Bidirectional effects of beta-carbolines in rats with spontaneous petit mal-like scizures

Bruin Resrurch

Bulkfin,

0361-9230187 $3.00 + .OO

Vol. 19, pp. 327-335. e Pergamon Journals Ltd., 1987.Printed in the U.S.A

Bidirectional Effects of Beta-Carbolines in Rats With Spontaneous Petit Ma&Like Seizures C. MARES~A~X,*~’ M. VERGNES,*~ L. H. JENSEN,3 E. PETERSEN,5 A. DEPAULIS,*S G. MICHELETTI”? AND J. M. WARTERt

“Groupe de Recherche en Epilepsie E;xpPrimentale Winique Neur~~~giq~~e, C.H. U., 67091 Strasb(~arg Cedex, France Waboratoire de Near~ph~s~ul~gie, Centre de Neur~~himie du CNRS 5 rue Blaise Pascal, 67084 Strasbow-g Cedex, France and WS Ferrosan Research Division, Sydmarken 5, 2860 Soeborg, Denmark

MARESCAUX, C., M. VERGNES, L. H. JENSEN, E. PETERSEN, A. DEPAULIS, G. MICHELETTI AND J. M. WARTER. Bidirectional effects of beta-carbolines in ruts with spontaneous petit mal-like seizures. BRAIN RES BULL 19(3) 327-335, 1987.-Seven benzodiazepine-receptor ligands of the beta-carbolines’ group were administered IP in Wistar rats from (1) a strain displaying spontaneous petit mal-like seizures (PMLS) characterized by spike and wave discharges (SWD) and, (2) a strain where no seizure is ever observed (NS). Five different types of effects were observed. (1) Injection of a full agonist (ZK 93 423) suppressed SWD in PMLS rats, in a dose-dependent manner, and induced marked sedation with alteration of EEG background activity; (2) Injection of partial agonists (ZK 95 962, ZK 91 2%) suppressed SWD in PMLS rats without sedation; (3) Injection of low doses of a full inverse agonist (DMCM) significantly increased the total duration of SWD in PMLS rats and induced SWD in NS rats. Higher doses of DMCM induced convulsions in both strains; (4) Injection of partial inverse agonists (FG 7142, ZK 90 886) aggravated SWD in PMLS and induced SWD in NS rats. FG 7142 induced convulsions only in PMLS animals, whereas no convulsions were ever observed with ZK 90 886; (5) Injection of an antagonist (ZK 93 426) did not significantly modify SWD in PMLS rats. However, this compound was able to reverse both ant~epileptic effects of agonists and epileptogenic effects of inverse agonists. These results suggest the involvement of the benzodiazepine-GABA receptor complex in the control of petit mal-like seizures in rats. Benzodiazepine

Receptor

Beta-carboline

Epilepsy

to Dr. C. Marescaux,

Rat

can be reversed by a subsequent injection of RO 1.5-1788, a BZD antagonist [ 181. Recently, a new group of BZD-receptor ligands, the beta-carbolines-which are chemically distinct from BZDs-has been described. According to both electrophysiological and biochemical data, these compounds have three possible physiological effects: the agonists facilitate the GABA-induced opening of the chloride ionophore and the binding of GABA agonists whereas the inverse agonists have the opposite effects, and the antagonists have no effect 11, 2, 11, 12, 311. In this respect, the beta-carbolines provide a useful pharmacological tool for the study of the involvement of BZD receptors in the genesis and/or the control of petit mal epilepsy. In the present study, the effects of systemic administra-

SPECIFIC binding sites for benzodiazepines (BZD) have been demonstrated within the central nervous system of mammals (e.g., [9,34]) and it has been shown that these BZD receptors modulate the activity of the GABA-chlo~de ionophore receptor complex [3, 8, 26, 33, 351. BZDs have suppressive effects in most of experimental models of epilepsy (for review see [28,39]). Spontaneous and recurrent paroxysmal EEG discharges have been recorded in various rodents and in Wistar rats from our breeding colony (for review see [15,40]). This EEG pattern appears to correspond to an eiectroencephalo~aphic model of spontaneous and genetically determined petit mallike seizures [19, 21, 24, 401. In this model, we have shown that systemic administration of BZDs suppresses spike and wave discharges [lo, 20, 241. Furthermore, such an effect ‘Requests for reprints should be addressed Cedex, France.

