Effects of β-endorphin and its fragments on inhibitory avoidance behavior in rats

PsLchoneuroendocrtnoh~g~, Vol. 8, No. 4, pp. 411 419, 1983.

0306-4530/83 $3.00 + 0.00 c 1983PergamonPressLtd.

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EFFECTS OF 13-ENDORPHIN A N D ITS F R A G M E N T S O N INHIBITORY A V O I D A N C E B E H A V I O R IN RATS GA,BOR L. KovAcs*, BI~LABOHUS~"and DAVID DE WIED Rudolf Magnus Institute for Pharmacology, Medical Faculty, University of Utrecht, Vondellaan 6, 3521 GD Utrecht, The Netherlands

(Received 3 December 1980; in final form 8 March 1983) SUMMARY The effects on retrieval of a one-trial learning inhibitory avoidance response of [3-endorphin, cc-endorphin, and y-endorphin, given prior to test have been studied in rats. 13-Endorphin (13-LPH ..... ) in a relatively low dose (1.5 lag sc. or 50 ng icv.) facilitated inhibitory avoidance behavior, while a higher dose (10 lag so. or 100 ng icv.) caused bimodal changes (facilitation in 50% of the animals and attenuation in another 40°7o. Peripheral injection of y-endorphin attenuated inhibitory avoidance behaviour in a dose-dependent manner. The C-terminus of 13-endorphin (I3-LPH,~_~,I was ineffective, c¢-Endorphin facilitated inhibitory avoidance behavior in a dosedependent manner. Naltrexone pretreatment antagonized the bimodal effect of [3-endorphin: following pretreatment with the opiate antagonist the low latency component disappeared, but the facilitatory effect of the neuropeptide remained the same. It is suggested that 13-endorphin carries more than one bit of behavioral information. Inherent activities either related or unrelated to naltrexone-sensitive opiate receptors as well as biotransformalion into c~- and "¢-endorphin may contribute to the multiple behavioral effects of this neuropeptide.

Key Words--f3-Endorphin;

a-endorphin; y-endorphin; inhibitory avoidance behavior.

E N D O R P H I N S , neuropeptides which derive from 13-1ipotropin (13-LPH), have been shown to influence central nervous functions other than nociception. Subcutaneous administration of 13-endorphin in subanalgesic doses increased resistance to extinction of a pole-jumping avoidance response and caused a shift in the dominant frequency of the hippocampal theta rhythm towards higher frequencies during paradoxical sleep episodes (De Wied et al. 1978a). Fragments of 13-endorphin, such as tt-endorphin (I3-LPH ..... ), 13-LPH6,-69 and met-enkephalin (I3-LPH6,_6s), show similar effects on avoidance extinction. ~/-Endorphin, on the other hand, facilitates avoidance extinction (De Wied et al., 1978b; Kir~ly et al., 1981; Le Moal et al., 1979). u-Endorphin and 7-endorphin affect inhibitory avoidance behavior in an opposite manner (De Wied et al., 1978a; Kov:~cs et al., 1981; Kovhcs & De Wied, 1981). In addition, ¢~-endorphin restores avoidance extinction of rats pretreated with the opiate antagonist naltrexone. Naltrexone itself, in doses which are lower than those necessary to block the antinociceptive action of peptides, *On leave of absence from the Institute for Pathophysiology, University Medical School, Szeged, Hungary. t T o whom correspondence should be addressed. Present address: Department of Animal Physiology, University of Groningen, P.O. Box 14, 9750 AA Harem The Netherlands. Correspondence to: Prof. Dr. B. Bohus, Dept. of Animal Physiology, University of Groningen, P.O. Box 14, 9750 AA Haren (Gn), The Netherlands. 411

