxiety state of rats tested in the elevated plus-maze paradigm. Results are presented a s m e a n s ± SE" P <0.05 (ANOVA, Tukey's test) G r o u p s No. of animals Open/total time Open/total entries
%
Control (saline) 7 29.53 ± 2.48 48.21 ± 5.74
25 ng CNP 7 26.65 ± 2.68 35.48 ± 3.86
50 ng CNP 9 38.98 ± 3.90 41.88 ±5.65
100 ng CNP 9 54.51 ± 7.46* 46.16 ±4.68
200 ng CNP 9 66.69 ± 3.48* 54.31 ± 4.48 •
400 ng CNP 9 58.3 ± 6.35 54.29 ± 5.53
1000 ng CNP 9 31.45 ±3.71 41.81 ±3.5
Neuropeptides (1996) 30(1), 59-65 © Pearson Professional Ltd 1996
t
Effect of receptor blockers on brain natriuretic peptide and C-type natriuretic peptide caused anxiolytic state in rats 6 3
Table 4 Effects of neurotransmitter blockers on CNP-induced anxiolytic state in rats. Results are presented as means ± S E ' P <0.05 (ANOVA, Tukey's test)
G r o u p s No. of a n i m a l s Open/total time Open/total entries
% Haloperidol (10 pg/kg i.p.)
Control (saline) 6 23.20 ± 2.89 35.56 ± 3.98
CNP (200 ng i.c.v.) 7 50.14 ±4.13* 56.19 ±6.24
Haloperidol + saline 6 28.3 ± 4 . 1 3 41.67 ±4.77
Haloperidol + CNP 7 35.64 ± 6.45 50.00 ±5.59
Phenoxybenzamine (2 mg/kg.i.p.)
Control (saline) 6 24.94 ± 1 . 9 7 47.92 ± 4 . 2
CNP (200 ng I.c.v.) 8 44.85 ± 5.97* 41.49 ± 3 . 4 3
Phenoxybenzamine + saline 7 29.87 ± 3.04 55.17 ± 6 . 4 9
Phenoxybenzamine + CNP 7 49.52 ± 3.12 49.52 ± 4.01
Propranolol (10 mg/kg i.p.)
Control (saline) 6 24.81 ± 1 . 7 8 40.20 ± 4.75
CNP (200 ng i.c.v.) 8 44.41 ± 3.06' 47.44 ± 3.72*
Propranolol + saline 7 25.44 ± 3.99 35.66 ± 7.32
Propranolol + CNP 9 25.38 ± 1 . 9 0 47.59 ± 5 . 2 5
Atropine (2 mg/kg i.p.)
Control (saline) 7 22.32 ± 2 . 4 3 41.77 ± 4 . 4 7
CNP (200 ng i.c.v.) 7 52.72 ± 6.32* 47.72 ± 5.04
Atropine + saline 8 19.5 ± 2 . 7 3 40.73 ± 5.30
Atropine + CNP 8 52.16 ±2.16* 37.17 ± 2 . 1 8
Methysergide (5 mg/kg i.p.)
Control (saline) 7 20.92 ±2.14 41.43 ± 3 . 8 4
CNP (200 ng i.c.v.) 8 50.96 ± 2.73* 43.58 ± 3.81
Methysergide + saline 7 19.03 ± 0 . 7 8 43.55 ± 4.68
Methysergide + CNP 7 50.75 ± 3.38* 48.62 ± 4.76
Bicuculline (1 mg/kg i.p.)
Control (saline) 7 20.29 ± 3.85 38.5 ± 4.58
CNP (200 ng i.c.v.) 8 44.69 ±5.13* 44.11 ± 2 . 5 8
Bicuculline + saline 8 22.00 ± 3 . 1 5 45.89 ± 4.46
Bicuculline + CNP 7 50.35 ±2.16* 43.81 ± 5.22
Naloxone (0.1 mg/kg i.p.)