Petit ma1

Clinique Nellrologique,

327

C.H.U.,

1 Place de l’hopital, 67091 Strasboutg

328

MARESCAUX TABLE SUMMARY

Ligands

1

OF EFFECTS OF THE BETA-CARBOLINES USED IN THIS STUDY ON SPIKE AND WAVES DISCHARGES TWO STRAINS OF RATS (PMLS: PETIT MAL-LIKE SEIZURE; NS: NO SEIZURE)

Classification

Doses (mgkg)

PMLS

IN

NS

ZK 93 423

Full Agonist

0.5-4 >I

suppression (sedation + EEG abnorm.)

ZK 95 962

Partial Agonist

0.25-2

suppression

-

ZK 91 296

Partial Agonist

1-16

suppression

-

ZK 93 426

Antagonist

I-10 20

no effect* slight suppression

_* -

ZK 90 886

Partial Inverse Agonist

no effect enhancement

no effect slight induction

FG 7142

Partial Inverse Agonist

2.5-40 >5

enhancement (convulsions)

induction (no convulsion)

DMCM

Full Inverse Agonist

0.25-2 l-2

enhancement (convulsions)

induction (convulsions)

lo-20 40

ET AL.

*Antagonism of agonist (ZK 93423) and inverse agonists (FG 7142 and DMCM) EEG effects.

tion of seven different beta-carbolines

were examined in our model of petit mal-like seizures in the Wistar rat.

L,sa ZK 96962

ZK 93423

METHOD

0

Animals Male Wistar rats (400-500 g) were used in this study. They were chosen from two strains of rats which have been selected in our laboratory. In the first strain (petit mal-like seizure: PMLS strain), g-10 Hz bilateral spike and wave discharges (SWD) which last 5 to 50 set and which commonly appear once per minute can be electroencephalographically recorded in 100% of the animals. These SWD are concomitant with behavioral arrest and rhythmical twitches of the vibrissae, and sometimes facial myoclonus. In the second strain (No seizure: NS strain), no SWD are ever observed in any of the animals. All animals were implanted under pentobarbital anaesthesia (40 mg/kg, IP) with 4 stainless steel electrodes aimed bilaterally at the frontal and parietal cortex, as previously described [40]. The animals were allowed at least a week for recovery before the first experiment.

0

100

0.25

0.5

0

300 [secl

LA-Al

2

1

I

Z

ZK 91296

I

1

I

‘

K 93426

Q 0 5

20

loa

EEG Recordings The electroencephalograms (EEG) were recorded from ipsilateral fronto-parietal electrodes. After a 15 min habituation period to the test cage, the EEG was recorded for a 20 min reference period. The drug under study was then injected and the EEG was recorded continuously for up to two hours. During the recording periods, the freely moving rats were continuously watched and were prevented from falling asleep by gentle sensory stimulation. EEG recordings were analyzed by consecutive 20 min periods: background activity, occurrence of convulsive seizures and cumulative duration of SWD.

-20

0 tinj

80

-20

0 tinj

80 [min)

FIG. 1. Effects of ZK 93 423, ZK 95 962, ZK 91 296 and ZK 93 426 on mean cumulative duration of SWD per 20 min periods pre- and postinjection in PMLS rats (N=g to 10). The results obtained for some intermediate doses have been omitted for the sake of cfarity. Full symbols: n.s. when compared to control (dose 0); half open symbols: ~~0.05; open symbols: ~~0.01 vs. control condition.

BETA-CARBOLINES

AND PETIT MAL-LIKE

329

SEIZURES

FIG. 2. EEG patterns in PMLS rats injected with ZK 93 423, ZK 95 962 or ZK 91 296. Vertical bar: 200 JAV; Horizontal bar: 2 sec.

