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Prevention of cysteamine-induced myoclonus blocks the long-term inhibition of kindled seizures
Brain Research, 412 (1987) 161-164 Elsevier
161
BRE 22278
Prevention of cysteamine-induced myoclonus blocks the long-term inhibition of kindled seizures G.A. Cottrell and H.A. Robertson Department of Pharmacology, Facultyof Medicine, Dalhousie University, Halifax, N.S. (Canada) (Accepted 17 February 1987)
Key words: Cysteamine; Kindling; Myoclonus; Midazolam; Seizure; Long-term inhibition
In kindled rats, the administration of cysteamine (CSH, 200 mg/kg, i.p.) 4 h prior to a kindled seizure leads to long-term (up to 10 days) inhibition of kindled seizures. CSH (200 mg/kg, i.p.) also induces myoclonic seizures in kindled rats. We suggest that the longterm inhibition of kindled seizures might be the result of the myoclonus, not the somatostatin depletion as previously suggested. Prior administration of the short-acting benzodiazepine midazolam (5 mg/kg, i.p.) eliminated the CSH-induced myoclonus and prevented the long-term inhibition of kindled seizures. These results suggest that the CSH-induced long-term inhibition of kindled seizures is the result of an interaction between the myoclonic seizure and a subsequent kindled seizure. In kindled rats, a single injection (200 mg/kg, i.p,) of cysteamine (CSH), followed 4 h later by a kindled seizure results in long-term suppression of kindled seizures n4. Four h after CSH administration, electrical stimulation induces a generalized, tonic-clonic convulsion in all kindled rats. However, at 24 and 48 h, no seizures could be elicited in either amygdaloidkindled rats 4 or hippocampal-kindled rats I. This suppression of kindled seizures lasts, in individual rats, from 4 to 10 days ha. It has been reported that CSH depletes brain and gastrointestinal immunoreactive somatostatin content 9'~2 while somatostatin injections into the cerebral ventricles precipitate generalized seizures with E E G spiking 3. Immunoreactive somatostatin content is increased in the brains of amygdaloid-kindled rats 5. Higuchi et al. 4 assumed that if increasing somatostatin levels is convulsant, decreasing somatostatin levels should be anti-convulsant. They therefore suggested that CSH produced prolonged suppression of amygdaloid-kindled seizures by reducing the kindling-induced increase in somatostatin in the brains of kindled animals 4. However, the time course of the somatostatin-depleting action of CSH 11 does not coincide with the time course for sup-
pression of kindled seizures. We recently demonstrated that CSH (200 mg/kg, i.p.) induces myoclonic seizures in all kindled rats studied but not in naive rats 1. Myoclonic seizures have now been observed in over 100 hippocampaland amygdala-kindled rats following i.p. CSH injection. None of the naive rats, tested with 200 mg/kg i.p. in a quiet room, exhibited myoclonus, although some exhibited trembling (ref. 1 and on-going observations). The myoclonus that is seen in kindled animals is a severe myoclonus; it lasts for up to 90 rain, with 10-20 jerks/min. The animals often exhibit trembling for hours afterwards. Approximately 10% of the animals die from this insult 1. Mucha and Pinel 6 have shown that a series of kindled seizures will result in long-term inhibition of kindled seizures 24-72 h later. In fact, the time course of the inhibition of kindled seizures is similar whether the long-term inhibition is produced by repetitive seizures or by CSH 1'2'4'6. We have shown elsewhere that the CSH must be given approximately 4 h prior to the kindled seizure; administration of CSH 24 h prior to or 6 h after the kindled seizure does not produce inhibition of kindled seizures 2. Since the injection-to-kindled-sei-
Correspondence: H.A. Robertson, Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, N.S., B3H 4H7 Canada. 0006-8993/87/$03.50 © 1987 Elsevier Science Publishers B.V. (Biomedical Division)
