Postictal behavioral arrest in the rat: “catalepsy” or “catatonia”?

Life Sciences, Vol. 28, pp. 2287-2293 Printed mn the U.S.A.

POSTICTAL BEHAVIORAL ARR£ST IN THE RAT Michael S

Pergamon Press

"CATALEPSY" OR "CATATONIA''v

Myslobodsky and Mattl Mintz

Psychobiology Research Unlt Department of Psychology T e l - A w v Unlverslty (Recelved in f~nal form March 2, 1981) Summary A perlod of immob111ty following chemacall) (plcrotoxln, metrazol) or electrlcally-actlvated (maximal electroshock) convulsions was demonstrated to possess features of neuroleptlc-type catalepsy. During postictal ~ m m o b l h t y rats had w v l d rlghtlng and corneal reflexes and responded to the tall-plnch Like haloperldol-pretreated animals they were able to remain on the vertlcal grid or the horizontal bar for 15- 60 sec or longer. Yen-f~fteen mlnutes after seizure when catalepsy was minimal or not detectable, animals became totally unresponslve to pressure applied to the tall ("delayed analgesla") Systemzcally admlnlstered haloperldol (0 2S - 2 mg/kg) dld not affect postlctal catalepsy whlle naloxone (5 - i0 mg/~g) and apomorphxne (I0 mg/kg) reduced the duration of the immobility perlod. U n h k e naloxone, apomorphzne dlmlnlshed the Intensxt> of cataleptlc behav±or Higher doses of naloxone (20- 70 mg/kg) when in3ected durlng the postlctal period induced vxo!ent convulsions. None of the two drugs antagonlzed delayed analgesia Daily admnlstratlon of electroshock caused a bulld up of postictal rlgldlty and analgesla, coexisting with symptoms of catalepsy Naloxone antagonlsea rlgldlty but fa~led to interfere with catalepsy and analgesia. The term~natlon of a full-blown tonIc-clonlc convulsion leaves an animal temporarlly torpid (behavlorally "depressed", "paralysed") wlth drastically reduced responsiveness to environmental s~imull The mechanisms contrlbutlng to thls phenomenon are not clear The bellef that the primary dlsturbance in postlctal immobillty is chemical has long been plauslble, that it is a dlsturbance of neuro-chemlcal function is supported by observations that electrographic postlctal depression and postlctal behavior cml be modlfled by drugs that act on speclflc transmltters (9,15,17J The present study exanunes a posslb111ty that certaln endogenous active processes are impllcated in the postlctal behavloral qulescence Two major types of beha~1ora! syndrome ma) be hidden behind thls postlctal torpldlty, rlgld-catatonlc and flaccld-cataleptlc condltlons, both suggestlng involvement of extrapyranudal mechanisms Although "catatonla" and "catalepsy" are often used interchangeably, they have d l s s l m l a r behavloral profiles and Imply dlfferent categories of partlclpatlng transmatter systems (3,6,8,10,20]. If postlctal immoD111ty is regarded as either of these two behavloral syndromes, the area of search for the h>-pothetlcal transmztter system contrlbutlng to posticta! i m m o b l h t y could be narrowed to elther a system causlng oplate-type rlgld catatonla or neuroleptlc-type catalepsy 0024-3205/81/202287-07502.00/0 Copyrlgot (c) 1981 Pergamon Press Lt@

