The effects of inferior olive lesion on strychnine seizure.

Bilateral inferior olive lesions, produced by systemic administration of the neurotoxin 3-acetylpyridine (3AP) produce a proconvulsant state specific for strychnine-induced seizures and myoclonus. We have proposed that these phenomena are mediated through increased excitation of cerebellar Purkinje cells, through activation of glutamate receptors, in response to climbing fiber deafferentation. An increase in quisqualic acid (QA)-displaceable [3H]AMPA [(RS)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid] binding in cerebella from inferior olive-lesioned rats was observed, but no difference in [3H]AMPA binding displaced by glutamate, kainic acid (KA) or glutamate diethylester (GDEE) was seen. The excitatory amino acid antagonists GDEE and MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10 imine] were tested as anticonvulsants for strychnine-induced seizures in 3AP inferior olive-lesioned and control rats. Neither drug effected seizures in control rats, however, both GDEE and MK-801 produced a leftward shift in the strychnine-seizure dose-response curve in 3AP inferior olive-lesioned rats. GDEE also inhibited strychnine-induced myoclonus in the lesioned group, while MK-801 had no effect on myoclonus. The decreased threshold for strychnine-induced seizures and myoclonus in the 3AP-inferior olive-lesioned rats may be due to an increase in glutamate receptors as suggested by the [3H]AMPA binding data.

Regional distribution of calcium/calmodulin-dependent phosphatase activity of calcineurin in rat brain.

The regional distribution of calcineurin activity (measured using p-nitrophenyl-phosphate which detects the phospho-tyrosylphosphatase activity of calcineurin) shows that the striatum, hippocampus and cerebral cortex contains high calcineurin activity. Within the striatum, calcineurin activity does not appear to be present in dopaminergic terminals, since lesions of the nigro-striatal dopaminergic pathway (which reduce striatal dopamine levels by 97%) had no effect on calcineurin activity. On the other hand, kainic acid, which destroys neurons whose perikarya are in the striatum, reduced calcineurin activity by 86% indicating that calcineurin activity is localized in striatal intrinsic neurons. Calcineurin apparently does not exist in glia, since glial cells actually proliferate in kainic acid lesioned striatal tissues.

Age-dependent changes in brain glycine concentration and strychnine-induced seizures in the rat.

Glycine levels and receptor binding were measured in the medulla and spinal cord of 2-month, 10-month, and 24-month-old Fischer 344 rats. The behavioral response to the administration of the glycine antagonist, strychnine, was also evaluated in 2- and 24-month-old animals to investigate the relevance of these parameters to the susceptibility to seizures. Significant reductions in glycine in both the spinal cord and medulla occurred from 2 to 24 months of age. The glycine precursors, serine and threonine, were decreased only in the spinal cord. [3H]Strychnine binding was also decreased by 38% and 34% in the medulla and spinal cord, respectively, of 24-month-old rats compared to 2-month-olds. [3H]GABA binding was similarly reduced while no age-related changes in [3H]diazepam binding in the spinal cord were detected. Comparison of 2- and 24-month-old animals after systemic injection of 1.75 mg/kg strychnine showed that senescent animals have a higher incidence of seizures and mortality compared to young animals. Decreases in glycinergic neurotransmission may lower strychnine seizure threshold in the aged animal.

Platelet monoamine oxidase in Parkinson patients: effect of L-deprenyl therapy.

Platelet MAO activity was measured in 79 Parkinson patients (56 males and 23 females) before and during L-deprenyl therapy. Baseline platelet MAO activity was higher in females than in males with no age dependent differences. During chronic L-deprenyl therapy, MAO activity was inhibited greater than 98%. Four hours after the oral administration of the first 5 mg dose of L-deprenyl, platelet MAO activity was inhibited by 86%. By 24 hours, greater than 98% inhibition was achieved and this degree of inhibition was maintained during continuous L-deprenyl administration. Following oral administration of 10 mg L-deprenyl once a day versus 5 mg L-deprenyl twice a day, the time course of platelet MAO inhibition was similar. Five days after the termination of chronic L-deprenyl therapy, platelet MAO activity was still inhibited by 96%. MAO activity returned to normal by 2 weeks after stopping L-deprenyl. Platelet MAO activity is a useful method of monitoring bioavailability, compliance, dose-response relationship and optimal dosage schedules for L-deprenyl in Parkinson patients.

Strychnine seizure potentiation by azaspirodecanedione anxiolytics in rats.

Buspirone, gepirone and ipsaperone administered intraperitoneally (40 mg/kg) to naive rats were found to be proconvulsive for strychnine-induced seizures. The dose of strychnine required to induce seizures in 50% of test animals (CD50) was 2.18 mg/kg in naive rats, while CD50s for rats treated with the azaspirodecanediones ipsaperone, gepirone and buspirone were 1.65, 0.97 and 0.70 mg/kg respectively. Azaspirodecanediones have high affinity for the 5-HT1A serotonin receptor, however, the specific 5-HT1A agonist, 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT) had no effect on strychnine seizure in naive rats (CD50 = 2.0 mg/kg). The strychnine specific proconvulsive effects of inferior olive lesions and buspirone were additive, resulting in a CD50 of 0.1 mg/kg. This observation indicates that the buspirone-induced decrease in strychnine seizure threshold does not require intact inferior olive-climbing fiber pathways. Cerebellar sites for possible azaspirodecanedione action are discussed.