162 zure interval is critical for the anticonvulsant effect of CSH, we proposed that the CSH must interact in some manner with the kindled seizure to produce the anticonvulsant effect. We now propose that the longterm inhibition of seizures is caused by the effects of the interaction of the myoclonus with the kindled seizure. As repetitive seizures can produce long-term inhibition, it would not be unreasonable to suggest that if the myoclonus associated with the administration of CSH is prevented, the long-term inhibition of kindled seizures may not be observed. To test this idea, we prevented the myoclonus by injection of midazolam, a benzodiazepine with a short (approx. 90 min) duration of action. Because of its short duration of action, midazolam would be expected to block the myoclonus following CSH injection but not interfere with the kindled seizure 4 h later. Ten male Sprague-Dawley rats (500-600 g at the time of the experiment) were stimulated through an electrode implanted in the dorsal hippocampus (incisor bar at 0, AP -2.4 ram, L +2.0 mm, V from dura -3.7 mm). The animals were housed under a 14:10 h light-dark cycle (lights on from 08.30-22.30 h) and were fed and watered ad libitum. The rats were stimulated daily, at about the same time each afternoon, with 2 s of bipolar square-wave current (60 Hz, 160 or 240/~A peak-to-peak current). A rating scale, modified after Racine 7, was used to score seizure severity (stage 1 - - immobility, stage 2 - - head nodding, stage 3 - - front paw clonus, stage 4 - - rearing and front paw clonus, stage 5 - - falling and/or hind paw clonus). All rats were well-kindled and exhibited at least 3 stage 5 seizures on consecutive days before the day of drug administration. Thus, each rat could be used as its own control in determining the effects of drug treatment on the kindled seizure. Midazolam (a gift from Dr. W. Haefely, Hoffmann-La Roche, Basle) and CSH (Sigma) were dissolved in saline and were given intraperitoneally. Midazolam was injected 10 min before the CSH. Pilot studies had demonstrated that 5 mg/kg i.p. was effective in preventing CSH-induced myoclonus without interferring with a hippocampal kindled seizure 4 h later. The dose of CSH was 200 mg/kg as in previous studies TM. As shown previously in both hippocampal kindled rats 1 and amygdaloid kindled rats (unpublished observation), CSH injected 4 h prior to kindling induces
GO
CSH
~lOOr
MIDAZOLAM AND CSH
mm
.
4 3
U
2 1 --1
AO
1 TIME
--1
AO
1
( days )
Fig. 1. The upper left panel shows the percentage of rats exhibiting myoclonus after cysteamine injection. The upper right
panel shows the percentage of rats exhibiting myodonus after the midazolam-cysteamine injections. The lower left panel shows the effect of cysteamine, injected 4 h before a kindling session, on kindled seizure stage. The lower right panel shows the effect of midazolam, injected 10 min before the cysteamine, on the anticonvulsant effect of cysteamine. The number of rats/group was 5 and is shown inside the circles. The arrow indicates the time of the injections. myoctonus in all rats (Fig. 1, upper left) but has no effect on that kindling session (a stage 5 seizure occurs) (Fig. 1, lower left). However. it suppresses the kindled seizure one day later in 5/5 rats, as also shown previously 1,4 (Fig. 1, lower left). When midazolam is injected 10 min before the CSH, the myoclonic seizure was suppressed in 5/5 rats (Fig. 1, upper fight). A kindling stimulus4 h later produced, as expected, a stage 5 seizure in all animals (Fig. 1, lower right). However, one day later when the animals were tested with a kindling stimulus, 5/5 animals had stage 5 seizures (Fig. 1, lower fight). Eliminating the myoclonic seizure prevented the long-term inhibition of kindled seizures. From these results, it appears that the cysteamineinduced myoclonus is responsible for the anticonvulsant effect of cysteamine administration in kindled rats. However, we know from previous work z that the kindled seizure is also necessary and that the temporal relationship between the two events is important. The conditions necessary to produce long-term
