Effects of drugs affecting dopaminergic neurotransmission in rats with spontaneous petit mal-like seizures

Neuropharmacology

Vol. 27, No. 3, pp. 269-214, 1988 Printed in Great Britain. All rights reserved

0028-3908/88$3.00+ 0.00 Copyright 0 1988Pergamon Journals Ltd

EFFECTS OF DRUGS AFFECTING DOPAMINERGIC NEUROTRANSMISSION IN RATS WITH SPONTANEOUS PETIT MAL-LIKE SEIZURES JEAN-MARIE WARTER,’ MARGUERITE VERGNES,’ ANTOINE DEPAULIS,’ CHRISTINE TRANCHANT,’ L. RUMBACH,’ G. MICHELETTI’ and C. MARESCAUX’ ‘Groupe de Recherche de Physiopathologie Nerveuse, Clinique Neurologique, Hopital Civil, 67091 Strasbourg Cedex and 2Centre de Neurochimie, C.N.R.S., 5 rue Blaise Pascal, 67084 Strasbourg Cedex, France

(Accepted

10 September

1987)

Summary-Drugs interacting with dopaminergic neurotransmission were studied on a model of genetic peril ma/-like seizures in a strain of Wistar rats. Dopamine participates in the control of seizures in this model, as in other models of petit ma1 or of genetic epilepsy. Mixed dopaminergic D,/D, agonists: L-DOPA, apomorphine, amphetamine and nomifensine, gave dose-dependent reductions of the duration of spike and wave discharges. Mixed D,/D, antagonists: haloperidol, flupentixol and pimozide, caused dose-dependent increases of duration of spike and wave discharges. The findings with specific agonists or antagonists of D, or D, receptors did not reveal clearly the respective roles of these receptors in controlling the spike and wave discharges. The D, agonists, lisuride and pergolide, had no effect on spike and wave discharges, except at toxic doses; bromocriptine decreased the duration of the discharges, but without clear-cut dose-dependency. The D, antagonists: sulpiride and tiapride, had no effect. The D, agonist SKF 38393 decreased duration of the spike and wave discharges in a dose-dependent manner. The D, antagonist SCH 23390 had a biphasic effect: increasing the duration of spike and wave discharges at small doses and decreasing it at large doses. These results suggest that the simultaneous stimulation or inhibition of both receptors, D, and D,, is necessary for influencing spike and wave discharges in this model. Key words: petit mal, epilepsy, rat model, dopamine agonists, dopamine antagonists, D,, D, receptors.

Recent experimental work has been directed toward clarifying the role of different neuromediator systems in the control of epileptic seizures. The common working hypotheses have been, first, that epileptic seizures result from either an excessive excitation, or a reduced inhibition, and second, that a better understanding of the biochemical mechanisms underlying the different epileptic syndromes should lead to a rational search for new anticonvulsive drugs (Meldrum, 1982). At least two classes of neuromediators, the inhibitory and excitatory amino acids, seem to be clearly implicated in the occurrence of certain forms of epilepsy. Many other substances, however, participate to some degree in the control of seizures: neuropeptides, serotonin, acetylcholine and noradrenaline (Meldrum, 1982). The part played by dopamine (DA) in the control or propagation of epileptic seizures is still obscure. In the human subject, neurologists have long been familiar with the beneficial or, on the contrary, the aggravative effects of certain substances known to interact Correspondence to: C. Marescaux, Clinique Neurologique, Hopital Civil, 67091 Strasbourg Cedex, France.

with DA neurotransmission, such as amphetamines, apomorphine, some antidepressants and neuroleptics (Toone and Fenton, 1977; Meldrum, 1982). The many studies in laboratory animals have shown that the effects of DA vary with the experimental model of epilepsy and with the species (Woodbury, 1983). Here, the effects of drugs modifying DA neurotransmission have been studied in a model of spontagenetically-determined, generalized nonneous, convulsive epilepsy in a strain of Wistar rats the inbred offspring of which all presented the trait. The seizures are characterized by immobility and clonus of the facial and cervical musculature, simultaneously with bilateral, synchronous spike and wave discharges on the EEG, 7-l 1 c/s, 25&800 PV in amplitude, lasting 2-90 set (10-I 5 set on average) (Vergnes, Marescaux, Micheletti, Reis, Depaulis, Rumbach and Warter, 1982). Seizures usually start at about 3 months of age and persist until death (Vergnes, Marescaux, Depaulis, Micheletti and Warter, 1956). In the awake, calm rat, the frequency of seizures is about 1 per min. These seizures are selectively abolished by those antiepileptic drugs which are efficacious against human petit mal, whereas 269

JEAN-MARIE WAKTER et al.

