- Email: [email protected]
Effects of GABA mimetics and other inhibitory amino acids on experimental models of epilepsy
ABSTRACTS
697
Al75
Al78
EFFECTS OF BACMFEN CR) ON STRIATAL DOPAMINE (ma, AND SEROTONIN (5-M) METABOLISM. P.C. Waldmeier, Research. Dept., Pharmaceuticals Division, CIBA-GEIGY Ltd., Basle, Switzerland. 8, by inhibiting DA neurons, increases intraneurona1 DA an.3 its
EFFECTS OF GAEA Ml,%TICS ANr) OTHER IIlHlBITORY AHIRO ACIUS ON EXPERIMENTAL MODELS OF EPILEPSY
deaminated tiusation
metabolites
in
the
striatun,.
due
to
decreased
DA
u-
fallowed only later by reduced syntbesie. B similarly affects striatal 5-HT. This is prevented by lesion of the nigrostriatal DR systeia, indicating that the latter mediates tile effects Of B on striata1 S-ST. After repeated administration of 30 mg/kg 1.p. B, its effects on DA and its metabolites as well as that on 5-W and 5-hydroxyindoleacetic acid (~-SD&, are reduced. The time-course of the development of this "tolerance” is similar for the DA (t of regr-essian or DA levels = 3.0 8&s, systenl. This supports the ~;B"~~f'.~~~,:;~~,'~~r~ = B effacts on 5-HT are mediated by the DA system and indicates that the "tolerance" developed by the latter has functional consequences. Incidentally, tolerance to 1 mq/kg p.0. haloperidol (acutely maximally increasing homcwanillic acid levels1 develops with e tbsa,;Lm,f.S days. This may indicate a consnon basic adaPtiona me So,"e 5-HT agonists and antagonists alter the effect of S on striatal 5-W metabolism. Metergoline f.125-lmg/kg i.p.1 increases the effect of B on S-HIAA and, less, on 5-W. Methysergide 12-20 mg/kg i.p.1. quipazine (.625-5 mg/kg i.e.1 and the 5-W uptake blocker CGP 6085 1.3-10 mg/kg p.o.1 decrease the effect of B on 5-"IA?+); only CGP 6085 reduces 5-HIAA levels on its own. Mianserin (S-20 mg/kg i.p.1 does not alter B effects. Differential actions of these drugs on pre- and postsynaptic 5%HT recqators could be responsible fox these results.
Al76
Ru;gero 6. Farlello Clinical Neurophysfology, university Of Wisconsin Aadiron, Wisconsfn 53792
Oepartment of Neurology
These studies investigate the actfon of 3 ami~pro~nesulfnnic acid (3APS) fn acute models of focal and seneraltred eptlepsy in tats. Acute foci were induced in neocortical and liabic stru&res by local injcctfon of various convulsant agents and epfleptfform activity waz monitored wfth EEG and extracellular unit recordings. Three APS. GABA. TAU, Balanine and glycfne were systemically injected and their effect on the epileptiform activity monitored. With the exception of glycine all other aminoacids tenrporarily blocked the spiking activity fraw epileptic nwrons. Potency of the inhibition was increasing from Sala to GABA, ThU and nsxfmal with 3 APS whose effective dose was l!l times lower than that of TAU (5 ing,Kg versus 50 ng/Kg). Epileptic neurons whose activity was blocked by 3 APS stf,, respended t., antfdtaofc and synaptic activation elicited by electrical stimulation. In other experiments generalized cortico-retfcular epflepsy ~8s induced fn cats by parenteral penicillin injection. The action of 3 APS and other arino acids was similarily tested. Three APS, GABA and TAU potentfated epileptiform discharges and again 3 APS showed the strongest action. Inhfbftory aminoacids are capable of blocking focal epileptiform discharges but seens to potentiate generalized epilepsy of "petit mal" type. The effects of systenically injected 3 APS is similar to GABA's and its own action when directly applied with the CW. suggesting that 3 APS might cross the Blood-Brain Rarrier. The wallability of a powerful GABA mimetfc agent exerttng central effects upon systenfc admfnistratton may have inpirtant therapeutic ~*p,~~~t~~"~.