163 inhibition of kindled seizures seem to be a myoclonic seizure followed by a kindled seizure. The long-term inhibition of kindled seizures which is produced by cysteamine followed by a kindled seizure can be viewed as similar in some ways to the long-term inhibition of kindled seizures demonstrated by Mucha and Pinel 6. In their study, rats were given 19 kindled motor seizures at 90-min intervals via electrodes implanted in the amygdala. There was no obvious decrement in the motor seizures over the 19 trials. Kindling stimuli administered 24 h after the last of the 19 repetitive stimulations, however, would not elicit a seizure and the kindling response recovered only slowly over the course of about 3 days 6. Furthermore, the degree of long-term inhibition appears to be related to the number of prior kindled seizures. Sainsbury et a1.1° observed less suppression following 5 kindled motor seizures at 70-min intervals than Mucha and Pinel 6 reported following 19 kindled seizures. Thus, it would appear that the combination of CSH-induced myoclonus plus a kindled seizure is a very potent inducer of long-term inhibition, as it induces suppression of longer duration than either of the repetitive (kindled) seizure paradigms 6,1°. It was originally proposed 4 that the suppression of kindled seizures, or what we have called long-term inhibition, was due to the depletion of somatostatin by CSH. Although the effects of CSH on somatostatin levels in kindled rat brain have not yet been reported, the time course of the somatostatin-depleting action of CSH in naive rats 11 does not coincide with the time course for suppression of kindled seizures (refs. 1, 2, 4 and the present study). The most striking inconsistency is 4 h after CSH administration when CSH has no effect on kindled seizures but when somatostatin levels in brain are maximally depleted 11. In fact, depletion of somatostatin begins within 5 min
of CSH injection 11. Another inconsistency is that 24 h after CSH, cortical somatostatin levels have returned to normal 11 while the inhibition of kindled seizures is greatest at 24-48 h TM. Thus decreased somatostatin levels would not seem to be responsible for the suppression of kindled seizures. In previous experiments 2 we showed that the kindled seizure elicited 4 h after CSH is important for the suppression effect, while in the present experiment we have shown that the CSH-induced myoclonus is important for the suppression effect. Thus we propose that the suppression of kindled seizures is not an anticonvulsant effect due to CSH-induced somatostatin depletion but is long-term inhibition due to the seizure history. On a neurochemical level, the exact mechanism by which CSH produces its effect remains unknown. Our experiments do not rule out the possibility that somatostatin is involved in some way in this effect, as we did not measure somatostatin. However, CSH has effects on a wide variety of neurotransmitter mechanisms and other endocrine systems. For example, CSH has marked effects on glutamate receptors 8. Whatever the mechanism of action of CSH at the molecular level, it is clear that in kindled animals CSH induces severe myoclonic seizures. The interaction between this myoclonic seizure and a kindled seizure then leads to a long-term inhibition of kindled seizures. The mechanism by which multiple kindled seizures 6'1° or cysteamine-induced myoclonus coupled with a kindled seizure produce long-term inhibition of kindled seizures may offer an insight into the kindling process itself.
1 Cottrell, G.A. and Robertson, H.A., Induction and suppression of seizures by cysteamine in hippocampal kindled rats, Brain Research, 365 (1986) 393-396. 2 Cottrell, G.A. and Robertson, H.A., Suppression of kindled seizures by cysteamine: Dependence on injectionto-kindled seizure interval, Eur. J. Pharmacol., 134 (1987) 225-228. 3 Havlicek,V. and Friesen, H.G., Comparisonof behavioural effects of somatostatin and fl-endorphin in animals. In E. Collu, J.R. Ducharme, A. Barbeau and J.G. Rochefort (Eds.), Central Nervous System Effects of Hypothalamic Hormones and Other Peptides, Raven, New York, 1979, pp. 381-402.
