Substance P (SP), a member of the tachykinin family, is widely distributed in the central nervous system and is involved in a variety of physiological processes including cardiovascular function, inflammatory responses, and nociception. We show here that intrahippocampal administration of SP triggers self-sustaining status epilepticus (SSSE) in response to stimulation of the perforant path for periods too brief to have any effect in control rats, and this SSSE generates a pattern of acute hippocampal damage resembling that known to occur in human epilepsy. The SP receptor (SPR) antagonists, spantide II and RP-67,580, block both the initiation of SSSE and SSSE-induced hippocampal damage and terminate established anticonvulsantresistant SSSE. SSSE results in a rapid and dramatic increase in the expression of preprotachykinin A (a precursor of SP) mRNA and SP in principal neurons in CA3, CA1, and the dentate gyrus as well as in hippocampal mossy fibers. SP also increases glutamate release from hippocampal slices. Enhanced expression of SP during SSSE may modulate hippocampal excitability and contribute to the maintenance of SSSE. Thus, SPR antagonists may constitute a novel category of drugs in antiepileptic therapy.Feed-forward excitation travels along a hippocampal trisynaptic circuit, in which dentate gyrus (DG) granule cells make excitatory synaptic connections via mossy fibers onto CA3 pyramidal neurons that, in turn, form excitatory synaptic connections onto CA1 pyramidal neurons (1, 2). This hippocampal circuit displays considerable neurochemical plasticity in response to lesions and change in afferent activity (3-6). Substance P (SP), a member of peptides belonging to the tachykinin family, is present in low concentration in the rat hippocampus (7,8). However, its expression, like that of other neuropeptides, shows considerable plasticity and can be regulated by drugs (9-11), neuronal activity (12, 13), and convulsant kainic acid (14,15). SP is well established as a neurotransmitter͞neuromodulator (16) and is released by various stimuli (17, 18). There is evidence to suggest that SP modulates neuronal membrane excitability by virtue of slow synaptic currents (19), raises intracellular Ca 2ϩ concentrations (20), and enhances responses to excitatory amino acids (21). Using a new animal model (22), we now present evidence that SP plays an important role in the severe seizures seen in selfsustaining status epilepticus (SSSE) and in modulating hippocampal excitability.
MATERIALS AND METHODS
Induction and Analysis of Status Epilepticus (SE).Male Wistar rats (240-280 g) were implanted under anesthesia (ketamine 60 mg kg Ϫ1 ͞xylazine 15 mg kg
Ϫ1) with a bipolar stimulating electrode into the angular bundle of the perforant path and a bipolar recording electrode into the granule cell layer of the ipsilateral DG. To standardize the position of the electrode, only animals in which population spike amplitude was Ն2 mV were used. Seven days after surgery, animals were stimulated in the awake state for 30 min wit...