412

GABOR L. KOVA~S, B[I ,x BOHt:S a n d D,X\ID D~ W r i t )

facilitates extinction behavior (De Wied et al., 1978a). These findings suggest that endorphins like enkephalins (Kastin et al., 1976; Rigter et al., 1977), may affect adaptive behavioral processes by actions which are independent from their analgesic properties. The aim of the present experiments was to analyse further the characteristics of the effects of graded doses of 13-, u- and y-endorphin. Retention of a one-trial learning inhibitory (passive) avoidance response was used as a behavioral measure. The peptides were administered shortly before the retention test. Preretention treatments are considered to affect retrieval of memory. It has been demonstrated that endorphins may influence retrieval processes (Bohus, 1980; Kova_cs et al., 1981). The influence of [3-endorphin was studied following both peripheral and intracerebroventricular administration with or without pretreating the rats with the opiate antagonist naltrexone. The other peptides were given subcutaneously only. The observations suggest that [3-endorphins may affect adaptive behavior through multiple mechanisms. The inherent behavioral potency of the peptide, via opiate or non-opiate mechanisms, and its probable transformation into shorter fragments such as c¢- and y-endorphin may contribute to the complex changes in passive avoidance behavior caused by [3-endorphin. ]\IATERIAI.S AND MFTH()I)% M a l e W i s t a r rats of an inbred s t r a i n l C P B - Y N O , Zeist, The Netherlands), ~'+cighing 160 1 8 0 g , xsere u',ed. The a n i m a l s were kept under a s t a n d a r d i l h n n i n a l i o n schedule (light on betx~,een 0500 and 1900 hr), x'+ere housed fi'+e per cage, and had free access to water and food.

Inhibitoo' fpas6ive) avoidance behavior I n h i b i t o r y a v o i d a n c e b e h a v i o r ++'+'asstudied in a one-trial learning, step t h r o u g h i n h i b i t o r y a v o i d a n c e situation (Ade:' et u/., 1972). The a p p a r a t u s consists of a d a r k c o m p a r t m e n t ~'+ith a grid floor and an i l l u m i n a t e d elevated p l a t f o r m attached to its front center. A guillotine d o o r connects the p l a t f o r m to the dark c o m p a r t m e n t . On da3 1, the a n i m a l s were h a b i t u a t e d to the dark c o m p a r t m e n t for 2 min. I m m e d i a t e l y after the h a b i t u a t i o n the rats were placed on the p l a t f o r m and allowed to enter the dark. Three more a p p r o a c h trials were given on the next day, ~ i t h an intertria] inter,,al of at least 10 min. Rats ~'+hich score a c o m p o s i t e latent?, (/1 31 sec or longer to e n t e r the dark d u r i n g these three trials are con',enlionally excluded from further experiments, but no a n i m a l s ~b~ad to be excluded in this p a r t i c u l a r study. At the end of the third trial, una,,oidable s c r a m b l e d electric l'oolshock (0.25 or 0.35 m A a.c. for 2 sec) ~'+as delivered t h r o u g h the grid floor of the dark c o m p a r t m e n t (,[,earning trial). The rats '+'+'ere removed from tile dark c o m p a r t m e m 10 sec after t e r m i n a t i o n of the shock. h'tki.bitory a v o i d a n c e b e h a v i o r ,.'+as tested 24 hr after the learning trial b?, placing the a n i m a l s on the p l a t f o r m and m e a s u i i n g the latency to re-enter the dark c o m p a r t m e n t . A cut-off time of 300 sec ~ a s used. The median a v o i d a n c e latenc~ ~'+as calculated and used as a measure of inhibitor,,' a'+oidancc beha'+ior. "-...

Electric jootshock responsiveness Re~ponsi'+'eness to electric footshock ++'+asinvestigated a c c o r d i n g to Gispen et al. (1970). T'+++o ',cls of l5 shocks varying, in intensity between 20 and 200 p.A ,,'+ere used. The d u r a t i o n of the shock ~ a s I sec, and the inter-trial interval."-,,,~ :'+,,as 60 sec. B e h a v i o r a l responses recorded at each shock level ~erc: ilo reaction, flinch, erk rull x,,lump and '+ocalization. The frequency of these responses d u r i n g the 30 trials ~'+as used as the index of shock respon';.iveness. Tre~ll/lletl I~ T r e a t m e n t s '+++ere given either s u b c u t a n e o u s l y or intracerebro'+entricularl_,,. [o~ intracerebro,,entricular a d m i n i s t r a t i o n of peptides, a plastic c a n n u l a v, as i m p l a n t e d into the lateral cerbral ventricle (l)e Wied, 1976). The rats `+'+'ereallowed to recover for four days before the behavioral experiments. Inl tax entricular treatment x~as p e r f o r m e d withoul restraining the rats. The peptides (13-endorphin, c~-endorphin, y+endorphin and 13-LPH-~ ,, ) x++ercdissol'+ ed it3 saline c o n t a i n i n g 10 Psi HCI. The final v o l u m e ',+'as 0.5 m l / r a t for s u b c u t a n e o u s and 1.0 Ill for i n t r a c e r e b r o v e n t r i c u l a r a d m i n i s t r a t i o n . C o n t r o l rats received the same v o l u m e of vehicle. M o r p h i n e sulfate and n a l t r e x o n e h y d r o c h l o r i d e were dissolved in saline.

