Excitatory neurotransmission within substantia nigra pars reticulata regulates threshold for seizures produced by pilocarpine in rats: Effects of intranigral 2-amino-7-phosphonoheptanoate and n-methyl- d-aspartate

Abstract

Seizures produced by pilocarpine given i.p. to rats provide an animal model lor studying the initiation, spread and generalisation of convulsive activity within the forebrain. Pilocarpine. 380 mg kg. produces a sequence of behavioural and electroencephalographic alterations indicative of motor limbic seizures and status epilepticus, which is followed by widespread damage to the limbic forebrain resembling that occurring subsequent to prolonged intractable seizures. Microinjections of a selective antagonist at the n-methyl- d-aspartate receptor, (±)-2-amino-7-phosphonoheptanoate, into the substantia nigra pars reticulata, bilaterally, protects against the behavioural, electrographic and morphological features of seizures produced by pilocarpine, 380 mg kg. with an ed 50 of 0.0007 μmol (0.0004–0.0011). Microinjections of (±)-2-amino-7-phosphonoheptanoate, 0.005 or 0.01 μmol, into the substantia nigra pars compacta or into the dorsal part of mid-anterior striatum do not modify the electrographic and morphological sequelae of pilocarpine, 380 mg kg. In rats pretreated with microinjections of, N-methyl- d-aspartate into the substantia nigra pars reticulata, a non-convulsive dose of pilocarpine, 100 mg/kg, results in recurrent motor limbic seizures and status epileptieus. The ed 50 of, N-methyl- d-aspartate for the generation of seizures alter pilocarpine. 100 mg kg. is 0.0014μmol (0.001–0.0019). Electrographic monitoring shows a pattern and sequence of evolution of convulsant activity within the hippocampus and cortex similar to that produced with pilocarpine, 380 mg kg, alone. Morphological examination of brains from rats treated with, N-methyl- d-aspartate in the substantia nigra pars reticulata and subsequently given pilocarpine. 100 mg kg. which underwent status epilepticus, reveals widespread damage to the amygdala, thalamus, olfactory cortex, substantia nigra. neocortex and hippocampus. Microinjections of, N-methyl- d-aspartate, 0.002 μmol, into either the substantia nigra pars compacta or dorsal striatum, bilaterally, do not augment seizures produced by pilocarpine, 100 mg kg. The results indicate that the threshold for pilocarpine-induced seizures in rats is modulated by excitatory amino acid neurotransmission within the substantia nigra pars reticulata.