ZK

FG

90888

OMCM

7142

300 csec1

500 (8OCl

FG

2 K ~0866

DMCM

7142

2,

40

40

v ~

1oc

20 20 0

/ 100

0.5

Oa -20

1 f

‘

0 t Inj

80

-20

0 iinj

80

-20

0 linj

80

5

fminl C

FIG. 3. Effects of ZK 90886, FG 7142 or DMCM on mean cumulative duration of SWD per 20 mm periods pre- and postinjection in PMLS rats (N=8). Full symbots: ns. when compared to control (dose 0); half open symbols: p
-20

0 tinj

60

-20

-

4

80

-20

0 I ini

t

60 IminI

FIG. 4. Mean cumulative duration of SWD per 20 min periods induced in NS rats (N=lO) by injections of ZK 90 886, FG 7142 and DMCM. No statistical analysis was performed on this data.

330

MARESCAUX

ET AL.

FIG. 5. EEG recording showing SWD induced in NS rats by injections of ZK 90 886, FG 7142 and DMCM. Vertical bar: 200 pV; Horizontal bar: 2 sec.

Drugs Seven different beta-carbolines from either Ferrosan or Schering Laboratories were used in this study (Table 1). They were all suspended in a mixture of Tween 80 (2 drops per 10 ml of 0.9% NaCl) prepared on the day of the experiment. All drugs were injected IP in a volume of 2 ml/kg.

RESULTS

Infrin~ic Effects of ~et~-~~rb~li~es

k PMLS Rats

In this experiment, the effects of seven different betacarbolines (see Table 1) were examined in PMLS rats (one group per drug). The rats in each group received all doses of the given drug including dose 0 (i.e., vehicle only), so that they were used as their own control. The groups were composed of 8 rats, except the ZK 93 426 group composed of 10 animals. A one week recovery period was allowed between two injections. For each chug, the EEG was recorded for 80 min after the injection. For each animal, the SWD duration in set during the reference period and the four consecutive 20 min postinjection periods were measured. The results were expressed in mean cumulative SWD duration for each 20 min period and were analyzed within each period using a non-parametric analysis of variance for related samples (Friedman test). Experimental versus control conditions (dose 0) were then compared using the Wilcoxon test. Systemic administration of ZK 93 423 (0.5 to 4 n&kg), ZK 95 %2 (0.25 to 2 n&kg) and ZK 91 2% (1 to 16 n&kg) significantly suppressed SWD in PMLS rats in a dose-

dependent fashion for more than 80 min postinjection when compared to control treatment (Fig. 1). These 3 compounds differed in terms of EEG background activity. Injection of doses of ZK 93 423 greater than or equal to 1 m&g induced behavioral signs of sedation which were confirmed by a slowing down of the EEG activity along with numerous rapid beta rhythms (Fig. 2). On the contrary, only a slight sedation was observed following treatment with ZK 95 962, and some rapid beta rhythms were recorded at the dose of 1 mglkg (Fig. 2). Administration of ZK 91 2% at doses up to 16 mg/kg did not modify the EEG background activity (Fig. 2) and did not induce sedation. Injections of ZK 90 886, FG 7142 and DMCM significantly increased the total duration of SWD. The aggravating effect of ZK 90 886 was significant only at the dose of 40 mg/kg (Fig. 3). No convulsive seizure was observed with this compound. Ad~nis~atio~ of FG 7142 (2.5 to 40 mg&g) significantly increased the total duration of SWD for 80 min in a dosedependent fashion (Fig. 3). In addition, at doses greater than or equal to 5 mg/kg, this compound induced short convulsive seizures in some animals, between 20 and 80 min after the injection. Injections of small doses of DMCM (0.5 mg/kg or below) si&ficantly increased the total duration of SWD for 40 to 60 rnin (Fig. 3>. Administration of doses superior or equal to I mg/kg induced in all animals long lasting and repeated tonic-clonic convulsions always appearing during the first 20 min postinjection period. No s&&cant or dose-dependent m&cation of the EEG background activity or duration of SWD was noticed following the administration of 5 to 20 mg/kg of ZK 93 426.

BETA-CARBOLINES

AND PETIT MAL-LIKE

331

SEIZURES TABLE 2

CONVULSIVE

EFFECTS OF FG 7142 AND OF DMCM IN PMLS fN=lO) AND NS fN= 10) RATS NS

PMLS

Doses (mg/kg) FG 7142 5 10 20 40 DMCM 0.5 1.0 2.0

Nb Animals With Convulsions

1 4* 7* ii* 0 7 10

2 5* 8* 7* 0 9 25

The animals were observed during 100 min postinjection *~~0.02; PMLS vs. NS.