Control (saline) 6 21.13 ± 2 . 8 7 40.24 ± 2.82
CNP (200 ng i.c.v.) 8 47.89 ± 2.74* 45.77 ± 2.63»
Naloxone + saline 7 23.67 ± 3 . 1 6 41.30 ±4.39
Naloxone + CNP 7 45.87 ± 3.81* 43.79 ±4.56
trol a n i m a l s . In t h e g r o u p pretreated w i t h t h e m u s -c a r i n e r g i -c a -c e t y l -c h o l i n e re-ceptor blo-cker atropine, t h e s i g n i f i c a n t increase in t h e percentage time s p e n t in t h e o p e n a r m s w a s not p r e v e n t e d (ANOVA F3, 2 9 = 2 5 . 0 6 , P
< 0 . 0 0 0 1 , T u k e y ' s test) a n d t h e f r e q u e n c y of entries i n t o t h e o p e n a r m s w a s not m o d i f i e d as c o m p a r e d w i t h t h e c o n t r o l rats (ANOVA F3, 29=0.98, P < 0 . 4 1 , T u k e y ' s test).
P r e t r e a t m e n t w i t h t h e GABA receptor blocker b i c u c u l l i n e (1 m g / k g i.p.) did not block t h e increase in t h e p e r c e n t a g e t i m e s p e n t in t h e o p e n arms (ANOVA F3, 2 9 = 1 5 . 9 9 , P
< 0 . 0 0 0 1 , T u k e y ' s test) and it did not affect t h e m a r k e d i n c r e a s e in t h e f r e q u e n c y of entries into t h e o p e n a r m s o f t h e m a z e (ANOVA F3, 29=0.55. P < 0 . 6 5 , Tukey's test) as c o m p a r e d w i t h the control animals.
T h e i n c r e a s e in t h e percentage time s p e n t in t h e o p e n a r m s w a s n o t affected by pretreatment w i t h t h e 5 - H T r e c e p t o r b l o c k e r m e t h y s e r g i d e (0.5 m g / k g i.p.) (ANOVA F3, 2 8 = 5 1 . 7 3 , P < 0 . 0 0 0 1 , Tukey's test), a n d nor w a s t h e m a r k e d i n c r e a s e in t h e f r e q u e n c y of entries i n t o t h e o p e n a r m s (ANOVA F3, 28=0.5, P < 0 . 6 8 , Tukey's test) as
© Pearson Professional Ltd 1996 Neuropeptides (1996) 30(1), 59-65
6 4 Birö et al
c o m p a r e d w i t h t h e c o n t r o l rats. Pretreatment w i t h t h e e n d o g e n o u s o p i o i d s y s t e m blocker n a l o x o n e (0.1 m g / k g i.p.) d i d n o t b l o c k t h e increase in t h e p e r c e n t a g e t i m e s p e n t in t h e o p e n a r m s (ANOVA F3, 27=19.8, P < 0 . 0 0 0 1 , T u k e y ' s test), n o r t h e increase in the f r e q u e n c y of e n t r i e s i n t o t h e o p e n a r m s o f t h e e l e v a t e d p l u s - m a z e (ANOVA F3, 2 7 = 1 . 8 9 , P C 0 . 4 6 , T u k e y ' s test) as c o m p a r e d w i t h t h e c o n -trol a n i m a l s .
D I S C U S S I O N
T h e p r e s e n t r e s u l t s d e m o n s t r a t e that central administra-t i o n of B N P a n d C N P i n differenadministra-t d o s e s c a u s e d a n 'anxi-olytic-like' e f f e c t i n a n e l e v a t e d p l u s - m a z e paradigm.