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Postmctal Behavioral Arrest

Vol. 28, No. 20, 1981

~thod Subjects and Con~alsants Experiments were performed on adult naive female Was. tar rats (IS0- 200 g) ma~ntaaned under controlled experimental condltlons w~th 12 hr l~ght-dark cycle. Selzures were activated c h e m c a l l y w~th either p~crotox~n (3- 4 mg/kg) or metrazol (30 -50 mg/kg) as described elsewhere (14,15) or electr~call> (maximal electroshock (~S)) through the intra-aureal or corneal electrodes [21) Drugs: Drugs used were haloperldol HCI (McNeil), apomorphlne HCI (Sandoz) and naloxone HCI (Endo). Haloperldol was admlnlstered 15 - 20 mln before the convulsant. Since about I0 man is requlred for the peak braln levels of naloxone to be reached it was admlnlstered 8- I0 man before the electroshock and 2 - 5 m~n after plcrotox~n, as the latter as known to' ~nduce convulsions wltn a cons~derable delay (17). During the apomorphlne pretreatment con~ulslons were actzvated when s~gns of stereotyp~c b e h a w o r s (snlff~ng, llckang, gnawing) were notzced. Drugs were a d m n i s t e r e d z.p ~n a volume of 1 0 ml/kg body weight Drug doses are expressed in terms of the salt. Behavloral tests Rats were placed a n d l w d u a ! l y in open rectangular plastlc boxes (45 x30 x 1 3 cm) for continuous observation of selzure development, gross abnormalltles of b e h a w o r , responses to noxlous s t l m u h (tail-plnch) ana corneal reflexes. The ta~l-plnch response was rated on a semlquantltatlve scale of 0 to 3 as aosent (0), present l!) when a clearly detectable forward motlon was emltted unaccompanled by a jerk, and moderate (2) when a clear forward or lateral avoldance response wlth or wathout vocal~sataon was emitted. The response was rated as strong (5) when the rat produced a tight devlatlon toward the tall accompanled by a squeak Thls was a typlcal response to the palnfal tall-plnch in normal rats (16) Rlgldlty was inspected by handling the rat and assessed on the basis of the results of the "bridge" test a posltlve score required that the rat would remain self-supportlng for I0 sec when placed across metal bookends (20) Catalepsy was evaluated by placing the rat on the ~ertlcal grld or the horizontal bar (6,18) The intenslty of the response was rated on a scale reflectlng the tlme that the rat remalned on the grld or the bar (I - not less than 15 sec, 2 and 3 - immobillty for not less than 30 and 60 sec respectively). Occaslonally rats were tested for catalepsy by placing one forepaw on a cork ~5 cm hlgh) wlth subsequent observatlon of body and head ammobiilt> Statlstlcal treatment Each animal was retested three times and the maximal score was recorded. Standard error of group mean values were calculated and the dlfference between means was determlned by the ×2 and Students t-test Results Durlng postlctal Immobillty all rats showed vlvld corneal and rlghtlng reflexes and shared reproducible behavloral patterns irrespectlve of the convulsant employed (Table i). Placed on the horlzontal bar, ~ertlcal grld or cork (data not shown), the rats would remaln in uncomfortable postures. Typlcally they stayed on the bar longer than on the grid. However, the rats were unable to sustaln themselves when placed between the two metal bookends for ten sec or longer after termlnatlon of seizure. Although the rlghtlng and corneal reflexes, as well as the response to the ta11-plnch, were detectable r~ght after cessation of seizure, the cataleptic featdres of behavior typlcally requlred I0- 30 sec to develop If tested earller the anlmals would passlvely "hang" rather than ~upport them-

Vol. 28, No. 20, 1981

Post~ctal Behavioral Arrest

selves on the bar and would prematurel>

2289

slide off the gr~d

All rats inltlallv showed reaction to the tail-p~nch. A low score of the response indlcates that the rat, although squeaklng, seldom exhlb~.ted a tight devlat~on of the body wlth circling component toward the tall as normal rats would typically do (16) Interest~ngl~, the ta~l-p~nch response was maximal w~th~n about 20 sec after seizure (values In Table 1 reflect thls period) wh~le 5 - 15 mxn later when cataleps~ was elther reduced or hardly detectable,the pressure applled to the taxl would leave the rat totall) unresponsive ("delayed analgesia") However, when the food pellets were placed on the floor of the cage during the testing, the ta11-plnch would produce voracious eating ~n 90% of animals. TABLE 1