Al79 TREATHENT OF TARDIVE DYGKINESIA WITH DIAZGPAH: INDIRECT EVIDENCE I?,R THE INVOLVEllENT OF LIMBIC. POG%BLY GABAKINERGIC MwtLwISKs. x. H. Singh, N. Nasxxllah, R. F&x, T. Kucbarski. R. Beck== and H. LarVA
Wedical Center and Uni" of Tennessee, t&q&is, m, VA IledicalCenter and i&i" of Iowa. Iowa City. IA. Rhode Island Inst of Mental Health, Cranston. RI and University of Rhode Island, Kingston. RI. The patbogeoesis of tardive dyskinesia (TD) is poorly understood. Much of the interest in recent yews has heen &cussed on the dopaminergic neurones in basal ganglia and the cholinergic neuwnea which act in ODDosition to them. We present evidence to suaast that limbic me'c'hanisms, perhaps invol&g MBAminergic ne&&s, need to be considered. The data are from a multicenter investigation and consist of earlier case histories of successful symptomatic treatment of TD with diazepam and aare recent blind studies involving ratings of video-recordings of TD patients while on and off diazepam. Our observations suggest rhaf diazepam inproves TD symptoms and that, contrary to connmn belief, this is not due nainly to the sedative hypnotic effect of these dngs. Considering (a) the worsening of TD by situational distress, (b) major actions of benzcdiazepines on the limbic structuree~, and (cl the anatomical a~?angement whereby the limbic system seenci to have a strong input into the basal ganglia through the limbic striatun, we propose that TD may involve defective limbic controls on the basal ganglia. Since OLBAminergic newones seem to be inwlved in the nade of action of benzadiamepines, we suspect that such nell~~neswithin the limbie-striopallidal organization ray be implicated in TD.
A180 Al77
Intrsperitaneal (i.p.1 administration of muscimol (3 mg/kg) resulted in the complete inhibition of the locomotor activity of male Swiss mice (Hilltop Labs, Scottdale, PA). However, these animals showed myoclonic jerks involving their hindquarters which occurred af a frwquency of 27-150 per minute during the initial 60 min. This response rapidly diminished after this period. The jerky movements were recorded using a Varimex Activity Meter and a printing co~llte~(both from Columbus Inst-ruments,OH). The influence of various prwtreatmnts (i.p.) on the frequency of these jerks was assessed. Drugs which caused significant blockade of this xwsponst!were (-f baclofer;(1 mg/kg, 10 min prior), diazepam (1 &kg, 10 min), HA-966 (5 mg/kg, 10 min), alpha methyl-p-qrosine (280 &kg, 3 hr), phenoxybenzamine (15 mg/kg, 2 hr), reserpine (5 mg/kg, II hr), chlorpromazine (5 mg/kg, (50 mglkg + 200 mg/kg, 10 min).
10 min) and Ro-Q-4602 + S-HTP bugs which failed to reduce
the myoclonic jerks were picrotoxin (3 mg/kg, 10 min), atropine (3 mg/kg, 10 nin). (t) baclofen (5 mg/hg, 10 min), d-amphetamine (3 m&kg, 10 min), apomorphine (10 mgikg, 10 min), propranolol (IO n&kg, 10 min), clonidine (0.3 n&kg, 10 min), quipazine (10 mg/kg, 10 n&n), inetbysergide(3 &kg. 10 min). LSD (1 mgikg, 5 nin), naloxone (lc m&kg. 10 min), So-ii-4602+ 1-dopa (50 mg/kg + 200 mS/kg, 10 min), and the anticonvulsants (50 mglkg, 10 minf dilantin sodium, trimethadione OP ethosuximide. Several neurotransmitters teem to be involved in this response of muscimol.