At high doses (20 mgikg), however, this compound decreased the duration of SWD (Fig. 1).

slightly

Comparisons of ~p~leptogen~c Effects of ZK 90 886. FG 7142 and DMCM Between PMLS and NS Rats Six groups of 10 PMLS rats and 6 groups of 10 NS rats were used to study the epileptogenic effects of ZK 90 886, FG 7142 and DMCM. In order to avoid any “kindling effect,” each rat was injected once and a few animals were treated twice with an interval period of at least 15 days. After the reference period, each dose of each drug was injected. EEG was recorded for 60 min after DMCM and for 100 min after FG 7142 and ZK 90 886. For each dose of these compounds the number, the latency and the duration of convulsive seizures were compared in PMLS and NS animals using a chi-square test. In NS animals the occurrence of SWD similar to those recorded in PMLS rats was controlled, and their mean cumulative duration per 20 min period was measured. No statistical analysis was performed on this data. Administration of ZK 90 886 (10 to 40 mg/kg) did not result in any convulsion either in the PMLS or the NS animals. In 3 out of 10 NS rats, a few bilateral brief SWD similar to spontaneous ones in PMLS rats were observed for doses superior or equal to 20 mg/kg (Figs. 4 and 5). Following injection of FG 7142 (5 to 40 mg/kg) convulsions were observed in the PMLS animals (Table 2, Fig. 6). No convulsion was observed with this compound in NS rats, beside one animal injected with a dose of 40 mg/kg (Table 2). In these latter animals, injection of FG 7142 induced long lasting SWD in all animals. These seizures were very similar to spontaneous SWD as observed in PMLS rats (Figs. 4 and 5). Ad~nistration of DMCM (1 and 2 mg/kg) induced repeated convulsions in both all PMLS and NS animals (Table 2 and Fig. 7). In addition, administration of this compound induced SWD in NS rats at doses superior or equal to 0.5 mg/kg (Figs. 4 and 5). Antagonism of Antiepiieptic 426 in PMLS Rats

Effects of ZK 93 423 by ZK 93

One group of PMLS rats (N=4) was used to study the

Total Number of Convulsions

Nb Animals With Convulsions

Total Number of Convulsions

0 0 0 1

0 0 0

0 7 10

0 11 22

1

for FG 7142 and during 60 min for DMCM.

antagonism of antiepileptic effects of ZK 93 423 (2 mg/kg) by ZK 93 426 (10 me/kg). In a first experiment, after a 20 min reference period, the animals were injected with ZK 93 423 (2 mg/kg) followed, 20 min later, by an injection of either ZK 93 426 (10 mglkg) or vehicle. In a second experiment, the rats were injected, after a 20 min reference period, with ZK 93 426 (10 mg/kg) or vehicle only followed 20 min later by an injection of ZK 93 423 (2 mg/kg). A week of recovery was allowed between two experiments. Because of the small number of animals used in this experiment, no statistical analysis was performed on this data. Both pre-treatment or post-treatment with ZK 93 426 (10 mg/kg) antagonized ZK 93 423-induced suppression of SWD in all PMLS rats when compared to control condition (i.e., ZK 93 423 + vehicle) (Fig. 8). Injection of lower doses of ZK 93 426 (2.5 and 5 mglkg) were found to be less efficient to reverse the antiabsence effects of ZK 93 423 (data not shown). Antagonism of Epileptogenic by ZK 93 426 in NS Rats

Effects of DMCM and FG 7142

Four groups of NS rats (N=S) were used in this experiment. After a 20 min reference period, the animals were injected with ZK 93 426 (2 groups with 0 mg/kg and 2 groups with 1 mg/kg). After the injection, the EEG was recorded for 20 min. The animals were then injected with either FG 7142 (10 mglkg) or DMCM (1 mg/kg). The EEG was again recorded for 2 periods of 20 min. The number of rats with convulsions and/or absences was counted. ZK 93 426 pre-treatment completely abolished both convulsions and SWD induced in NS rats either by FG 7142 or DMCM (Table 3). DISCUSSION