270

antiepileptics which are specific for focal or convulsive seizures have no effect (Micheletti, Vergnes, Marescaux, Reis, Depauhs, Rumbach and Warter, 1985). In order to clarify the respective roles of D, and Dz DA receptors (Stoof and Kebabian, 1984) the rats were given drugs acting simultaneously at both receptors and others acting more specifically at one or the other receptor.

charges of the reference period, taken as 100%. For each dose, the duration of spike and wave discharges during each period after the injection was compared to the reference pre-in,jection period, using a nonparametric analysis of variance for related samples (Friedmann test. Siegel, 1956). The behavioural effects of each drug were also recorded. Individual rats were used not more than once a week, RESULTS

METHODS

Animals Male rats, 35&45Og, of the inbred strain in the laboratory colony were equipped with 4 single contact electrodes on the left and right frontoparietal cortex (Vergnes et al., 1982). All showed spike and wave discharges characteristic of petit nzal-like seizures. Drugs The drugs given, listed in Table I, were dissolved or suspended in 0.9% NaCI, containing 2 drops of Tween 80 per ml, and injected intraperitoneally (i.p.) in a final volume of 1 ml/kg body weight. A wide range of doses was used to reveal biphasic effects, if any. The doses of drugs having no antiepileptic or aggravating effect were increased to toxic levels. Metho& Eight rats were used for each dose of each drug. After the rats were habituated to the experimental conditions, a 20 min reference EEG was recorded, the drug was injected and the EEG was recorded for 4-l 5 consecutive periods of 20 min, depending on the drug. For each group of 8 rats, the total duration of spike and wave discharges during each 20 min period was measured and the results were expressed as a percentage of the duration of spike and wave dis-

The effects of the different drugs are summarized in Table I and illustrated in Figs l-4. Mixed DA antagonists, acting on D,/D: receptors: ha~operidol, ~upentixol and pimozide, induced a dose-dependent increase of the duration of spike and wave discharges (Fig. I). At the largest doses, the discharges were continuous. These drugs also had a sedative effect and provoked a dose-dependent catatonia. None of these neuroleptics caused convulsions. Mixed agonists, acting on D,/D2 receptors: L-DOPA, associated with benserazide, a dopa decarboxylase inhibitor, and apomorphine or drugs facilitating DA transmission: amphetamine and nomifensine. gave a dose-dependent decrease of the duration of spike and wave discharges (Fig. 2). At doses greater than those required for the effect on spike and wave discharges. L-DOPA (200 mg/kg), apomorphine (1 mg/kg), amphetamine (3 mg/kg) and nomifensine (IO mg/kg) caused agitation. stereotyped behaviour and frequent rearing. Specific DA antagonists of the Dz receptor: sulpiride and tiapride, did not significantly alter the duration of spike and wave discharges (Fig. 3). At large doses. sulpiride (>50 mg/kg) and tiapride (> 200 mg/kg) induced sedation and decreased motor activity. A few minutes after the injection of sulpiride at 200 mg/kg, 6 of 8 rats died and a few hours after tiapride, at 300 mg/kg, 3 of 8 rats died.

Table I. Effects of drugs influencing dopaminergic transmission on the duration of spike-wave discharges (SWD) in rats with spontaneous, genetic petif mu!-like seizures Drug action D,/D,

D,/D,

Drug

receptor

receptor

antagonist

agonist

Stimulator of DA release Inhibitor of DA reuptake D, receptor antagonist D, receptor

agonist

Haloperldol Flupentixol Pimozide L-DOPA Apomorphine Amphetamine Nomifensine Suipirlde Tiapride Lisuride Pergolide

D, receptor

antagonist

Bromocriptine SCH 23390

D, receptor

agonist

SKF 38393

Arrows up; duration

Dose fmgjkg)

Duration SWD

0.1 -5 0.5-3 I-16 50-400 0.1-I 0.75-5 I--IO 50-200

1’ 1 1

100-300 0.25..0.5

(L

1.o 0.5-1.0

1“ 1

2.0 5-40 0.1-0.2 0.5-2 5-10

of

: T 1

i” Ih 1

of spike and wave discharges increased; arrows down: duration of spike and wave drscharges decreased; ‘no effect; %oxic doses: some rats died. SKF 38393: 7,8.dihydroxy-2,3,4,5-tetrahydro-l-phenyl-lH-3-benzazep~ne SCH 23390: 7-chloro-8 hydroxy-2,3.4,5-tetrahydro-3-methyl-I-phenyl-lH-3-benzazepine.