THE INFLUENCE OF A GABA AWNIST, DIAZEPAM, ON THE VESTIBLWOCULAR REFLEXES OP THE RABBIT. Neal H. BaFmack and Vito E. Pettorossi. Depalrment of OphthalnQopi. Ne-loaical Sciences Institute. Uxrd S&ritan Hospiial t l&d&l Center,~Pwtlend, OR 97209. The horizontal vestibulooctiar reflex (HVOR) helps to zaintain a relatively fixed spatial reference during horimntal head novement. Activity originating fmm the ampulla of a horizontal semicircular canal excites the ipsilateral medial vcstibtir nucleus (MM) via a direct projection and inhibits the activity of the con+zalateral HVN indirectly via B MBA-mediated cornd88wa1 patbvay which origirates from the ipsilateral MVN. We haYe studied the influence of intravenowly administered diazepam on the HVOR of rabbits. Tbc HVOR was ewked by sinusoidal oscillation of rabbits on a rate table (0.01~0.E Hz, *IO degf and eye m)wmeats were measured with an infrared light projection technique. The &of the WOR (e~ked eye velocity/head velocity) waa reduced by diazepam injections of 5 &kg. The dose required to Pmduce a 50 pexeot reduction in HVOR aain was 500 uz/kn. The time rrouired to reduce the HVOR gain to 30 percent of reduc&on at a dose of MO Irg/kg(0.4 Hz, fiO deg) was 60 sec. We haw also examined the effect of intravenous injection of diazepam on the activity of single secondary vestibular neurons stimulated by sinusoidal angular acceleration. Intravenous injections of diazepam (100 pg/kS) caused a decreased sensirivity of secondwy "estibtiar neurons to sinusoidal angular accelerations. This reduct%on in sensitivity was observed in secondary ne-ns which were excited by ipsilateral ~?f contralateral angular acceleration. Thus, diazepam in 1~ doses depresses the vestibtioacular reflex and this reflex depression can be observed at the level of the secondary wstibular neuron. These data suggest that diazepam might be effective as an acute antimotion sickness agent.
?'cs-neximl
697
Al75
Al78
EFFECTS OF BACMFEN CR) ON STRIATAL DOPAMINE (ma, AND SEROTONIN (5-M) METABOLISM. P.C. Waldmeier, Research. Dept., Pharmaceuticals Division, CIBA-GEIGY Ltd., Basle, Switzerland. 8, by inhibiting DA neurons, increases intraneurona1 DA an.3 its
EFFECTS OF GAEA Ml,%TICS ANr) OTHER IIlHlBITORY AHIRO ACIUS ON EXPERIMENTAL MODELS OF EPILEPSY
deaminated tiusation
metabolites
in
the
striatun,.
due
to
decreased
DA
u-
fallowed only later by reduced syntbesie. B similarly affects striatal 5-HT. This is prevented by lesion of the nigrostriatal DR systeia, indicating that the latter mediates tile effects Of B on striata1 S-ST. After repeated administration of 30 mg/kg 1.p. B, its effects on DA and its metabolites as well as that on 5-W and 5-hydroxyindoleacetic acid (~-SD&, are reduced. The time-course of the development of this "tolerance” is similar for the DA (t of regr-essian or DA levels = 3.0 8&s, systenl. This supports the ~;B"~~f'.~~~,:;~~,'~~r~ = B effacts on 5-HT are mediated by the DA system and indicates that the "tolerance" developed by the latter has functional consequences. Incidentally, tolerance to 1 mq/kg p.0. haloperidol (acutely maximally increasing homcwanillic acid levels1 develops with e tbsa,;Lm,f.S days. This may indicate a consnon basic adaPtiona me So,"e 5-HT agonists and antagonists alter the effect of S on striatal 5-W metabolism. Metergoline f.125-lmg/kg i.p.1 increases the effect of B on S-HIAA and, less, on 5-W. Methysergide 12-20 mg/kg i.p.1. quipazine (.625-5 mg/kg i.e.1 and the 5-W uptake blocker CGP 6085 1.3-10 mg/kg p.o.1 decrease the effect of B on 5-"IA?+); only CGP 6085 reduces 5-HIAA levels on its own. Mianserin (S-20 mg/kg i.p.1 does not alter B effects. Differential actions of these drugs on pre- and postsynaptic 5%HT recqators could be responsible fox these results.