ENDORPHIN AND AVOIDANCEBEHAVIOR

413

The peptides were given I hr prior to the retention lest o f the inhibitory avoidance response. Naltrexone was injected two hours before the behavioral testings in a dose of 90 ~g/rat. Morphine sulfate (30 mg/kg) was administered 30 min prior to testing of footshock responsiveness.

Statistical analysis Avoidance latencies and the behavioral responsiveness to electric fooishock were calculated as medians, and the differences were analysed by M a n n - W h i m e y ' s nonparametric test. Differences in the distribution of latencies were evaluated by X: test. ovoidon ce t o t e n c y (rnedion in sec ) 160 i i

F'I

120

80

F 0.2

1.5

10.0 ,ug

p - EN DORPHIN ( n-LPH 61- 91 ) FJ(;. 1. Effect of g,-endorphin (g,-LPH ..... ) on the retention of passive avoidance behavior. Bars with broken lines represent the median avoidance latencies in two sub-populations of rats. Subcutaneous treatment one hour prior to the retention test. Figures in bars indicate the numbers of rats. *p < 0.02.

RESULTS

Subcutaneous administration of 13-endorphin caused different effects on retrieval of inhibitory avoidance behavior, depending on the dose (Fig. 1). The latency of inhibitory avoidance response was not different from controls after the administration of 0.2 Bg/rat. A significant increase in avoidance latency was observed in rats receiving 1.5 Bg of 13-endorphin. Administration of 10 p.g of the peptide resulted in a decrease in the median of the latencies, but the difference was not significant. Analysis of the distribution of the avoidance latencies showed a bimodal distribution in rats which received 10 ~g of 13-endorphin. Fifty per cent of the rats scored lower and 40% scored higher latencies than the controls. This distribution pattern was significantly different from the controls. Bimodal distribution of the latencies was absent in rats which received 1.5 or 0.2 ~g of [3-endorphin. The group which was treated with 1.5 Bg showed an unimodal shift towards the higher latencies (Table 1). Figure 2 depicts the influence of y-endorphin and I~-LPHT,-9, on the retention of the avoidance response, ~'-endorphin in a dose of 10.0 lag per rat significantly attenuated inhibitory avoidance behavior. No effect of 0.5 or 1.5 p.g of this peptide was found. 13-LPHT,_9, failed to influence inhibitory avoidance behavior in any of the doses studied. A dose-dependent facilitation of inhibitory avoidance behavior was observed after the subcutaneous administration of ~-endorphin (Fig. 3).

414

GABOR L. KovA('s, BEI A BOHUS and DAVID DE WI[~I) TABLE I. DISTRIBUHON ()F PASSIVE AVOII)AN(E LAJI N('I[S FOI I ()V~IN(; St B( I. IANt OUS ,~DMINISTRATION OF VARIOUS ENI)ORPHINS

Treatment n

Saline (0.5 ml) ~,-Endorphin (10 ~tg) ct-Endorphin (10 ~tg) 7-Endorphin (10 ~g) [3-LPH-._~, (10 p.g)

Medians (sec)

Avoidance latency Distribution ( % ) ' Lob Medium High

p-

20 10

54 28

5 50

75 10

20 7(1

0.001

7

262*'

0

29

71

0.05

9

6*'