B N P in d o s e s o f 100, 2 0 0 a n d 4 0 0 ng, a n d C N P in d o s e s o f 1 0 0 a n d 2 0 0 n g a b o l i s h e d t h e normal preference for t h e c l o s e d a r m s o f t h e m a z e , a n d increased t h e p e r c e n t -a g e t i m e s p e n t in t h e o p e n -arms; this is c o n s i s t e n t w i t h a n 'anxiolytic-like' effect. D o s e s of 5 0 a n d 1 0 0 0 n g BNP, a n d d o s e s o f 2 5 , 5 0 , 4 0 0 a n d 1 0 0 0 n g C N P p r o d u c e d n o b e h a v i o u r a l e f f e c t s i n t h e elevated p l u s - m a z e m o d e l . T h i s is i n a g r e e m e n t w i t h t h e results of p r e v i o u s s t u d i e s w h i c h d e m o n s t r a t e d 'anxiolytic' responses. Similar i n c r e a s e s i n g e n e r a l a c t i v i t y h a v e b e e n f o u n d for o t h e r 'anxiolytic' c o m p o u n d s , s u c h as chlordiazepoxide, d i a z e p a m a n d p h e n o b a r b i t o n e ,9 b o t h in t h e e l e v a t e d p l u s - m a z e test a n d in m o s t o t h e r tests of anxiety. Pret r e a Pret m e n Pret w i Pret h a p a d r e n o r e c e p Pret o r anPretagonisPret or a m u s -carinergic c h o l i n e r g i c b l o c k e r a n t a g o n i z e d t h e effect of 2 0 0 n g B N P in t h e e l e v a t e d p l u s m a z e test. A d o p a m i n e r -g i c blocker, a n a - a d r e n o r e c e p t o r anta-gonist, a GABA r e c e p t o r a n t a g o n i s t , a 5 - H T receptor antagonist a n d a n o p i a t e a n t a g o n i s t did n o t m o d u l a t e t h e 'anxiolytic-like' e f f e c t s of BNP. A d o p a m i n e receptor antagonist, or a n CL-OT p - a d r e n o r e c e p t o r b l o c k e r p r e v e n t e d t h e a n x i o l y t i c e f f e c t of CNP, w h i l e a m u s c a r i n e r g i c cholinergic blocker, a GABA r e c e p t o r a n t a g o n i s t , a 5 - H T receptor a n t a g o n i s t a n d a n o p i a t e r e c e p t o r a n t a g o n i s t did not block t h e effect of C N P . T h e e l e v a t e d p l u s - m a z e test h a s an a d v a n t a g e o v e r o t h e r c o n f l i c t t e s t s in that it requires o n l y t h e s p o n -t a n e o u s a c -t i v i -t y o f -t h e animals.
A v a r i e t y o f e v i d e n c e s u g g e s t s that m e m b e r s of t h e natriuretic p e p t i d e family affect n u m e r o u s n e u r o e n d o c r i n e s y s t e m s , i n c l u d i n g t h e h y p o t h a l a m o p i t u i t a r y -a d r e n o c o r t i c -a l -a n d h y p o t h -a l -a m o - n e u r o h y p o h y s e -a l -axes.
A N P c a n i n h i b i t t h e basal a n d CRF-induced release o f corticotropin,1 0 a n d o f vasopressin, t h e m o s t p o t e n t c o f a c t o r o f CRF in pituitary ACTI1 sccretion." In a previ-o u s s t u d y , w e f previ-o u n d a n 'anxiprevi-olytic-like' a c t i previ-o n previ-of A N P in a n e l e v a t e d p l u s - m a z e m o d e l of anxiety, a n d i n c r e a s e d CRFLI l e v e l s in d i f f e r e n t h y p o t h a l a m i c a n d e x t r a h y p o -t h a l a m i c brain r e g i o n s af-ter cen-tral A N P adminis-tra-tion