Electrophysioiogical, biochemical and behavioral effects of the BZD receptor ligands allow for their classification in three overlapping groups [l, 2, 11, 31, 331. (1) The agonists, like the classical BZDs, are anxiolytic, hypnotic, anticonvulsant, myorelaxant and amnesic; (2) the effects of the inverse agonists are opposite to those of BZDs (i.e., they are anxiogenic , convulsant and increase arousal); (3) the

332

MARESCAUX

BEFORR

AFTER

FIG. 6. EEG recording before and after injection of FG 7142 in a PMLS rat. SWDs are increased and a convulsion is induced (lines 6 and 7). Vertical bar: 200 yV; Horizontal bar: 2 sec.

BEFORE

DMCM

,. iT__. .

143764

.

._

AFTER

FIG. 7. EEG recording before and after injection of DMCM in a PMLS rat. After DMCM, a convulsion is induced (lines 4 and 5). Vertical bar: 200 pV; Horizontal bar: 2 sec.

ET AL.

BETA-CARBOLINES

300 (SSCI

AND PETIT

1t

MAL-LIKE

333

SEIZURES

\

TABLE 3

,s:,

ANTAGONIST EFFECTS OF ZK 93 426 ON FG 7142-INDUCED SWD AND DMCM-INDUCED SWD AND CONVULSIONS IN NS RATS (N=S)

Drugs (m&g) Saline ZK 93 Saline ZK 93

:\... O423[2lt

ttl

6 t

1423[21

423(21t

42mo1t

8 0 8 0

Nb of Rats With Convulsions 0 0 6 0

t426ClOl

1423(21

FIG. 8. Antagonism of ZK 93 423 (2 mg/kg)-induced antiabsence effects by pre- and post-treatment with ZK 93 426 (10 mg/kg). Data are expressed as mean cumulative SWD duration per 20 min periods (N=4). No statistical analysis was performed on this data.

reverse the effects of both agonists and inverse agonists without any intrinsic activity. However, agonist and/or inverse agonist activities have been reported for some antagonists [5, 12, 181 and it has been suggested that these compounds can act as partial agonists and/or partial inverse agonists of the BZD receptors. Our study using both PMLS and NS rats is in agreement with this classification (see Table 1). ZK 93 423, which has been considered in several studies as a full agonist [2, 17,22,38], suppressed spontaneous SWD and induced sedation as noticed from both EEG recording and behavioral observation. In addition, administration of this compound induced an alteration of EEG background activity. We have previously reported a similar effect following administration of diazepam [lo]. ZK 95 962 and ZK 91 296, which have been classified as partial agonists [2, 10, 17, 23, 321, suppressed spontaneous SWD but did not modify EEG background activity, nor induce any sedative effects. Our data, along with previous studies [lo, 17, 231, suggest that these two compounds are more selective antiepileptics than BZDs. DMCM is a full inverse agonist in all the models studied [l, 2, 4, 11, 22, 29, 301. In our study, this compound increased SWD in PMLS rats and induced SWD in NS animals. In addition DMCM could induce convulsions in both PMLS and NS rats. ZK 90 886 and FG 7142 are generally considered as partial inverse agonists [6, 11, 12, 27, 30, 311. Both increased spontaneous SWD in PMLS rats and induced SWD in NS animals as did full inverse agonists. These two compounds never induced convulsive seizures in NS animals. However, FG antagonists

+ FG 7142 (10) 426 (I) + FG 7142 (10) + DMCM (1) 426 (1) + DMCM (1)