4 Higuchi, T., Sikand, G.S., Kato, N., Wada, J.A. and Friesen, H.G., Profound suppression of kindled seizures by cysteamine: possible role of somatostatin in kindled seizures, Brain Research, 288 (1983) 359-362. 5 Kato, N., Higuchi, T., Friesen, H.G. and Wada, J.A., Changes in immunoreactive somatostatin and/3-endorphin content in rat brain after amygdaloidkindling, Life Sci., 32 (1983) 2415-2422. 6 Mucha, R.F. and Pinel, J.P.J., Postseizure inhibition of kindled seizures, Exp. Neurol., 54 (1977) 266-282. 7 Racine, R.J., Modification of seizure activity by electrical stimulation. II. Motor seizures, Electroencephalogr. Clin. Neurophysiol., 32 (1972) 281-294.
This study was supported by the Medical Research Council of Canada (MA9157). G.A.C. is a fellow of the Dalhousie Medical Research Foundation.
164 8 Robertson, H,A., Peterson, M.R. and Cottrell, G.A,, Inhibition of Ca++-dependent 3H-glutamate binding in vivo and in vitro: a possible mechanism for the cysteamine-induced suppression of kindling, Soc. Neurosci. Abstr., 11 (1985) 823. 9 Sagar, S.M., Landry, D., MiUard, W.J., Badget, T.M., Arnold, M.A. and Martin, J.B., Depletion of somatostatinlike immunoreactivity in the rat central nervous system by cysteamine, J. Neurosci., 2 (1982) 225-231. 10 Sainsbury, R.S., Bland, B.H. and Buchan, D.H., Electri-
cally induced seizure activity in the hippocampus: time course for post-seizure inhibition of subsequent kindled seizures, Behav. Biol., 22 (1978) 479-488. 11 Srikant, C.B. and Patel, Y.C., Cysteamine-induced depletion of brain somatostatin is associated with up-regulation of cerebrocortical somatostatin receptors, Endocrinology, 115 (1984) 990-994. 12 Szabo, S. and Reichlin, S., Somatostatin in rat tissues is depleted by cysteamine administration; Endocrinology, 109 (1981) 2255-2257.
161
BRE 22278
Prevention of cysteamine-induced myoclonus blocks the long-term inhibition of kindled seizures G.A. Cottrell and H.A. Robertson Department of Pharmacology, Facultyof Medicine, Dalhousie University, Halifax, N.S. (Canada) (Accepted 17 February 1987)
Key words: Cysteamine; Kindling; Myoclonus; Midazolam; Seizure; Long-term inhibition
In kindled rats, the administration of cysteamine (CSH, 200 mg/kg, i.p.) 4 h prior to a kindled seizure leads to long-term (up to 10 days) inhibition of kindled seizures. CSH (200 mg/kg, i.p.) also induces myoclonic seizures in kindled rats. We suggest that the longterm inhibition of kindled seizures might be the result of the myoclonus, not the somatostatin depletion as previously suggested. Prior administration of the short-acting benzodiazepine midazolam (5 mg/kg, i.p.) eliminated the CSH-induced myoclonus and prevented the long-term inhibition of kindled seizures. These results suggest that the CSH-induced long-term inhibition of kindled seizures is the result of an interaction between the myoclonic seizure and a subsequent kindled seizure. In kindled rats, a single injection (200 mg/kg, i.p,) of cysteamine (CSH), followed 4 h later by a kindled seizure results in long-term suppression of kindled seizures n4. Four h after CSH administration, electrical stimulation induces a generalized, tonic-clonic convulsion in all kindled rats. However, at 24 and 48 h, no seizures could be elicited in either amygdaloidkindled rats 4 or hippocampal-kindled rats I. This suppression of kindled seizures lasts, in individual rats, from 4 to 10 days ha. It has been reported that CSH depletes brain and gastrointestinal immunoreactive somatostatin content 9'~2 while somatostatin injections into the cerebral ventricles precipitate generalized seizures with E E G spiking 3. Immunoreactive somatostatin content is increased in the brains of amygdaloid-kindled rats 5. Higuchi et al. 4 assumed that if increasing somatostatin levels is convulsant, decreasing somatostatin levels should be anti-convulsant. They therefore suggested that CSH produced prolonged suppression of amygdaloid-kindled seizures by reducing the kindling-induced increase in somatostatin in the brains of kindled animals 4. However, the time course of the somatostatin-depleting action of CSH 11 does not coincide with the time course for sup-
