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...
The y-aminobutyric acid antagonist, bicuculline methiodide (BMI), induces myoclonic seizures in rats when injected into the deep prepyriform cortex at concentrations lower than those that induce convulsions from the amygdala, hippocampus, or neocortex. This observation prompted the suggestion that the deep prepyriform cortex was responsible for seizure generation regardless of the neurotransmitter and neuronal circuits involved. Bilateral intrastriatal application of BMI protects rats against seizures induced by (i) local application of BMI into the deep prepyriform cortex and (ii) systemic application of bicuculline, pilocarpine (a cholinergic agonist), or kainic acid (a glutamate receptor agonist). The region of the striatum sensitive to the previously unknown anticonvulsant action of BMI is located in the immediate vicinity of the deep prepyriform cortex and is 100-150 times more sensitive to the anticonvulsant action relative to the sensitivity of the deep prepyriform cortex to the convulsant action of BMI. These data suggest a powerful y-aminobutyric acid-dependent gating role of the basal ganglia in determining the seizure threshold in the forebrain. This argues against the suggestion that the deep prepyriform cortex plays a crucial role in the generation of seizures following systemic administration of convulsants. The discovery of an anticonvulsant action of BMI in the rat striatum contradicts the r-aminobutyric acid theory of epilepsy, which implies that deficits in the yaminobutyric acid-mediated inhibition in the central nervous system lead to the emergence of seizures.The search for morphological substrates of seizures in the brain has been the major goal of epilepsy research over the last three decades. The function of the basal ganglia in the spread of seizures has received considerable attention since the discovery of anticonvulsant activity ofdrugs that enhance y-aminobutyric acid (GABA)-mediated inhibition in the substantia nigra (1). The entopeduncular nucleus has been subsequently identified as another site where GABA agonists act to block seizures (2). The anatomical background for these actions was the finding that pathways linking the striatum and either substantia nigra or entopeduncular nucleus regulate the seizure threshold in the forebrain (3).Clinical studies in humans and lesion studies in primates and rodents have described a role for the striatum in determining seizure threshold (3-5). However, the actions and interactions of different striatal transmitters possibly involved in modulating seizure spread have not been identified. We recently discovered that microinjections of nanomole amounts of the excitatory amino acid N-methyl-D-aspartate into the striatum of rats suppressed amygdala kindling (6) and pilocarpine-induced seizures (3). The anticonvulsant action of N-methyl-D-aspartate in the striatum was reversed by blocking GABA-mediated inhibition in the substantia nigra pars reticulata or in the entopeduncular nucleus (3). This finding suggested that activation of striata...
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