Nb of Rats With SWD

7142 induced convulsions in some PMLS rats. In most experimental models of epilepsy, administration of FG 7142 alone does not induce convulsions, whereas it can facilitate them when it is associated with the administration of an epileptogenic compound at subconvulsive doses [ll, 12, 161. Following chronic administration of FG 7142, the animals become more sensitive to this compound and convulsions generally occur [ 161. This effect has also been reported following chronic administration of other beta-carbolines and has been considered as a kindling effect [16,25]. In our study, PMLS animals are more sensitive to convulsive effects of FG 7142. A similar difference in sensitivity has been observed with other beta-carbolines in other genetic models of epilepsy [ 141 and may result from either a genetical difference in the absorption/metabolism of the compound and/or a genetical biochemical dysfunction which correlates with the genesis of the seizures [4, 7, 361. ZK 93 426 generally acts as an antagonist with weak partial agonist effects [13,17]. In our model, it had very little effect per se, although it slightly reduced SWD in PMLS rats. On the contrary, it significantly reversed antiepileptic effects of ZK 93 423 as well as epileptogenic effects of DMCM and FG 7142. These results provide further support to the evidence that these three compounds act on the same receptor. A similar antagonism was obtained with RO 151788, another BZD receptor antagonist, following injection of diazepam in our PMLS rats [18]. In our model of petit ma1 epilepsy, the effects induced by the beta-carbolines used (i.e., full agonists, partial agonists, antagonists, partial inverse agonists and full inverse agonists) constitute a continuum correlated with their activity at the receptor level. Similar results have been reported with beta-carbolines-as well as with other ligands of the BZD receptors-in other models of epilepsy and in behavioral models for the study of anxiety [l, 5, 11, 12, 28, 301. However, according to the species, the experimental conditions or the mode of administration, the same compound can act either as a partial agonist, an antagonist or an inverse agonist [4, 5, 22, 311. In our model, FG 7142 was an inverse agonist more potent in inducing convulsions in PMLS and SWD in NS rats than ZK 90 886, while in other studies using different test situations [ 11,301 this latter compound has been shown to be more potent. In other models, antiepileptic effects have been reported for high doses of FG 7142 [ 15,3 11. In conclusion, it appears that our genetic model of petit ma1 absences is very convenient for analysing the neurophysiological effects of the BZD-receptor ligands such as the beta-carbolines, as well as imidazodiazepines and quinolones ([18] and unpublished data). The sensitivity of the

334

MARESCAUX

PMLS rats to these ligands and the possibility to induce SWD in NS animals as a result of administration of inverse agonists (see also [37]) suggest a possible involvement of BZD receptors in the elicitation of this form of epilepsy. Two hypotheses can be formulated from our data. First, some functional modifications of BZD receptors might be responsible for the induction of petit ma&like seizures. However, recent results obtained in rats from our laboratory failed to show any difference between PMLS and NS

ET AL.

animals, in both affinity and number of BZD receptors of the central type (Rouj~sky, personal communization). Second, the possible existence of an endogenous ligand with inverse agonist properties would account for the development of petit mal-like seizures. Further studies will examine these hypotheses.

We thank Any Boehrer for her valuable technical assistance.

REFERENCES 1. Braestrup, C., T. Honor&, M. Nielsen, E. N. Petersen and L. H.

Jensen, Ligands for benzodiazepine receptors with positive and negative efficacy. Biochem Pharmacol3.3~ 859-8621 1984. 2. Braestruo. C.. R. Schmiechen. G. Neef. M. Nielsen and E. N. Petersen: Interaction of convulsive ligands with benzodiazepine receptors. Science 216: 1241-1243, 1982. 3. Costa, E., M. G. Corda, B. Epstein, C. Forchetti and A. Guidotti. GABA-be~odi~epine interactions. In: The Benzodiazepines:

From

Molecular

Biology

to Clinical

Practice,

edited by E. Costa. New York: Raven Press, 1983, pp. 117-136. 4. Croucher, M., G. de Sarro, L. Jensen and B. Meldrum. Behavioural and convulsant actions of two methyl esters of &carboline-3-carboxylic acid in photosensitive baboons and in DBAl2 mice. Eur J Pharmaco~ 100: 55-60, 1984. 5. File, S. E., R. G. Lister and D. J. Nutt. The anxiogenic action of benzodiazepine antagonists. Neuropharmacology 21: 10331037, 1982.

6. File, S. E. and S. PelIow. The anxiogenic action of FG 7142 in the social interaction test is reversed by chlordiazepoxide and Ro IS-1788 but not by CGS 8216. rlrch In? Pharmacodyn Ther 271: 198-205,

1984.