78

22

0

0.00 I

0

80

20

NS

5

61

'Mann - Whitney test; * p < 0.01. -'Distribution analysis by X'-test vs saline controls. ' L o w - latencies below 20 sec, Medium = latencies between 21 and 100 sec, and High = latencies above 100 sec.

ovoidonce totency (rr~lion-in sec) 160

120

80

40 o

9 SAt.

0.5

1.5

Z~- LPH(61-77)

lO.O~lg

;I I: 0.5

1.5

~-

lOB~g

LPH(7e-gl)

FI(;. 2. Effect o f y - e n d o r p h i n d 3 - L P H . , _ - - ) a n d D - L P H - . ~, o n the retention o f passive avoidance behavior. *p < 0.01. ( F o r other details see Fig. 1.)

The effects of intracerebroventricular administration of 13-endorphin are shown in Table II. Changes in inhibitory avoidance behavior depended on the dose of the peptide. As compared to saline-treated controls, no changes in median latencies and in the distribution of latencies were found after the administration of 10 ng [3-endorphin. A significant increase in median avoidance latencies and a shift towards the long latencies were observed in rats which received 50 ng [3-endorphin. The median avoidance latency in rats which were treated with 100 ng of D-endorphin was lower than in the controls. The distribution of latencies was bimodal and significantly different from the controls. Fifty per cent of the rats scored low, while 30% exhibited higher latencies. Pretreatment with naltrexone in a dose of 90 I.tg subcutaneously altered the inhibitory avoidance behavior of

415

ENDORPHIN AND AVOIDANCE BEHAVIOR TABLE II. PASSIVE AVOIDANCE BEHAVIOR FOLLOWING INTRAVENTRICULAR ADMINISTRATION OF B-ENDORPHIN IN NORMAl- AND NALTREXONE-PRETREATED RATS Treatment

Saline 13-Endorphin 10 ng 50 ng 100 ng Naltrexone (90 ~tg sc.) Naltrexone + 13-endorphin (100 ng)

Avoidance latency Distribution (°70)3 Low Medium High

n

Median (sec)

17

58

12

55

33

8 8 17 9

82 154" 19 94

13 0 53 22

50 12 18 33

37 88 29 44

NS 0.01 0.05 NS

10

78

20

30

50

NS

p2

' M a n n - W h i t n e y lest; *p < 0.05. 2X-" analysis; significance of differences vs saline-treated controls. SLow - latencies below 20 sec, Medium = latencies between 21 and 100 sec and High = latencies above 100 sec.

avoidance Latency (median insec) 28o

240

-I]

160 120 8O

~o~ ~ SAL

0.5

16

7

1.5

10.0~J

~-£NDORPHIN (/3-LPH61.76) F,(;. 3. Effect of u-endorphin (13-LPH~,_-~) on the retention of passive avoidance behavior. *p < 0.02; **p < 0.01. (For other details see Fig. 1.)

rats which received 100 ng of I~-endorphin. The median avoidance latency was not different from the controls, but no bimodal distribution of the latencies were observed. Instead, 50% of the rats showed longer avoidance latencies. Comparison of the distribution patterns of rats which received 100 ng of I~-endorphin alone or nahrexone and the peptide together showed a significant difference. Naltrexone pretreatment alone failed to alter inhibitory avoidance behavior.

G,XBOR L. KovAcS, BEIa BoHUs and DA\ID Df: Will)

416 TAB[ t

11I.

T H t - Icif:l-ECT ()1- M O R P H I N I SUI P H A T I

ANI) N A I I R t X O N t

tl'f I)R()( HI O R I I ) t

()N

El E ( T R I ( l OOFSftOCK RESPONSI\"[{NESS IN R&TS

Behavioral responses

Morphine (n = 6)

Naltrexone (n = 6)

14,0' 9.(J 0.0 0,0

3.0 8.5 13.5 7.0

No reaction Flinch Jerk, jump, run Vocalization 'Median values. * p < 0.02 a n d * * p < 0.01 (Mann

Naltrexone + morphine (n = 6) 2.0" 7.0 13.5"* (~.5"*

Whilneytest).