Al76
Ru;gero 6. Farlello Clinical Neurophysfology, university Of Wisconsin Aadiron, Wisconsfn 53792
Oepartment of Neurology
These studies investigate the actfon of 3 ami~pro~nesulfnnic acid (3APS) fn acute models of focal and seneraltred eptlepsy in tats. Acute foci were induced in neocortical and liabic stru&res by local injcctfon of various convulsant agents and epfleptfform activity waz monitored wfth EEG and extracellular unit recordings. Three APS. GABA. TAU, Balanine and glycfne were systemically injected and their effect on the epileptiform activity monitored. With the exception of glycine all other aminoacids tenrporarily blocked the spiking activity fraw epileptic nwrons. Potency of the inhibition was increasing from Sala to GABA, ThU and nsxfmal with 3 APS whose effective dose was l!l times lower than that of TAU (5 ing,Kg versus 50 ng/Kg). Epileptic neurons whose activity was blocked by 3 APS stf,, respended t., antfdtaofc and synaptic activation elicited by electrical stimulation. In other experiments generalized cortico-retfcular epflepsy ~8s induced fn cats by parenteral penicillin injection. The action of 3 APS and other arino acids was similarily tested. Three APS, GABA and TAU potentfated epileptiform discharges and again 3 APS showed the strongest action. Inhfbftory aminoacids are capable of blocking focal epileptiform discharges but seens to potentiate generalized epilepsy of "petit mal" type. The effects of systenically injected 3 APS is similar to GABA's and its own action when directly applied with the CW. suggesting that 3 APS might cross the Blood-Brain Rarrier. The wallability of a powerful GABA mimetfc agent exerttng central effects upon systenfc admfnistratton may have inpirtant therapeutic ~*p,~~~t~~"~.
Al79 TREATHENT OF TARDIVE DYGKINESIA WITH DIAZGPAH: INDIRECT EVIDENCE I?,R THE INVOLVEllENT OF LIMBIC. POG%BLY GABAKINERGIC MwtLwISKs. x. H. Singh, N. Nasxxllah, R. F&x, T. Kucbarski. R. Beck== and H. LarVA
Wedical Center and Uni" of Tennessee, t&q&is, m, VA IledicalCenter and i&i" of Iowa. Iowa City. IA. Rhode Island Inst of Mental Health, Cranston. RI and University of Rhode Island, Kingston. RI. The patbogeoesis of tardive dyskinesia (TD) is poorly understood. Much of the interest in recent yews has heen &cussed on the dopaminergic neurones in basal ganglia and the cholinergic neuwnea which act in ODDosition to them. We present evidence to suaast that limbic me'c'hanisms, perhaps invol&g MBAminergic ne&&s, need to be considered. The data are from a multicenter investigation and consist of earlier case histories of successful symptomatic treatment of TD with diazepam and aare recent blind studies involving ratings of video-recordings of TD patients while on and off diazepam. Our observations suggest rhaf diazepam inproves TD symptoms and that, contrary to connmn belief, this is not due nainly to the sedative hypnotic effect of these dngs. Considering (a) the worsening of TD by situational distress, (b) major actions of benzcdiazepines on the limbic structuree~, and (cl the anatomical a~?angement whereby the limbic system seenci to have a strong input into the basal ganglia through the limbic striatun, we propose that TD may involve defective limbic controls on the basal ganglia. Since OLBAminergic newones seem to be inwlved in the nade of action of benzadiamepines, we suspect that such nell~~neswithin the limbie-striopallidal organization ray be implicated in TD.