7. Fisher, T. E., L. G. Davis, J. M. Tuchek, D. D. Johnson and R. D. Crawford. Benzodiazepine receptors and seizure susceptibility in epileptic fowl. Can .! Physiol Pharmucol63: 85-88, 1985. 8. Haefely, W. Benzodiazepine interactions with GABA receptors. Neurosci Left 47: 201-206, 1984. 9. Haefeiy, W., P. Pole, L. Pieri, R. Schatfner and J. P. Laurent. Neu~ph~ma~ology of ~nzodi~epines; synaptic mechanisms and neural basis of action, In: The Benzodiazepines: From Molecular to Clinical Practice, edited by E. Costa. New York: Raven Press, 1983, pp. 21-66. 10. Jensen. L. H.. C. Marescaux. M. Vergnes, G. Micheletti and E. N. Petersen. Antiepileptic action of the p-carboline ZK 91296 in a genetic petit ma1 model in rats. Em J Pharmac~~f 102: 521-524, 1984. 11. Jensen, L. H. and E. N. Petersen. Bidirectional effects of benagainst picrotoxinand zodiazepine receptor ligands pentylenetetrazol-induced seizures. J Neural Transm 58: 183191, 1983. 12. Jensen, L. H., E. N. Petersen and C. Braestrup. Audiogenic seizures in DBA12 mice discriminate sensitively between low efficacy benz~iazepine receptor agonists and inverse agonists. Life Sci 33: 393-399, 1983. 13. Jensen, L. H., E. N. Petersen, C. Braestrup, T. Honor& W. Kehr, D. N. Stephens, H. Schneider, D. Seidelmann and R. Schmiechen. Evaluation of the p-carboline ZK 93 426 as a benzodiazepine receptor antagonist. Psychopharmacology (Beriin) 83: 249-256, 1984. 14. Johnson, D. D., T. E. Fisher, J. M. Tuchek and R. Il. Crawford.

Pharmacology of methyl- and proply-@carboIines in a hereditary model of epilepsy. Neuropharmacofogy 23: 1015-1017, 1984. 1.5. Kaplan, B. J. The epileptic nature of rodent electrocortical polyspiking is still unproven. Exp Nemo1 88: 425-436, 1985. 16. Little, H. J., D. J. Nutt and S. C. Taylor. Acute and chronic effects of the benzodiazepine receptor ligand FG 7142: nroconvulsant oronerties and kindling. Br J Pharmacol 83: $51-958, 1984. - -

17. Liischer, W., H. Schneider and W. Kehr. Evaluation of different &carbolines in monogolian gerbils with reflex epilepsy. Eur J Pharmacol 114: 261-266, 1985. 18. Marescaux. C.. G. Micheletti. M. Veranes. A. Denaulis, L. Rumbach and J. M. Warter. Biphasic effects of Ro l-5-1788 on spontaneous petit ma&like seizures in rats. Em J Pharmacol 102: 355-359, 1984. 19. Marescaux, C., G. Mi~heietti,

M. Vergnes, A. Depaulis, L. Rumbach and J. M. Warter. A model of chronic spontaneous petit ma&like seizures in the rat: comparison with pentylenetetrazol-induced seizures. Epilepsia 25: 32633 1, 1984. 20. Marescaux, C., G. Micheletti, M. Vergnes, L. Rumbach and J. M. Waiter. Diazepam antagonizes GABAmimetics in rats with spontaneous petit ma&like epilepsy. Eur J Pbarmacol 113: 19-24, 1985. 21. Marescaux, C., M. Vergnes, G. Micheletti, A. Depaulis, J. Reis, L. Rumbach, J. M. Warter and D. Kurtz. Une forme genetique d’absences petit maJ chez le rat Wistar. Rev Nemo1 (Paris) 140: 63-66, 1984. 22. Meld~m, B. ~oconv~sant and anticonvulsant actions in photosensitive baboons of g-carboline derivatives. Neuropharmacology 23: 845-846, 1984. 23. Meldrum, B. S., M. C. Evans and C. Braestrup.

24.

25. 26. 27.