Table 111 shows that pretreatment with 90 ~tg of naltrexone significantly reduced the antinociceptive effect of morphine as determined with the electric footshock responsiveness test. Morphine administration resulted in a complete disappearance of vocalization, significant reduction of jerk, jump, run and flinch, and a consequent increase in no reactions. No difference was found between the groups which received naltrexone alone or naltrexone plus morphine, intracerebroventricular administration of [3-endorphin in a dose of 100 ng failed to alter electric footshock responsiveness (data are not shown). DISCUSSION

The present observations show that both peripheral and central administration of 13-endorphin profoundly influences retrieval of an adversively motivated behavior. The direction of the effects appears to be dose-dependent. Lower doses (both peripheral and central) facilitated inhibitory avoidance behavior. Higher doses (10 t.tg subcutaneously or 100 ng intracerebroventricularly) had both facilitatory and inhibitory effects on the investigated rat population. The similarity between the influences of peripherally and centrally administered [B-endorphin suggests that the peptide interacts with central nervous mechanisms independently from the route of administration. There are two alternative explanations for the diversity of the effects of 13-endorphin. On one hand, facilitation and attenuation of inhibitory avoidance behavior may be caused by different fragments of 13-endorphin. in this case, ]3-endorphin may be regarded as a source of behaviorally active peptides. On the other hand, [3-endorp'hin may have inherent behavioral activities, and the diversity of the actions might be caused by interactions with different opiate receptors in the brain. Former analysis of the influence of ]3-endorphin and fragments of this peptide on the extinction of an active avoidance response showed that, although 13-endorphin increases resistance to extinction, its potency was much lower than that of some fragments such as cc-endorphin (De Wied el al., 1978a). It was suggested that ]3-endorphin may carry more than one behavioral information, and the eventual behavioral effect may depend on biotransformation of the peptide into other fragments. This idea was supported by the findings of Austen el al. (1977), who reported the generation of y- and c~-endorphin from 13-endorphin in brain homogenates. Subsequently, Burbach et al. (1979, 1980) showed

ENDORPHIN AND AVOIDANCE BEHAVIOR

417

that I~-endorphin can be transformed into y- and ct-endorphin and their des-tyrosine' fragments by pH-dependent enzymes of brain synaptosomal origin. Furthermore, that a-and ~,-endorphin and their des-tyrosine~-fragments are present in rat brain and pituitary (Verhoef et al., 1980) also supports the possibility that 13-endorphin might have effects on avoidance behavior via biotransformation. Since y-endorphin and ct-endorphin differ in one amino acid residue (leucine) in position 77, the presence or absence of a single amino acid residue may determine the direction of action of these I~-endorphin fragments on avoidance behavior. It has been reported that administration of ),- and ct-endorphin immediately or shortly (up to 3 hr) after learning leads to opposite effects on later retention of an inhibitory avoidance behavior (Kov~cs et al., 1981). This time-dependent facilitation by et-endorphin and attenuation by ),-endorphin has been interpreted in terms of effects on consolidation of memory (Kovhcs et al., 1981; Kov~cs & De Wied, 1981). These peptides also affect retention behavior in an inhibitory avoidance test, when given shortly before the retention trial (Kov~.cs et al., 1981). Influences on active avoidance extinction have been observed when these peptides were administered 2 hr before the extinction session (De Wied et al., 1978a, b). These observations suggest that t~- and ~/-endorphin affect retrieval processes as well. The present findings reinforce this notion by showing dose-related opposite effects of ,i,- and c¢-endorphin on inhibitory avoidance behavior upon pretest administration. It remains to be shown whether the opposite behavioral changes are true memory effects or they are due to changes in performance by altered motivation, attention etc. The first described behavioral effects of I~-endorphin were typical opiate-like activities such as catatonia, antinociception, etc. (Guillemin et al., 1977; Loh & Li, 1977; Bloom e! al., 1976). In addition, disruption of learned and genetically determined behavioral patterns has also been reported (Meyerson & Terenius, 1977; Lichtblau et al., 1977). Furthermore, the opiate antagonist naloxone retards acquisition of active avoidance and habituation responses (lzquierdo, 1980), but enhances later retention of various behavioral responses upon post-learning administration (Gallagher & Kapp, 1978; Izquierdo, 1979; Messing et al., 1979). Our former observations (De Wied et al., 1978a) and the present experiments show that 13-endorphin influences avoidance behavior in amounts which are much lower than those required to induce antinociception. Furthermore, the opiate antagonist naltrexone failed to prevent facilitation of inhibitory avoidance behavior by low amounts of 13-endorphin (Bohus, 1980; Kovb.cs & De Wied, 1981). It has been concluded that 13-endorphin facilitates inhibitory avoidance behavior independently from naltrexone-sensitive opiate receptors. The finding that 1.5 ~tg of I~-endorphin facilitates retrieval of inhibitory avoidance reaction agrees with the observations of Izquierdo (1980), who found that pretest administration of 15-endorphin facilitates performance of an active avoidance and habituation task. Accordingly, facilitation of avoidance behavior by 13-endorphin is not restricted to a single task. Attenuation of inhibitory avoidance behavior by peripheral (10 Ixg) or central (100 ng) administration of 13-endorphin in the majority of the rats may have been due to an effect of the peptide on opiate receptors, in fact, intracerebroventricular administration of 13-endorphin (100 ng), although insufficient to cause catatonia or sedation (Holaday et al., 1978), induces vigorous grooming behavior in the rat. This behavioral effect can be

