strychnine and 3-acetylpyridine

The effects of iontophoretically applying the presumed Purkinje cell inhibitory neurotransmitters, GABA and taurine, were tested on neurons of the cerebellar nuclei in normal and in climbing-fiber-deafferented cerebella. Rats treated with 3-acetylpyridine to totally destroy the inferior olive were used for acute experiments 105-185 days after treatment. In controls, nearly all neuronal firing was dose-dependently depressed by both inhibitory amino acids. The depression in firing for both were antagonized by bicuculline and picrotoxin but not by strychnine while TAG specifically antagonized only responses to taurine. At sufficient doses, bicuculline and TAG induced disinhibitory responses (significant release of neuron discharge) in the absence of applied antagonist. In deafferented animals, the inhibitory efficacy of GABA and taurine were drastically reduced; most of the neurons failed to respond to these amino acids at the same iontophoretic parameters as for the control rats. Moreover, high doses of bicuculline and TAG did not induce any disinhibitory response (no significant increase in discharge rate) in most of the neurons tested. These results clearly demonstrate that climbing fiber deafferentation reduces postsynaptic sensitivity of the cerebellar nuclei neurons for the presumed Purkinje cell inhibitory neurotransmitters.

Topics: Action Potentials; Afferent Pathways; Animals; Bicuculline; Cerebellar Nuclei; gamma-Aminobutyric Acid; Iontophoresis; Male; Neurons; Olivary Nucleus; Picrotoxin; Pyridines; Rats; Rats, Inbred Strains; Reference Values; Strychnine; Taurine

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

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.

Topics: Animals; Anti-Anxiety Agents; Buspirone; Drug Synergism; Male; Olivary Nucleus; Pyridines; Pyrimidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Seizures; Strychnine; Syndrome

A series of psychopharmacological agents were administered to adult male Fischer-344 rats pretreated with a tremorigenic dose of chlordecone in an attempt to elucidate the involvement of spinal and supraspinal processes in the mediation and/or expression of chlordecone-induced tremor. Agents effective in attenuating the frequency of tremor were chlordiazepoxide, muscimol, and mecamylamine; quipazine exacerbated the tremor. Catecholaminergic agents including yohimbine, clonidine, propranolol, and haloperidol did not affect the frequency of chlordecone-induced tremor. Disinhibition of postsynaptic inhibitory sites in the spinal cord with strychnine and antagonism of spinal and supraspinal polysynaptic pathways with mephenesin exacerbated and attenuated the effects of chlordecone, respectively. Destruction of the climbing fibers with 3-acetylpyridine effectively blocked harmine, but not chlordecone-induced tremor, suggesting that chlordecone does not act through this pathway.

Topics: Animals; Chlordecone; Dimethyl Sulfoxide; Drug Interactions; Insecticides; Male; Psychotropic Drugs; Pyridines; Rats; Rats, Inbred F344; Strychnine; Tremor