pression of kindled seizures. We recently demonstrated that CSH (200 mg/kg, i.p.) induces myoclonic seizures in all kindled rats studied but not in naive rats 1. Myoclonic seizures have now been observed in over 100 hippocampaland amygdala-kindled rats following i.p. CSH injection. None of the naive rats, tested with 200 mg/kg i.p. in a quiet room, exhibited myoclonus, although some exhibited trembling (ref. 1 and on-going observations). The myoclonus that is seen in kindled animals is a severe myoclonus; it lasts for up to 90 rain, with 10-20 jerks/min. The animals often exhibit trembling for hours afterwards. Approximately 10% of the animals die from this insult 1. Mucha and Pinel 6 have shown that a series of kindled seizures will result in long-term inhibition of kindled seizures 24-72 h later. In fact, the time course of the inhibition of kindled seizures is similar whether the long-term inhibition is produced by repetitive seizures or by CSH 1'2'4'6. We have shown elsewhere that the CSH must be given approximately 4 h prior to the kindled seizure; administration of CSH 24 h prior to or 6 h after the kindled seizure does not produce inhibition of kindled seizures 2. Since the injection-to-kindled-sei-
Correspondence: H.A. Robertson, Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, N.S., B3H 4H7 Canada. 0006-8993/87/$03.50 © 1987 Elsevier Science Publishers B.V. (Biomedical Division)
162 zure interval is critical for the anticonvulsant effect of CSH, we proposed that the CSH must interact in some manner with the kindled seizure to produce the anticonvulsant effect. We now propose that the longterm inhibition of seizures is caused by the effects of the interaction of the myoclonus with the kindled seizure. As repetitive seizures can produce long-term inhibition, it would not be unreasonable to suggest that if the myoclonus associated with the administration of CSH is prevented, the long-term inhibition of kindled seizures may not be observed. To test this idea, we prevented the myoclonus by injection of midazolam, a benzodiazepine with a short (approx. 90 min) duration of action. Because of its short duration of action, midazolam would be expected to block the myoclonus following CSH injection but not interfere with the kindled seizure 4 h later. Ten male Sprague-Dawley rats (500-600 g at the time of the experiment) were stimulated through an electrode implanted in the dorsal hippocampus (incisor bar at 0, AP -2.4 ram, L +2.0 mm, V from dura -3.7 mm). The animals were housed under a 14:10 h light-dark cycle (lights on from 08.30-22.30 h) and were fed and watered ad libitum. The rats were stimulated daily, at about the same time each afternoon, with 2 s of bipolar square-wave current (60 Hz, 160 or 240/~A peak-to-peak current). A rating scale, modified after Racine 7, was used to score seizure severity (stage 1 - - immobility, stage 2 - - head nodding, stage 3 - - front paw clonus, stage 4 - - rearing and front paw clonus, stage 5 - - falling and/or hind paw clonus). All rats were well-kindled and exhibited at least 3 stage 5 seizures on consecutive days before the day of drug administration. Thus, each rat could be used as its own control in determining the effects of drug treatment on the kindled seizure. Midazolam (a gift from Dr. W. Haefely, Hoffmann-La Roche, Basle) and CSH (Sigma) were dissolved in saline and were given intraperitoneally. Midazolam was injected 10 min before the CSH. Pilot studies had demonstrated that 5 mg/kg i.p. was effective in preventing CSH-induced myoclonus without interferring with a hippocampal kindled seizure 4 h later. The dose of CSH was 200 mg/kg as in previous studies TM. As shown previously in both hippocampal kindled rats 1 and amygdaloid kindled rats (unpublished observation), CSH injected 4 h prior to kindling induces
GO
CSH
~lOOr
MIDAZOLAM AND CSH
mm
.