418

GABOR U. KOvAt.S, BEta BOHUS and DA~.II.',DE Will)

p r e v e n t e d b y p r e t r e a t m e n t w i t h a n o p i a t e a n t a g o n i s t ( G i s p e n et a l . , 1976). T h e p r e s e n t observations show that pretreatment with naltrexone, which completely blocked the a n a l g e s i c a c t i o n o f m o r p h i n e at t h e d o s e - l e v e l u s e d , p r e v e n t s t h e a t t e n u a t i n g e f f e c t o n passive avoidance behavior of intracerebroventricularly administered 13-endorphin ( 1 0 0 r i g ) . A c c o r d i n g l y , n a l t r e x o n e - s e n s i t i v e o p i a t e r e c e p t o r s s e e m t o m e d i a t e this behavioral effect of 13-endorphin. T a k e n t o g e t h e r , t h e p r e s e m e x p e r i m e n t s s u g g e s t t h a t [ 3 - e n d o r p h i n a n d its f r a g m e n t s have multiple effects on inhibitory avoidance behavior. The suppression of inhibitory a v o i d a n c e b e h a v i o r b y [ 3 - e n d o r p h i n is p o s s i b l y m e d i a t e d b y a c e r t a i n class ( n a l t r e x o n e s e n s i t i v e ) o f o p i a t e r e c e p t o r s . S i n c e y - e n d o r p h i n h a s a s i m i l a r k i n d o f a c t i v i t y in t h e i n h i b i t o r y a v o i d a n c e test, a n d t h e f r a g m e n t m a y b e f o r m e d f r o m [ 3 - e n d o r p h i n , it c a n n o t b e e x c l u d e d yet t h a t s u c h a b i o t r a n s f o r m a t i o n c o n t r i b u t e s t o t h e a U e n u a t i o n o f b e h a v i o r by [ 3 - e n d o r p h i n . F a c i l i t a t i o n o f i n h i b i t o r y a v o i d a n c e b e h a v i o r b y l o w e r d o s e s o f [ 3 - e n d o r p h i n m a y a l s o b e a n i n t r i n s i c a c t i v i t y o f t h e p e p t i d e via a n a l t r e x o n e - i n s e n s i t i v e mechanism. Contribution of biotransformation into c~-endorphin may also be considered, b u t f u r t h e r k n o w l e d g e a b o u t t h e in v i v o b i o t r a n s f o r m a t i o n o f 1 3 - e n d o r p h i n is n e c e s s a r y t o r e a c h a f i n a l c o n c l u s i o n o n t h e e x a c t r o l e o f e n z y m a t i c b i o t r a n s f o r m a t i o n in t h e a c u t e effects of 13-endorphin on inhibitory avoidance behavior. The peplides were donated by Dr. H. M. (;re,~en of Organon, B. V. Oss, The Netherlands. Endo 1 aboraloricn provided us ~vith nahrexone. This study ~as supported in part by Stichting Farmacologisch Studiefonds.

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