Anticonvulsant action in the photosensitive baboon, Papio papio, of a novel P-carboline derivative, ZK 91296. Em J Pharmacol91: 255-259, 1983. Micheletti, G., M. Vergnes, C. Marescaux, J. Reis, A. Depaulis, L. Rumbach and J. M. Warter. Antiepileptic drug evaluation in a new animal model: spontaneous petit ma1 epilepsy in the rat. Arzneimittfforsch 35: 483-485, 1985. Morin, A. M., A. L. Watson and C. G. Wasterlain. Kindling of seizures with norhannan, a p-carboline ligand of benzodiazepine receptors. Eur J Pharmacot 88: 131-134, 1983. Olsen, R. W. GABA-~n~di~epine-ba~iturate receptor interactions. .I Neurochem 37: I-13, 1981. Ongini, E.. C. Barzaghi and M. Marzanatti. Intrinsic antagonistic effects of /3-carboline FG 7142 on behavioral and EEG actions of benzodiazepines and pentobarbital in cats. Eur J Pharmacol 95: 125-129,

1983.

28. Pellow, S. Can drug effects on anxiety and convulsions be separated? Neurosci Bjobehav Rev 9: 55-73, 1985. 29. Petersen, E. N. DMCM: a potent convulsive benzodiazepine recentor liaand. Eur J Pharmacol 94: 117-124, 1983. 30. Petersen, E. N. and L. H. Jensen. Proconflict effect of benzodiazepine receptor inverse agonists and other inhibitors of GABA function. Em J Pharmacol 103: 91-97, 1984. 31. Petersen, E. N., L. H. Jensen, T, Honor6 and C. Braestrup. Differential ph~~olo~c~ effects of ~nz~~ep~e receptor inverse agonists. In: Benzodiazepine Recognition Site Ligands: Biochemistry and Pharmacology, edited by G. Biggie and E. Costa. New York: Raven Press, 1983, pp. 57-64. 32. Petersen, E. N.; L. H. Jensen, T. Honor& C. Braestrup, W. Kehr, D. N. Stephens, H. Wachtel, D. Seidehnan and R. Schmiechen. ZK 91 296, a partial agonist at benzodiazepine receptors. Psychopharmacology ~Beriin~ 83: 248-248, 1984.

BETA-CARBOLINES

AND PETIT

MAL-LIKE

SEIZURES

33. Pole, P., E. P. Bonetti, R. Schaffner and W. Haefely. A three-

state model of the benzodiazepine receptor explains the interactions between the benzodiazepine antagonist Ro 15-1788, benzodiazepine tranquilizers, P-carbolines, and phenobarbitone. Arch Pharmacol 321: 260-264, 1982. 34. Richards, J. G. and H. Mohler. Benzodiazepine receptors. Neuropharmacology 23: 233-242, 1984. 35. Schoch, P., J. G. Richards, P. Haring, B. Takacs, C. Stahli, T.

Staehelin, W. Haefely and H. Mohler. Co-localization of GABA, receptors and benzodiazepine receptors in the brain shown by monoclonal antibodies. Nature 314: 168-171, 1985. 36. Schweri, M. M., S. M. Paul and M. Skolnick. Strain differences convulsant actions of 3in susceptibility to the carbomethoxy-P-carboline. Pharmacol Biochem Behav 19: 951-955, 1983. 37. Skolnick P., M. M. Schweri,

S. M. Paul, J. V. Martin, R. L. Wagner and W. B. Mendelson. 3-carboethoxy+-carboline (pCCE) elicits electroencephalographic seizures in rats: reversal by the benzodiazepine antagonist CGS 8216. L@ Sri 32: 24392445, 1983.

335

38. Stephens, D. N., G. T. Shearman and W. Kehr. Discriminative stimulus properties of P-carbolines characterized as agonists and inverse agonists at central benzodiazepine receptors. Psychopharmacology (Berlin) 83: 233-239, 1984. 39. Thiebot, M. H. and P. Soubrie. Behavioural pharmacology of the benzodiazepines. In: The Benzodiazepines: From Molecular Biology to Clinical Practice, edited by E. Costa. New York:

Raven Press, 1983, pp. 67-92. 40. Vergnes, M., Ch. Marescaux, G. Micheletti, J. Reis, A. Depaulis, L. Rumbach and J. M. Warter. Spontaneous paroxysmal electroclinical patterns in rat: a model of generalized nonconvulsive epilepsy. Neurosci Lett 33: 97-101, 1982.