4 3
U
2 1 --1
AO
1 TIME
--1
AO
1
( days )
Fig. 1. The upper left panel shows the percentage of rats exhibiting myoclonus after cysteamine injection. The upper right
panel shows the percentage of rats exhibiting myodonus after the midazolam-cysteamine injections. The lower left panel shows the effect of cysteamine, injected 4 h before a kindling session, on kindled seizure stage. The lower right panel shows the effect of midazolam, injected 10 min before the cysteamine, on the anticonvulsant effect of cysteamine. The number of rats/group was 5 and is shown inside the circles. The arrow indicates the time of the injections. myoctonus in all rats (Fig. 1, upper left) but has no effect on that kindling session (a stage 5 seizure occurs) (Fig. 1, lower left). However. it suppresses the kindled seizure one day later in 5/5 rats, as also shown previously 1,4 (Fig. 1, lower left). When midazolam is injected 10 min before the CSH, the myoclonic seizure was suppressed in 5/5 rats (Fig. 1, upper fight). A kindling stimulus4 h later produced, as expected, a stage 5 seizure in all animals (Fig. 1, lower right). However, one day later when the animals were tested with a kindling stimulus, 5/5 animals had stage 5 seizures (Fig. 1, lower fight). Eliminating the myoclonic seizure prevented the long-term inhibition of kindled seizures. From these results, it appears that the cysteamineinduced myoclonus is responsible for the anticonvulsant effect of cysteamine administration in kindled rats. However, we know from previous work z that the kindled seizure is also necessary and that the temporal relationship between the two events is important. The conditions necessary to produce long-term
163 inhibition of kindled seizures seem to be a myoclonic seizure followed by a kindled seizure. The long-term inhibition of kindled seizures which is produced by cysteamine followed by a kindled seizure can be viewed as similar in some ways to the long-term inhibition of kindled seizures demonstrated by Mucha and Pinel 6. In their study, rats were given 19 kindled motor seizures at 90-min intervals via electrodes implanted in the amygdala. There was no obvious decrement in the motor seizures over the 19 trials. Kindling stimuli administered 24 h after the last of the 19 repetitive stimulations, however, would not elicit a seizure and the kindling response recovered only slowly over the course of about 3 days 6. Furthermore, the degree of long-term inhibition appears to be related to the number of prior kindled seizures. Sainsbury et a1.1° observed less suppression following 5 kindled motor seizures at 70-min intervals than Mucha and Pinel 6 reported following 19 kindled seizures. Thus, it would appear that the combination of CSH-induced myoclonus plus a kindled seizure is a very potent inducer of long-term inhibition, as it induces suppression of longer duration than either of the repetitive (kindled) seizure paradigms 6,1°. It was originally proposed 4 that the suppression of kindled seizures, or what we have called long-term inhibition, was due to the depletion of somatostatin by CSH. Although the effects of CSH on somatostatin levels in kindled rat brain have not yet been reported, the time course of the somatostatin-depleting action of CSH in naive rats 11 does not coincide with the time course for suppression of kindled seizures (refs. 1, 2, 4 and the present study). The most striking inconsistency is 4 h after CSH administration when CSH has no effect on kindled seizures but when somatostatin levels in brain are maximally depleted 11. In fact, depletion of somatostatin begins within 5 min
of CSH injection 11. Another inconsistency is that 24 h after CSH, cortical somatostatin levels have returned to normal 11 while the inhibition of kindled seizures is greatest at 24-48 h TM. Thus decreased somatostatin levels would not seem to be responsible for the suppression of kindled seizures. In previous experiments 2 we showed that the kindled seizure elicited 4 h after CSH is important for the suppression effect, while in the present experiment we have shown that the CSH-induced myoclonus is important for the suppression effect. Thus we propose that the suppression of kindled seizures is not an anticonvulsant effect due to CSH-induced somatostatin depletion but is long-term inhibition due to the seizure history. On a neurochemical level, the exact mechanism by which CSH produces its effect remains unknown. Our experiments do not rule out the possibility that somatostatin is involved in some way in this effect, as we did not measure somatostatin. However, CSH has effects on a wide variety of neurotransmitter mechanisms and other endocrine systems. For example, CSH has marked effects on glutamate receptors 8. Whatever the mechanism of action of CSH at the molecular level, it is clear that in kindled animals CSH induces severe myoclonic seizures. The interaction between this myoclonic seizure and a kindled seizure then leads to a long-term inhibition of kindled seizures. The mechanism by which multiple kindled seizures 6'1° or cysteamine-induced myoclonus coupled with a kindled seizure produce long-term inhibition of kindled seizures may offer an insight into the kindling process itself.