*

Behavioral Profile of Postlctal I m m o b z h t y . Values represent the mean score (± S E bI ) %alue slgnzflcantly dlfferent from plcrotoxxn at p < 01 (t~o-talled)

~ertacal Grld

Horlzontal Bar

Con vul s ant

N

7al 1 -plnch

Metrazol

5

] 4 i 0 22

2 2 ± 0 11"

2.8 + 0.ii

Plcrotox~n

8

1.0 ± 0.18

3.0

2 8 ± 0.16

8

1.S -+ 0 18

2.5

Maxl ma I

Electroshock

*- 0 . 1 9

2 . 6 -+ 0 18

Notable differences of behavioral profiles were a l s o o b s e r v e d . Metrazol caused less consistent p e r f o r m a n c e on t h e v e r t i c a l grid since the rats would often slide off the grid after small residual postlctal jerks. S~mlar jerks after plcrotoxan would seldom interfere with the rats' performance unless a full-blown secondary seizure developed However, unlike metrazol and ~S, plcrotox~n would often cause oral dysklnetlc symptomatolo~" (che~lng, gnawing, teeth chattering). A l s o , p r e s s u r e a p p l i e d t o t h e t a ~ l was l e a s t e f f e c t i v e in ~nduclng eating behavior after plcrotoxxn. This con~,alsant even caused analgesia pre-lctally d u r i n g t h e " s e d a t i o n p h a s e " (17) Finally, t h e r i g h t i n g r e f l e x was V1Vld i n t h e m e t r a z o l and p l c r o t o x l n cond l t l o n s b u t d e l a y e d (1 - 2 r a n ) a f t e r ~ES e v e n t h o u g h t h e r a t s h a d n o r m a l c o r n e a l reflex and reactea to the taxi-pinch. Occasional sagns of rigidity when h a n d l i n g and " S t r a u b t a l l " were a l s o n o t i c e d a f t e r ~ I £ S P o s t ~ c t a l catalepsy in t h a s g r o u p may b e s o m e t x m e s s u p e r c e d e d o r i n t e r r u p t e d by a p e r x o d o f e x p l o s i v e behavior stmklngly slmlar to that developing after amygdalold kindling of epilepsy (15). Postlctal exc~tatlon ~as never noticed after chemacally activated convulsions. Drug effects Haloperldol (0.25- 2 mg/kg) dld not appreolably affect the postictal behavloral proflie except for the fac111tatlon of postlctal excmtatlon durlng the MES condltlon (jumping, bltlngi Naloxone (S - I0 mg/kg) tended to act in the same dlrectlon and in addltlon clearly shortened the duratlon of the • m m o b l h t y perlod, so that in most cases not more than 5 - 7 man were available to conduct a retest. Table 2, however, demonstrates that nelther naloperldol nor naloxone were able to slgnlflcantly change the scores of the rats' behavlor on the bar or grld

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Postictal Behavmoral Arrest

Vol. 28, No. 20, 1981

TAB LE 2 Effects of drugs onpostlctal catalepsy and ta~l-p~nch scores (Group mean±S.E.M.) * Value s~gn~f~cantly d~fferent from ~ S alone at p < 0S (two-ta~led)

Pretreatment (dose)

Convuls ant

N

Vertical Gr~d

Horizontal Bar

Ta~ l-p~nch

None

P~crotox~n ~ES

5 4

2.2 _+ 0 19 3

2 6 i 0 24 2.8 ± 0 25

1.4 +- 0.19 2.5 z 0.29

Haloper~dol (0.25 mg/kg)

P~crotox~n ~S

7 3

2 6 -+ 0 19 2 3 ± 0.28

3 3

1.4 z 0.30 1.5 ± 0.28

Apomorph~ne (i0 mg/kg)

P~crotox~n ~ES

4 4

2.0 -+ 0 57 2 2 + 0.25*

2.3 ± 0 25 1 0 ± 0.40

1 3 ± 0 47 2.3 -+ 0.47

Naloxone (i0 mg/kg)

