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Blockade of Photically Induced Epilepsy by 'Dopamine Agonist' Ergot Alkaloids

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Blockade of Photically Induced Epilepsy by 'Dopamine Agonist' Ergot Alkaloids Psychopharmacology 57, 57-62 (1978) Psychopharmacology © by Springer-Verlag 1978 Blockade of Photically Induced Epilepsy by 'Dopamine Agonist' Ergot Alkaloids GILL ANLEZARK and BRIAN MELDRUM Department of Neurology, Institute of Psychiatry, De Crespigny Park, London, SES 8AF, United Kingdom Abstract. The effect of the intravenous administration of the visual evoked response in the lateral geniculate of ergot alkaloids on epileptic responses to intermittent body or occipital cortex correlates well with the reduc- photic stimulation (IPS) has been studied in adolescent tion in photosensitivity (Vuillon-Cacciuttolo et aI., baboons, Papio papio, from Senegal. Ergocornine, 1973). In addition to the evidence for serotonin 1- 2 mgjkg, produced marked autonomic and be- agonist and antagonist actions of ergot alkaloids in havioural effects, slowed the EEG, and abolished the CNS, it has recently been demonstrated that some myoclonic responses to IPS for 30-90 min. Ergo- ergot derivatives interact with cerebral dopamine metrine, 1 mgjkg, activated the EEG and blocked the (DA) receptors. Thus several ergot alkaloids stimulate induction of myoclonic responses for 1- 3 h. Bromo- dopamine-sensitive adenylate cyclase (von Hungen criptine, 0.5-4 mgjkg, did not consistently prevent et aI., 1974; da Prada et aI., 1975) and modify motor myoclonic responses to IPS. After pretreatment with activity in intact or brain-lesioned rats in ways a subconvulsant dose of allylglycine (180- 200 mgjkg), indicative of dopaminergic activation (see Discus- lysergic acid diethylamide, 0.1 mgjkg, retained the sion). capacity to block myoclonic responses to IPS, and We previously reported that the dopamine agonist ergocornine 1 mgjkg reduced such responses. The apomorphine reduces photically induced epilepsy in convulsant effect of allylglycine was enhanced, how- Papio papio (Meldrum et aI., 1975a) and that ergot ever, so that prolonged seizure sequences began alkaloids which cause contralateral turning in mice 19- 96 min after ergocornine administration. The with unilateral lesions of the nigrostriatal pathway protective action of ergot alkaloids against epileptic reduce the severity of audiogenic seizures in an responses induced by sensory stimulation is inter- inbred strain of mice (Anlezark et aI., 1976). We now preted in terms of effects at several sites, including report the effects of ergocornine, bromocriptine, and dopaminergic and serotoninergic synapses. ergometrine on behaviour, EEG, and photically induced epilepsy in the baboon. Key words: Ergot alkaloids - Reflex epilepsy - The syndrome of photically induced epilepsy can Photosensitive baboons - Dopamine - Allylgly- be enhanced by subconvulsant doses of allylglycine cine - Ergocornine (Meldrum et aI., 1975b), a compound that leads to inhibition of cerebral glutamic acid decarboxylase activity (Horton and Meldrum, 1973). Most clinically useful anticonvulsant drugs are effective in this test Various ergot derivatives have been shown to block system (Meldrum et aI., 1975b), but apomorphine not photically induced epileptic responses in the Senega- only loses its anticonvulsant properties, but also tends lese baboon, Papio papio (Walter et aI., 1971; Mel- to augment the epileptogenic effects of allylglycine drum and Naquet, 1971; Vuillon-Cacciuttolo and (Meldrum et a1., 1975a). We therefore compared the Balzano, 1972). This effect appears at least partially actions of LSD and ergocornine in baboons pretreated attributable to diminution of synaptic transmission with subconvulsant doses of allylglycine to explore the in the lateral geniculate body by a serotoninlike action possibility that this test system differentiates anticon- of the compounds (Aghajanian et aI., 1972; Curtis and vulsant effects primarily dependent on serotoninergic Davis, 1962). Thus, after lysergic acid diethylamide mechanisms from those dependent on dopaminergic (LSD), the reduction in amplitude of the earliest wave actions. 