in rats ( u n p u b l i s h e d results). ANP, BNP a n d C N P are o f p o t e n t i a l i m p o r t a n c e in n e u r o e n d o c r i n e regulation, act-i n g a s n e u r o t r a n s m act-i t t e r s or neuromodulators act-in t h e brain, r e g u l a t i n g h o r m o n a l a n d cardiovascular f u n c t i o n s . It w a s p r e v i o u s l y reported that centrally administered e n d o t h e l i n i n d u c e d activation of t h e h y p o t h a l a m o -p i t u i t a r y - a d r e n o c o r t i c a l a x i s (increased ACTH secretion) w a s a t t e n u a t e d b y BNP.6 T h e inhibitory effects of B N P o n a n g i o t e n s i n I I - i n d u c e d dipsogenic, behaviour, pressor r e s p o n s e a n d v a s o p r e s s i n secretion were reported recently.1 3 A n a t o m i c a l localization indicates that C N P is c o n t a i n e d i n n e u r o n a l circuits h a v i n g a direct r e l e v a n c e t o s e v e r a l n e u r o e n d o c r i n e systems. T h e heaviest c o n c e n -tration o f C N P m R N A w a s o b s e r v e d in the anteroventral p e r i v e n t r i c u l a r n u c l e u s (AVPv), a region k n o w n t o regu-late t h e h y p o t h a l a m o p i t u i t a r y - g o n a d a l axis (LHRH release) a n d v a s o p r e s s i n release from t h e h y p o t h a l a m o -n e u r o h y p o p h y s e a l s y s t e m . I-n additio-n, localizatio-n of C N P t o t h e h y p o t h a l a m i c arcuate nucleus, t h e medial, m e d i a n a n d periventricular preoptic area, t h e supraoptic, d o r s o m e d i a l , v e n t r a l premamillary and lateral mamillary n u c l e i , a n d t h e posterior h y p o t h a l a m i c area3 h a s implica-t i o n s a s c o n c e r n s implica-t h e hypoimplica-thalamo-piimplica-tuiimplica-tary-gonadal f u n c t i o n a n d t h e r e g u l a t i o n of pituitary-adrenocortical s e c r e t i o n .
A N P1 3 1 4 a n d B N P1 5 1 6 participate in t h e processes of l e a r n i n g a n d m e m o r y . ANP, B N P and C N P h a v e b e e n f o u n d t o i n c r e a s e t h e severity of picrotoxin-kindled s e i z u r e s y n d r o m e in rats.17
In s u m m a r y , t h e p r e s e n t s t u d y appears to d e m o n s t r a t e that t h e 'anxiolytic-like' activity caused b y BNP c a n b e i n h i b i t e d b y p r e t r e a t m e n t w i t h a p-adrenoreceptor a n t a g o n i s t o r a m u s c a r i n e r g i c cholinergic blocker.
A d o p a m i n e r g i c blocker, a n aadrenoreceptor a n t a g o nist, a GABA r e c e p t o r antagonist, a 5HT receptor a n t a g o -nist a n d a n opiate a n t a g o n i s t did not m o d u l a t e t h e 'anxiolytic-like' e f f e c t s of BNP. A d o p a m i n e receptor a n t a g o n i s t , or a n a or padrenoreceptor blocker i n h i b ited t h e a n x i o l y t i c effect c a u s e d by CNP, b u t a m u s -c a r i n e r g i -c c h o l i n e r g i c blocker, a GABA receptor a n t a g o n i s t , a 5 - H T receptor antagonist and a n opiate r e c e p t o r a n t a g o n i s t did n o t block the effect of CNP. O u r e x p e r i m e n t s - a p p e a r i Q j n d i c a t e t h e i n v o l v e m e n t of differ-e n t n differ-e u r o t r a n s m i t t differ-e r s y s t differ-e m s in thdiffer-e mdiffer-ediation of B N P a n d C N P - i n d u c e d b e h a v i o u r a l action.
A C K N O W L E D G E M E N T S
T h i s w o r k w a s s u p p o r t e d by grants from the H u n g a r i a n M i n i s t r y o f Social Affairs a n d Health (T-i 1 5 4 9 / 9 3 ) a n d OTKA (T/3, 1 3 5 4 a n d T 6 0 8 4 , F 0 1 6 8 6 4 ) a n d FEFA ( 1 0 0 8 / 1 ) . .
Neuropeptides (1996) 30(1), 59-65 & Pearson Professional Ltd 1996
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THE E F F E C T S O F A T R I A L N A T R I U R E T I C P E P T I D E ( A N P , . « ) ON C O R T I C O T R O P I N R E L E A S I N G FACTOR I N B R A I N O F R A T S