dizocilpine-maleate and 3-acetylpyridine

3-Acetylpyridine (3AP) is a potent neurotoxin when administered to laboratory animals. However, its neurotoxic effects have not been investigated extensively in vitro. Cultured cerebellar granule cells are killed by concentrations of 3AP of 0.1-1 mM (ED50 = 220 microM) but not by its 2-acetyl and 4-acetyl analogues. The toxicity of 3AP is enhanced by preexposure to subtoxic concentrations of N-methyl-D-aspartate (NMDA) and is unaffected by the NMDA receptor antagonists MK-801 or APV, as well as by deprenyl, mazindol, or tetrahydrofolic acid. However, 3AP toxicity is completely blocked by preincubating cerebellar granule cells with low concentrations of niacinamide. These data lead us to suggest that 3AP toxicity is due to the substitution of 3AP for niacinamide in the formation of niacinamide adenine dinucleotides (NAD(P)).

Topics: 2-Amino-5-phosphonovalerate; Animals; Cerebellum; Dizocilpine Maleate; Drug Synergism; Excitatory Amino Acid Antagonists; Glutamates; Glutamic Acid; Mazindol; N-Methylaspartate; Neurons; Niacinamide; Pyridines; Rats; Rats, Sprague-Dawley; Selegiline; Tetrahydrofolates

The effect of a single injection of 3-acetylpyridine (3-AP), which led to a degeneration of the excitatory cerebellar climbing fibers, was studied on the binding of [3H]MK-801, a non-competitive NMDA antagonist, in the rat cerebellar cortex. The same treatment increased also the binding of [3H]CGP 39653, a new NMDA competitive antagonist. Saturation isotherms showed a significant increase of the maximal number of binding sites (Bmax) for [3H]CGP 39653 and [3H]MK-801 (+48 and 36% respectively) with no change in the affinity 4-9 days after the administration of 3-AP. Our data demonstrate that in the cerebellar cortex both NMDA recognition site labelled by [3H]CGP 39653 and its modulatory site labelled by [3H]MK-801 may undergo plastic changes when the glutamatergic receptors and transmission are denervated.

Topics: 2-Amino-5-phosphonovalerate; Animals; Cerebellar Cortex; Dizocilpine Maleate; Kinetics; Male; Nerve Degeneration; Nerve Fibers; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission

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.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anticonvulsants; Dizocilpine Maleate; Epilepsies, Myoclonic; Glutamates; Ibotenic Acid; Male; Olivary Nucleus; Pyridines; Quisqualic Acid; Rats; Rats, Inbred Strains; Seizures; Strychnine; Tritium