Effect of inferior olive lesion on seizure threshold in the rat.

Cerebellar stimulation has been associated with anticonvulsant activity in several experimental seizure models. We examined the effect of destruction of cerebellar climbing fibers, by systemic administration of 3-acetylpyridine (3AP) or electrothermic lesion of the inferior olive, on seizures produced by various chemical convulsants in rats. We found that inferior olive lesioned rats had lower threshold to seizures induced by strychnine and brucine, both glycine antagonists. The dose response curve for strychnine seizure was shifted 2.5 times to the left in 3AP lesioned rats. No difference in seizure threshold was seen when picrotoxin, bicuculline or pentylenetetrazole PTZ) were used to produce seizures. Abnormal motor behavior (AMB) including myoclonus, backward movement and hyperextension, produced by all of the convulsants tested, was significantly aggravated in 3AP pretreated rats. The inferior olive-climbing fiber projection to the cerebellum appears to modulate seizures induced by inhibition of glycinergic neurotransmission.

Ca2+/calmodulin-dependent phosphoprotein phosphatase activity of calcineurin in rat striatum: effect of kainic acid lesions.

Calcineurin, a Ca2+ and calmodulin (CM)-dependent phosphatase, has been shown to be present in high concentrations in the striatum. Using inhibitor-1(phosphorylated by cAMP-dependent protein kinase) as a substrate, we found Ca2+/CM-dependent phosphatase (calcineurin) to be more than 2-fold higher than non-Ca2+/CM-dependent phosphatase in the rat striatum. In order to determine the cellular localization of calcineurin, striatal kainic acid injections were used to destroy neurons whose cell bodies are present at the site of injection. Glutamic acid decarboxylase (GAD) activity was measured as an indicator of destruction of striatal GABA-ergic neurons. After intrastriatal injection of 1 and 2 ug of kainic acid, there was a significant decrease of both calcineurin and GAD. However, injection of 0.5 ug kainic acid into the striatum reduced GAD activity by 81%, but had no effect on calcineurin phosphatase activity. Thus calcineurin does not appear to be equally distributed among all types of striatal neurons, but rather may be concentrated in neurons that are less sensitive to kainic acid than the GABA-ergic neuron.

Urea-induced myoclonus: medullary glycine antagonism as mechanism of action.

Stimulus sensitive myoclonus is a prominent symptom of uremia in both man and animals. Intravenous injection of urea into cats had been previously reported to produce spike and sharp wave electrical discharges in the medullary reticular formation which correlated with the myoclonic movements. In the present investigations, intraperitoneal injections of 2 g/kg urea every 15 minutes for 4 injections produced myoclonus in rats accompanied by brain urea concentrations of 6.8 X 10(-2)M, which is sevenfold higher than normal. 10(-2) and 10(-1) M urea significantly reduced 3H-strychnine binding to rat medulla membranes by 30% and 43% respectively. Urea inhibition of 3H-strychnine binding was reversible and binding kinetics revealed that 10(-1)M urea decreased Bmax by 65% with no effect on the affinity. Brain glycine levels did not change after urea injections and urea had no effect on synaptosomal uptake of 3H-glycine. Urea did not alter 3H-GABA, 3H-glutamate and 3H-QNB receptor binding but decreased 3H-diazepam receptor binding in the medulla. Mannitol also reduced 3H-diazepam binding but had no effect on 3H-strychnine binding. Stereotaxic injection of the glycine receptor antagonist, strychnine, into the rat medullary reticular formation produced myoclonus, whereas Ro 15-1788, a benzodiazepine antagonist, had no effect. Urea may produce myoclonus by blockade of glycine receptors in the medullary reticular formation.

DDT myoclonus: sites and mechanism of action.

Intragastric injection of the insecticide DDT produces a stimulus-sensitive myoclonus in mice and rats. Unilateral stereotaxic infusions of DDT into rat medullary reticular formation also induced generalized myoclonus, identical to that produced by systemic administration. Similar myoclonus, but of lesser intensity, occurred when DDT was injected into cerebellar nuclei, red nucleus, and the inferior olive. Multiple other regions of the brain were resistant to the myoclonic action of locally infused DDT. Direct infusions into the medullary reticular formation of allethrin, which has a similar action on neuronal membranes as DDT, or the glycine receptor antagonist, strychnine, also elicited myoclonus.

Fluoxetine in the treatment of intention myoclonus.

Some types of intention myoclonus respond to serotonin precursor therapy (e.g., L-5-hydroxytryptophan, L-5HTP). Fluoxetine, a specific serotonin (5HT) uptake blocker, was found to have no antimyoclonic effect when administered by itself to four patients with intention myoclonus. However, in two patients with intention myoclonus responsive to L-5HTP and carbidopa, fluoxetine reduced the required dose of L-5HTP to approximately one-third, with greater antimyoclonic activity, decreased side effects, and reduction in platelet 5HT and plasma 5-hydroxyindoleacetic acid and L-5HTP concentrations. These findings further support the hypothesis that some forms of intention myoclonus are caused by a deficiency of brain 5HT, and suggest that the addition of fluoxetine to L-5HTP and carbidopa may improve antimyoclonic therapy.