1 Cottrell, G.A. and Robertson, H.A., Induction and suppression of seizures by cysteamine in hippocampal kindled rats, Brain Research, 365 (1986) 393-396. 2 Cottrell, G.A. and Robertson, H.A., Suppression of kindled seizures by cysteamine: Dependence on injectionto-kindled seizure interval, Eur. J. Pharmacol., 134 (1987) 225-228. 3 Havlicek,V. and Friesen, H.G., Comparisonof behavioural effects of somatostatin and fl-endorphin in animals. In E. Collu, J.R. Ducharme, A. Barbeau and J.G. Rochefort (Eds.), Central Nervous System Effects of Hypothalamic Hormones and Other Peptides, Raven, New York, 1979, pp. 381-402.
4 Higuchi, T., Sikand, G.S., Kato, N., Wada, J.A. and Friesen, H.G., Profound suppression of kindled seizures by cysteamine: possible role of somatostatin in kindled seizures, Brain Research, 288 (1983) 359-362. 5 Kato, N., Higuchi, T., Friesen, H.G. and Wada, J.A., Changes in immunoreactive somatostatin and/3-endorphin content in rat brain after amygdaloidkindling, Life Sci., 32 (1983) 2415-2422. 6 Mucha, R.F. and Pinel, J.P.J., Postseizure inhibition of kindled seizures, Exp. Neurol., 54 (1977) 266-282. 7 Racine, R.J., Modification of seizure activity by electrical stimulation. II. Motor seizures, Electroencephalogr. Clin. Neurophysiol., 32 (1972) 281-294.
This study was supported by the Medical Research Council of Canada (MA9157). G.A.C. is a fellow of the Dalhousie Medical Research Foundation.
164 8 Robertson, H,A., Peterson, M.R. and Cottrell, G.A,, Inhibition of Ca++-dependent 3H-glutamate binding in vivo and in vitro: a possible mechanism for the cysteamine-induced suppression of kindling, Soc. Neurosci. Abstr., 11 (1985) 823. 9 Sagar, S.M., Landry, D., MiUard, W.J., Badget, T.M., Arnold, M.A. and Martin, J.B., Depletion of somatostatinlike immunoreactivity in the rat central nervous system by cysteamine, J. Neurosci., 2 (1982) 225-231. 10 Sainsbury, R.S., Bland, B.H. and Buchan, D.H., Electri-
cally induced seizure activity in the hippocampus: time course for post-seizure inhibition of subsequent kindled seizures, Behav. Biol., 22 (1978) 479-488. 11 Srikant, C.B. and Patel, Y.C., Cysteamine-induced depletion of brain somatostatin is associated with up-regulation of cerebrocortical somatostatin receptors, Endocrinology, 115 (1984) 990-994. 12 Szabo, S. and Reichlin, S., Somatostatin in rat tissues is depleted by cysteamine administration; Endocrinology, 109 (1981) 2255-2257.