0033-3158/78/0057/0057/$ 1.20 58 Psychopharmacology 57 (1978) MA TERIALS AND METHODS after drug administration were similar to predrug responses. Thirteen adolescent baboons, Papio papio, from the Casamance region of Senegal, were used in 35 experiments. The animals were After ergometrine, 0.4-1.0 mg/kg, an increase seated in primate restraining chairs, and the EEG was recorded on in the proportion of irregular fast activity on the EEG a Galileo SLE 18channel EEG machine via 15chronically implanted was associated with a reduction in the incidence of epidural electrodes (Meldrum et al., 1975a). Stroboscopic stimula- spontaneous spikes and waves, lasting 2 - 3 h. EEG tion at 20-35 flashes/s was provided by a Dawe Strobotorch held 20 em from the animals' eyes. Standardised tests lasting 5 min were paroxysmal responses to photic stimulation were conducted before and 10-30 min after drug or vehicle adminis- absent 1.5 h after ergometrine, 1 rug/kg. tration, and then at hourly intervals for up to 6 h. In eight experi- Slowing of the EEG background rhythms was seen ments a subconvulsant dose of allylglycine, 180-200 mgjkg, was within 10 min of the administration ofbromocriptine, given 200 min before administration of LSD or ergocornine. Myo- 1-4 mg/kg. Subsequently, the incidence of spon- clonic responses were graded as follows: 0 = no response, 1 = eye- lid myoclonus, 2 = myoclonus of facial and neck muscles, 3 = myo- taneous spikes and waves was reduced. The enhanced clonus of all four limbs, 4 = myoclonus continuing beyond the end slow activity continued for 2 - 3 h after bromocriptine, of photic stimulation, S = tonic-clonic seizure. At least 1 week 4 mg/kg. A reduction in the incidence of photically intervened between drug tests in anyone animal. induced spikes and waves was most marked after Drugs. The following drugs were used: 2-bromo-o:-ergocryptine 1.5-2.5 h. methanesulphonate(bromocriptine), ergocornine hydrogenmalei- nate, D-lysergic acid diethylamide tartrate (LSD) (Sandoz), ergo- Photically Induced Myoclonus. The effects of ergo- novine maleate (ergometrine), and D,L-2-amino-4-pentenoic acid (allylglycine) (Sigma). cornine, ergometrine, and bromocriptine (or saline) Ergocornine and bromocriptine were dissolved, with an equal on photically induced myoclonic responses are shown weight of tartaric acid, in a few drops of 70 % ethanol and made up in Table 1. to volume with warm saline. Ergometrine, LSD, and allylglycine The loss of responsiveness to photic stimulation were dissolved in saline. Drugs (or vehicle) were injected i.v. after ergocornine was clearly dose-dependent. A slight transient reduction in myoclonic responses was seen 30 min after ergocornine 0.5 mg/kg, whereas none of RESULTS the animals treated with 1 mg/kg showed myoclonic responses at this interval after drug administration. Autonomic and Behavioural Effects. Ergocornine, ergo- A more prolonged effect was seen after 2 mg'kg. metrine, and bromocriptine induced pupil dilatation Ergometrine also reduced myoclonic responses within 1-10 min of administration. Within 1 min of to photic stimulation in a dose-dependent way. All ergocornine, 1- 2 mg/kg (or 10 min ergocornine three doses (0.15,0.4, and 1 mg/kg) were administered 0.5 mg/kg), ptosis, with the eyes rolled up, and some to the most photosensitive animal (SB 49) who con- chewing and licking were observed. Ergocornine also sistently showed a sustained epileptic response (4 or 5) induced, after 5 -10 min, profuse salivation, loss of in control tests. No definite drug-induced reduction muscle tone, and absence of visual following. After in photosensitivity was seen in this animal after 2 h, alert behaviour with spontaneous limb movements 0.15 mg/kg. (The decrease after 150-180 min is returned. probably a result ofthe tonic-clonic seizure at 90 min, Ergometrine, 0.4 and 1 mg/kg, induced licking and which is often followed by a refractory state in which chewing 1-2 min after administration. Aggressive the animal is less responsive.) A slight, transient dimi- and agitated behaviour with irregular cries subse- nution in myoclonic responses was seen 30 min after quently occurred and were accompanied by pilo- 0.4 mg/kg, whereas after 1 mg/kg the responses were erection. This condition lasted for up to 1 h and was absent at 90 min and considerably reduced for up to severe after 1 mg/kg. 150min. In baboon PD 8, myoclonic responses were The main behavioural effect seen after bromo- reduced or, at times, absent after all the doses. (In criptine (0.5-4 mg/kg) was yawning, lip-smacking, this animal responsiveness did not return to control and opening of the mouth. Aggressive responses after the two higher doses.) became difficult to elicit. Animals were very restless Reductions in myoclonic responses observed after 3 h after administration of 2 or 4 mg/kg. bromocriptine, 0.5, 1, 2, and 4 mg/kg, were not EEG Changes. Ergocornine, 0.5-2.0 mg/kg, induced uniformly related to the dose. In the most photosensi- high-voltage slow activities within a few seconds of tive animal, SB 49 (given 1 and 2 mg/kg), only a slight i.v. administration. Enhancement of slower back- transient reduction in myoclonic responses occurred ground rhythms was still evident 2 - 3 h later. EEG (the reduction after 1 mg/kg is possibly related to spikes and waves were absent during photic stimula- the tonic-clonic seizure at 30 min). Both animals tion 30 min after ergocornine, 1- 2 mg/kg, Paroxys- given 4 mg/kg showed reductions in responsiveness mal EEG responses during photic stimulation 3.5 h (compared to control tests and saline
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