The basal ganglia are involved in the organization of movement and function in the initiation and expression of generalized and limbic seizures. Dopamine is the principal neurotransmitter of the mesencephalic efferent pathways terminating in the mammalian striatum. No function has been ascribed to mesostriatal dopamine in the control of seizure spread in the brain. This work presents evidence that bilateral application of picomole amounts of apomorphine (a dopamine agonist) into the striatum confers protection against seizures produced by pilocarpine (a cholinergic agonist) in rats. The anticonvulsant effect of apomorphine is topographically confined to the caudate-putamen, nucleus accumbens, and olfactory tubercle. Bilateral application of nanomolar amounts of haloperidol (a dopamine antagonist) into the caudate-putamen or systemic application of haloperidol both lower the threshold for pilocarpine-induced seizures. Local application of an excitatory amino acid N-methyl-D-aspartate, into the substantia nigra pars compacta, ventral tegmental area, or retrorubral area, sites of origin of mesostriatal dopaminergic pathways, protects rats against seizures produced by pilocarpine. These results suggest that dopaminergic transmission in the striatum may be operative in complex neuronal networks modulating the seizure threshold.
We used limbic seizures induced in rats by systemic injection of the cholinergic agonist pilocarpine (380 mg/kg; i.p.) to study the neuronal pathways within the basal ganglia that modulate seizure threshold. N-Methyl-D-aspartate (N-Me-D-Asp) is an excitatory amino acid derivative that is a powerful convulsant agent when injected into the cerebral cortex, amygdala, or hippocampus in rats. Bilateral microinjections of N-Me-D-Asp into the caudate-putamen, however, protected against limbic seizures induced by pilocarpine (injected systemically), with an ED50 of 0.7 nmol (range 0.5-1.0 nmol). Lesioning the caudate-putamen (by bilateral microinjection of the excitotoxin ibotenate) converted subconvulsant doses of pilocarpine into convulsant ones. The anticonvulsant action of N-Me-D-Asp in the caudate-putamen was reversed by blocking y-aminobutyrate-mediated inhibition in the substantia nigra pars reticulata or in the entopeduncular nucleus. The results suggest that the caudate-putamen and its y-aminobutyrate-dependent efferent pathways modulate the threshold for seizures in the limbic forebrain.The function of the basal ganglia in the spread of seizures within the forebrain has interested neurologists, neurosurgeons, and neuropathologists since the 19th century (1). Clinical observations in humans and lesion studies in monkeys and dogs established that the globus pallidus (GP) and the substantia nigra (SN) serve as relay stations in the propagation of seizures elicited from the motor cortex or the limbic system (2, 3). However, the precise pathways in the basal ganglia that are involved in the spread of seizures and the specific neurotransmitters used in these pathways have not been identified.The SN has been proposed as a key site at which the anticonvulsant activity of drugs that enhance y-aminobutyric acid (GABA)-mediated inhibition is expressed (4, 5). Excitation within the SN is probably mediated by dicarboxylic amino acids (L-glutamate or L-aspartate). Blockade of excitatory neurotransmission in the SN by 2-amino-7-phosphonoheptanoate, an antagonist that acts selectively at the receptor site sensitive to N-methyl-D-aspartate (N-Me-D-Asp), raises the threshold for seizures and curtails their motor expression (6, 7).Temporal lobe, or "psychomotor," epilepsy is the most common form of epilepsy in humans (8). Prolonged limbic seizures in animals and humans result in selective damage to the forebrain, involving hippocampus, amygdala, and sometimes the thalamus (9). This form of epilepsy is particularly resistant to anticonvulsant medication and represents a major therapeutic problem (10).Seizures produced by pilocarpine in rats provide an animal model of temporal lobe epilepsy that permits the evaluation of behavioral, electroencephalographic, and morphological sequelae of intractable limbic convulsions (11-13). This experimental model of epilepsy serves to delineate the anatomical substrates essential for the motor expression of seizures (7,14).We recently observed that microinjections of the GABA agonist mu...
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