A180 Al77
Intrsperitaneal (i.p.1 administration of muscimol (3 mg/kg) resulted in the complete inhibition of the locomotor activity of male Swiss mice (Hilltop Labs, Scottdale, PA). However, these animals showed myoclonic jerks involving their hindquarters which occurred af a frwquency of 27-150 per minute during the initial 60 min. This response rapidly diminished after this period. The jerky movements were recorded using a Varimex Activity Meter and a printing co~llte~(both from Columbus Inst-ruments,OH). The influence of various prwtreatmnts (i.p.) on the frequency of these jerks was assessed. Drugs which caused significant blockade of this xwsponst!were (-f baclofer;(1 mg/kg, 10 min prior), diazepam (1 &kg, 10 min), HA-966 (5 mg/kg, 10 min), alpha methyl-p-qrosine (280 &kg, 3 hr), phenoxybenzamine (15 mg/kg, 2 hr), reserpine (5 mg/kg, II hr), chlorpromazine (5 mg/kg, (50 mglkg + 200 mg/kg, 10 min).
10 min) and Ro-Q-4602 + S-HTP bugs which failed to reduce
the myoclonic jerks were picrotoxin (3 mg/kg, 10 min), atropine (3 mg/kg, 10 nin). (t) baclofen (5 mg/hg, 10 min), d-amphetamine (3 m&kg, 10 min), apomorphine (10 mgikg, 10 min), propranolol (IO n&kg, 10 min), clonidine (0.3 n&kg, 10 min), quipazine (10 mg/kg, 10 n&n), inetbysergide(3 &kg. 10 min). LSD (1 mgikg, 5 nin), naloxone (lc m&kg. 10 min), So-ii-4602+ 1-dopa (50 mg/kg + 200 mS/kg, 10 min), and the anticonvulsants (50 mglkg, 10 minf dilantin sodium, trimethadione OP ethosuximide. Several neurotransmitters teem to be involved in this response of muscimol.
THE INFLUENCE OF A GABA AWNIST, DIAZEPAM, ON THE VESTIBLWOCULAR REFLEXES OP THE RABBIT. Neal H. BaFmack and Vito E. Pettorossi. Depalrment of OphthalnQopi. Ne-loaical Sciences Institute. Uxrd S&ritan Hospiial t l&d&l Center,~Pwtlend, OR 97209. The horizontal vestibulooctiar reflex (HVOR) helps to zaintain a relatively fixed spatial reference during horimntal head novement. Activity originating fmm the ampulla of a horizontal semicircular canal excites the ipsilateral medial vcstibtir nucleus (MM) via a direct projection and inhibits the activity of the con+zalateral HVN indirectly via B MBA-mediated cornd88wa1 patbvay which origirates from the ipsilateral MVN. We haYe studied the influence of intravenowly administered diazepam on the HVOR of rabbits. Tbc HVOR was ewked by sinusoidal oscillation of rabbits on a rate table (0.01~0.E Hz, *IO degf and eye m)wmeats were measured with an infrared light projection technique. The &of the WOR (e~ked eye velocity/head velocity) waa reduced by diazepam injections of 5 &kg. The dose required to Pmduce a 50 pexeot reduction in HVOR aain was 500 uz/kn. The time rrouired to reduce the HVOR gain to 30 percent of reduc&on at a dose of MO Irg/kg(0.4 Hz, fiO deg) was 60 sec. We haw also examined the effect of intravenous injection of diazepam on the activity of single secondary vestibular neurons stimulated by sinusoidal angular acceleration. Intravenous injections of diazepam (100 pg/kS) caused a decreased sensirivity of secondwy "estibtiar neurons to sinusoidal angular accelerations. This reduct%on in sensitivity was observed in secondary ne-ns which were excited by ipsilateral ~?f contralateral angular acceleration. Thus, diazepam in 1~ doses depresses the vestibtioacular reflex and this reflex depression can be observed at the level of the secondary wstibular neuron. These data suggest that diazepam might be effective as an acute antimotion sickness agent.
?'cs-neximl