P~crotox~n ~S

S 3

2 2 ~- 0 19 2.7 + 0.32

2.4 -+ 0 24 3

i -~ ± 0 19 1.7 -+ 0.66

Especlally important was the observatlon that naloxone admlnlstered before or after the selzure dld rot overcome delayed analgesla Small doses of naloxone (S- I0 mg/kgJ admlnlstered prlor to plcrotoxin aggravated convulslons but falled to antagonlse analgesla occurrlng elther durlng the "sedatlon phase" or postlctally A blg dose (20 - 70 mg/kg) admlnlstered after plcrotoxln-lnduced selzure or ~ S caused lethal selzures In a few anlmals, but did not reverse postlctal analgesla Pressure a p p h e d to the rats' tall may cause walklng or squeaklng, or vlgorous escape maneuvers wlth bltlng of any object placed In front of the anlmal but the rat would never attempt to execute the paln-dlrected response Apomorphlne acted in the dlrectlon of naloxone, shortenlng the duratlon of Immoblllty so that In three anlmals under apomorphlne, retest of thelr performance on the grld and bar was not posslble The intenslty of cataleptlc b e n a w o r was also reduced (Table 2) ~pomorphlne strlklngly facllltated exploslve behaw o r durlng the qES condltlon and falled to affect the ta11-plnch b e h a w o r immedlately after selzure ~llso, it did not interfere wlth delayed analgesla whlch developed after the symptoms of cataleptlc b e h a w o r vanlshed. Effect of repeated convulslons These data are summarlzed in Fig ! Dally Inductlon of ~ S caused the fam11~ar plcture of catalepsy Its Intenslty remalned on the same level through seven days of testlng Durlng the thlrd MES sesslon a bulld-up of rlgldlty was notlced wh~le at the fourth and subsequent sessions all rats were self-support~ng when placed across metal bookends ~ gradual decrease of latency of "delayed analgesia" was noted as the rats became w r t u a l l y unresponsive to the ta~_l-p~nch ~mmed~atel} after the sexzure The bu~id-up of analgesia was stat~stlcally s~gn~f~cant (×2 = 20 < p < 001) and roughly ~t pat3~ "' ralleled the development of r~g~dlt~ Naloxone pretreatment reduced rlg~dlty (F~g i), potentiated postzctai explosive b e h a w o r and appreciably shortened the duration of the ~mmob~l~ty period However, again the drug d~d not reduce the score of the cataleptic symptomatology when ~t was present Also, ~t dld not appreciably affect sensitivity to the ta11-p~nch Control MES delzvered the next morning resulted ~n a regular p~cture of rlg~d~ty wh~!e the ~at continued to show acceptance and retention of the pos~t~on assured on the gr~d or bar (F~g. I)

Vol

~

No. 20, 1981

Postlcta! Behavzoral Arrest

v)Q~

0 - - ---0 1 -" -'2

A

:S UJ

=

v;

:-:3

,4-1 v U,J

3'

r,

2-

<=

1-

I°'"

_I

o---.-~e---.--~-,----~

----~

I

UJ

:S O-

NALOXONE (lOmg/kg)