DA transmission and rat petit ma1 epilepsy FLU.

HAL.

-20

0

80

-20

271

PIM.

50

0

-20

80

0

nl,”

Fig. 1, Duration of spike and wave discharges of successive 20 min periods following intraperitoneal injection of haloperidol (HAL), flupentixol (FLU), and pimozide (PIM). Each point represents the total duration of spike and wave discharges of 8 rats, expressed as the percentage of duration of discharges in the 20 min reference period preceding the injection (100%). On the right, doses in mg/kg; some doses are omitted for clarity. Closed symbols: values not significant vs reference period; open symbols values significant at P < 0.01 vs reference period.

Dopaminergic agonists of the D, receptor: lisuride (Fig. 3) and pergolide (data not shown), made the spike and wave discharges disappear only at large doses, lisuride 1 mg/kg and pergolide 2 mg/kg, which induced behavioural alterations, periods of alternating agitation and sedation. At these doses, 3 of 8 rats given lisuride died and 4 of 8 given pergolide, in the hours after the injection. Bromocriptine, also a D, agonist, reduced the duration of spike and wave discharges about 3 hr after the injection, but the effect was not clearly dose-related (Fig. 3). The specific D, receptor antagonist SCH 23390, given in small doses (< 0.1 mg/kg), caused a transitory increase of the duration of spike and wave discharges. At large doses, >O.S mg/kg, this drug

L- DOPA 100

reduced the duration of discharges (Fig. 4) and the rats then showed sedation, interrupted by a few periods of intense agitation. At 1 and 2 mg/kg, 3 of 8 rats died. The D, receptor agonist SKF 38393 reduced spike and wave discharges in a dosedependent manner (Fig. 4). At a large dose, 40 mg/kg, motor activity increased. Monoamine oxidase inhibitors (results not shown) had no effect on the spike and wave discharges. DISCUSSION

In this model of generalized nonconvulsive epilepsy, DA agonists induced a decrease of the duration of spike and wave discharges, whereas DA antago-

y

APOM.

LISUR.

,o-25

BROMO.

/ ,b, ?+L-

”

-50

0.5 0.1

100

1

\

0

200

+A

-20

040

-20

0

140

.20

0

80

4 100

-20

0

100

ml”

Fig. 2. Duration of spike and wave discharges of successive 20 min periods following intraperitoneal injection of L-DOPA + benzerazide (L-DOPA), apomorphine (APOM), amphetamine (AMPHET.) and nomifensine (NOMIF.). Symbols and conventions as in Figure 1.

Fig. 3. Duration of spike and wave discharges of successive 20 min periods following intraperitoneal injection of lisuride (LISUR.; at 1 mg/kg, 3 of 8 rats died), bromocriptine (BROMO.), sulpiride (SULP.) and tiapride (TIAP.). Symbols and conventions as in Figure I.

JEAN-MAKE WAKTER PI d.

272 100

SKF

Fig. 4. Duration of spike and wave discharges of successive 20 min periods following intraperitoneal injections of SKF 38393 and SCH 23390 (at 1 and 2 mgikg. 3 of 8 rats given SCH 23390 died). Symbols and conventions as in Figure I.

nists increased the duration of the discharges to give a true petit mal status. The DA agonists also produced increased motor activity and the DA antagonists catatonia. But there was no correlation between the EEG and behavioural effects of the drugs; DA agonists at small doses reduced spike and wave discharges but did not modify behaviour. These results suggest that the simultaneous stimulation or inhibition of the two subclasses of DA receptors is indispensable for the control of spike and wave discharges. Thus benzamides, specific DZ antagonists, did not aggravate the discharges. even at doses which induced sedation and caused a marked reduction of motor activity. The beneficial effects of specific DZ agonists appeared only at toxic doses (lisuride, pergolide) or were not dose-dependent (bromocriptine); and at large doses these drugs are probably no longet Dz receptor-specific (Horowski, 1983). The drug SCH 23 390, a specific D, antagonist, moderately and transitorily increased spike and wave discharges at a dose of 0.1 mg/kg, but was not effective at or above 0.5 mg/kg. At these large doses, the drug actually reduced the discharges. but it then interacts with other types of receptors (Waddington, 1986). The drug SKF 38 393, a specific D, agonist, produced a dose-dependent decrease in spike and wave discharges, like a mixed D,/‘D, agonist. These findings agree with numerous neurophysiological and behavioural studies which show that the simultaneous stimulation of D, and D, receptors is required for the full expression of the effects of DA (Molloy, O’Boyle, Pugh and Waddington, 1986; Braun and Chase. 1986; Carlson, Bergstrom and Walters, 1987) and that the