Fig. 1 Mean group (n =4) score (-+ S E.M ) of the grld, bar and ta11-plnch tests durlng dally admanlstratlon of MES Stlppled shadlng represents the perlod when slgns of rlgldlty were detected (i), (2) and (3) - b a r , vertlcal grld and taxl-p~nch scores, respectively. Note that naloxone zn3ected on day 6 antagonlzed r~g~dltv but not analgesia as determlned b} the tall-p~nch test. Dzscusszon These flndlngs clearly show that the postlctal syndrome may be composed of both "cataleptlc" and "catatonlc" symptoms, albelt for the development of fullblown rlgldlty, repeated convulslons were requlred Given that catalepsy slgnals the fsalure of the "antlcataleptlc" strlatal dopsmune (DA) system whlle rlgld catatonla suggests an involvement of the endogenous oplate system (3,20) It ~.s possible that both systems are z m p h c a t e d in postlctal immob11~ty However, except for the antlcataleptlc effect of apomorphlne the present flndlngs dld not lend sufflclent welght to the assumptlon that falllng DA system contributes to postlctal catalepsy In fact, though rats' postictal behavlor was remlnlscent of neuroleptlc catalepsy, haloperldol falled to intenslfy It Moreover, glven profound and lastlng catalepsy caused by halopendol in a dose of 2 mg/kg before the selzure, postlctal catalepsy of the regular Intenszty may suggest that convulslons reduce rather than potentlate neuroleptlc-lnduced catalepsy. Also, naloxone, whlch zs known to Inhzblt DA-medlated stereotyplc behaw o r and to act svnerglstlcally wlth halopendol (13) actually shortened the duratlon of postlctal immoblhty, i e. acted in the same dlrectlon as apomorphlne whlch Is thought to produce DA-related effects F1naliy, tall pressureinduced eatlng whlch is probaoly dependent upon the nlgrostrlatal DA system (I) was not altered postlctally. Interestlngly, after repeated electroshocks an increase In responslveness of DA neurons has oeen reported (2).

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Postzctal

Behavioral Arrest

Vol. 28, No. 20, 1981

There are some ~nd~cat~ons that endogenous opiates speczf~cally contribute to the post~ctal syndrome (9,12) Also, ~n the present study the bu~id-~p of r~g~d~ty during repeated seizures, reversed by naloxone, may be taken as an additional behavioral correlate of the recently reported ~ncrease of met-enkephal±ne ~n the hypothalamus and a number of l~mblc areas after repeated electroshock (I0). F~nally, apomorph~ne, ~h~ch ~s ~nown to antagonize morph~ne~nduced cataton~a (8) would readily overcome postzctal ~mmob~i~ty The d~ff~culty ~n entertaining th~s hypotnes~s zs largely due to the fact that 8-endorph~ne which ~as belzeved to have neurolept~c properties when a d m n~stered ~ntracerebrally (ii) has been argued to ~nduce r~g~d cataton~a wzth poor r~ght~ng and corneal reflexes ~20) Th~s symptomatology does not readily f~t the p~cture of post~ctal b e h a w o r observed ~n the present study Therefore, a h i n t e d B-endorph~ne contribution could be surmised only on the bas~s of naloxone revers~b~l~ty of r~g~dzty when repeated ~'ES was ~ntroduced An alternative candidate neuropept~de contr~butzng to post~ctal zmmob~l~t~ ~s des-tvros~ne-~-endorph~ne, whose effects are reportedly s~malar to those of haloper~dol (5) S~nce this neuropept~de apparently does not act w a DA receptor (S,22) ~t ~s not surprising that haloper~dol would not potentiate post~ctal toxp~d~ty However, these fznd~ngs are ~nsuff~c~ent to evpla~n the ~nab~!~ty of naloxone to overcome catalepsy and to antagon~se analgesia One ~,ay to ~nterpret th~s puzzlzng phenomenon ~s to suggest that the effects of naloxone were confounded by its side effects Indeed, naloxone is known to act as a GABA receptor antagonlst (7) Therefore, the drug may enhance braln excltablllty especlally when the latter was already ~itered due to postlctally decreased GABA level (19) Naloxone ep~leptogenlc~ty ~as noted ~n the present study and it zs not unllkely that increased m o b l h t y and jumplng beha~lor reflect braln excltab111tv increase ~hlch masked antlc~.pated pa~n-!nduced behavloral response ,~Iternatlvel>, the selzure ~tself may have a~srupted the routinized sensory--motor pattern of defensive b e h a w o r . It has been demonstrated that postural and c~rcl~ng components of the ta~l-p~nch reaction are most closely related to the rats' rotation behavior under amphetamine (i~) Th~s particular component of b e h a w o r may be suppressed by the s)stem bringing post~ctal catalepsy to the fore Naloxone may have part~ally antagonized analgesia but deepened th~s a b n o r m a h t v as suggested by the present fzndlngs that locomot~on, eating b e h a w o r and squeaking produced by the ta~l-p~nch ~ould never lead to the ta~l-d~rected response Thus the poss~b*izty remains that d~fferent endogenous neuropept~des contributed to various aspects o~ the postzctal behaw o r a l syndrome Ackn o~ ledgement The study was supported by a grant from the H

Pardee Research

Fund

Re f e r e n c e s 1 2 3 4 S 6

-

S.H. AaNTELMAN, H SZEQW>i~,N, P C H I N and ¢ E FISHER, B i a l n R e s . 99 319-357 (1975) L A CHIODO a n d S M -~NTELVL4N, S c i e n c e ~10 7 9 9 - 8 0 1 ( 1 9 8 0 / B COSTALL a n d R J N ~ L O R , Psvchopharmacoi 3 4 _ a a - ~ a l (1974) G. bl DE HONTIS, M. C OLI~NQS, g SERK\, A TAGLI,%HONrE and J SCHEELKRUGER, E u r J Pharmacol 53 1 8 1 - 1 9 0 (1979~ D DE WIED, TINS, \ l a r c h 79-81 ( 1 9 7 9 ) G. DI CHI~,RA, ,~1 blORELLI, ,'1 L PORCEDDU a n ~ G [ GESSA, Neurosc,ence a 14S3-14~5 (19v9) ~. DINGLEDINE, L I~EKSE\ and E 8REDKER, Eur J Pharmacol 47 19-27 (1978)

Vol. 28. No. 20, 1981

8 9 I0 ii. 12 13. 14. 15. 16. 17. 18. 19. 20. 21. 22

Postlctal Behavlora! Arrest

2293

C. EZRIN-~ATERS, P. blULLER and P SEEMAN, Can J Physxol Pharmacol 54 516-519 (1976). H. FRENK, J. ENGEL Jr , R. F ACKERMANN, Y SHAVIT and J C LIEBESkIND, Brain Res. 167 435-440 (1979) J . S . HONG, J C. GILLIN, H. Y T IANC and E COSTA, Braln Res 1"7 273-278 (1979). Y F. JACQUET and N. MARKS, Sclence 194 632-634 (1976) R J. kATZ and K SCHMALTZ, Neurosclence Letters 19 85-88 (1980) B M. MOON, J. J FEIGENBAUM, P E CARSON and H L hLAW&NS, Eur J. Pharmacol 61 71-78 (1980). M. MYSLOBODSKY, Petlt Mal Eplleps~. A Search for the Precursors of WaveSpike Actlvlt), Acadermlc Press, Ne~ fork (1976). M MYSLOBODSKY, R F ACKERMANN and J ENGEL, Jr , Pharmacol B1ochem Behav. i! 265-271 (1979) M MYSLOBODSK~ and H. BRAUN, Pha_~nnacol. B1ochem Behav 15 743-745 (1980) M. S. ~9fSLOBODSKY and E S. VALENSTEIN, Epllepsla 21 163-175 (1980) M. C OLIA~NAS, G M DE MONTIS, G MUL&S and A TAGLIAMONTE, 5ur J. Pharmacol. 49 233-241 (1978). C E RIBAK, A B. HARRIS, J E. ~4UGHN and E ROBERTS, Sclence 205 211-214 (1979) D SEGAL, R G. BROWNE, F. BLOOM, N LING and R GUILLHMIN, Sclence 198 411-413 (1977). E. A. SWINIARD, Experlmental Models of Epilepsy ~ Manual for the Laboratory Workers, p 433, Raven Press, New hork (1972) ~. M. A. VERHOEVEN, H. M. ~AN PRAAG, P. A BO]FNER, A SUNIER, J. M. REEVEN and D. DE WIED, Lancet 1 1046-1047 (1978).