two subclasses of receptors interact (Pugh, Q’Boylc. Molloy and Waddington. 1985: Sallcr and Salama. 1986). Other experimental results on models of petit nd confirm the role of DA in the control of generalized nonconvulsive epilepsy. In a rat model similar to the one used here. Kleinlogel (1985) has shown that neuroleptics caused dose-dependent increases of duration of spike and wave discharges. King and Burnham (1980) using the flash-evoked afterdischarge model of petit tnd in the rat, found that amphetamines abolished the flash-evoked afterdischarge and pimozide increased it. In the penicilin-induced generalized photosensitive epilepsy in the cat, seizures increased significantly after a decrease of DA and rice ZYYSU(Quesney. I98 I; Quesney and Reader. 1984). For example. bilateral application of h-hydroxydopamine to the cortex induced in all cats the development of spontaneous photosensitive epilepsy without penicillin having been given, together with a significant selective depletion of DA in the cortex preferentially involving the occipital lobe. Finally. DA agonists blocked the photosensitive seizures. In the photosensitive baboon Papio pupio, DA agonists, apomorphine piribedil. nomifcnsine and L-DOPA associated with a monoalninc oxidase inhibitor, have an anticonvulsant effect (Anlczark, Marrosu and Meldrum, 1981). Dopamine antagonists, particularly haloperidol, at small doses enhanced spike-wave discharges occurring both spontaneously and in response to photic stimulation (Meldrum, Anlezark and Trimble, 1975). On the other hand, Killam and Killam (1984) found that the intraventricufar injection of DA, or treatment with L-DOPA for 50 days caused no change in seizures. In certain models of genetic convulsive epilepsy. DA clearly helps control convulsive seizures induced by outside stimuli. In the gerbil, drugs which increase DA transmission have antiepileptic effects against tonic-clonic seizures, induced by handling or by stimulation by an air blast, whcrcas neurolcptics intensify the seizures (Schonfeld and Click. 1980: Loscher and Czuczwar, 1986). In DBAj2 mice, susceptible to audiogenie seizures, DA agonists reduce both the frequency of clonic-tonic seizures and the mortality after auditory stimulation. In these mice, the turnover of DA is highly correlated with sensitivity to audiogenic seizures, and this independently of turnover of noradrenaline. These results suggest that the alteration in DA precedes and is directly responsible for the epileptic seizures, in DBA!Z mice (Jobe and Laird, 1981). On the contrary, in the rat, susceptible to audiogcnic seizures, and in the yztakitzg mouse. DA pathways are not involved (Laird, Dailey and Jobe, 1984; Chermat. Doare. Lachapefle and Simon, 1981). In other forms of experimental epilepsy, focal epilepsies caused by topical application of epileptogenic substances (Craig, I984), kindling (McNamara, I984), electroshock and pentylenetctrazol

DA transmission and rat petit ma1 epilepsy

(Burley and Ferrendelli, 1984) DA plays only a minor role. In the nonconvulsive model used here, DA pathways are not the only ones which modulate spike and wave discharges; 01noradrenergic and y-aminobutyric acid (GABA) transmission systems participate in the control of spike and wave discharges as well. Noradrenergic q-antagonists and or,-agonists increase the duration of spike and wave discharges whereas q-agonists and qantagonists decrease the The stimulation or inhibition of discharges. /i’-noradrenergic pathways are without effect (Micheletti, Warter, Marescaux, Depaulis, Tranchant, Rumbach and Vergnes, 1987). y-Aminobutyric acid agonists injected intraperitoneaily increase the duration of spike and wave discharges (Micheletti, Marescaux, Vergnes, Rumbach and Warter, 1985). Dopamine and GABA pathways are related in complex but little-known ways. y-Aminobutyric acid is generally considered to exercise an inhibitory control on nigrostriatal DA pathways (Wood, 1982) but in the opinion of some, GABA may facilitate the release of DA in certain experimental conditions (ScheelKruger, 1986). The observations made on the present model tally with the first hypothesis: the aggravative effects of increasing GABAergic transmission could be explained by an inhibition of DA transmission. In conclusion, DA participates in the control of epileptic seizures in the model in the rat of generalized nonconvulsive epilepsy, as in other models of petit ma1 and of genetically-determined epilepsy. Pharmacological findings alone cannot prove that petit mallike seizures are caused by a dysfunction of DA pathways. Only further biochemical and neurophysiological studies of the effects of destruction or selective stimulation of dopaminergic pathways will clarify the exact role of DA in the genesis and control of this form of epilepsy. Acknctwledgem~nts---The authors thank Sarah Dejours for

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